The DOI matches its Crossref record; 283 of the 283 references it cites were found in a registry or an index; 9 of the 323 sources its claims cite were checked for support.
Plasticity of synapses and reward circuit function in the genesis and treatment of depression
Open accessAbstract
What changes in brain function cause the debilitating symptoms of depression? Can we use the answers to this question to invent more effective, faster acting antidepressant drug therapies? This review provides an overview and update of the converging human and preclinical evidence supporting the hypothesis that changes in the function of excitatory synapses impair the function of the circuits they are embedded in to give rise to the pathological changes in mood, hedonic state, and thought processes that characterize depression. The review also highlights complementary human and preclinical findings that classical and novel antidepressant drugs relieve the symptoms of depression by restoring the functions of these same synapses and circuits. These findings offer a useful path forward for designing better antidepressant compounds.
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TL;DR
This review argues that chronic stress produces maladaptive weakening of excitatory synapses across reward and emotion circuits, contributing to depression symptoms. It further proposes that classical and rapid-acting antidepressants share a common action of restoring synaptic and circuit function, pointing toward synapse-targeted drug development.
Key findings
- Chronic stress and elevated glucocorticoids damage excitatory synapses in hippocampus, prefrontal cortex, nucleus accumbens, and lateral habenula, with circuit-specific effects: reward-promoting pathways weaken while negative-valence pathways strengthen. Reported examples include ~20% shorter PFC apical dendrites, ~30% lower axospinous synapse density, and ~50% reduced GluA1 expression in distal CA1 dendrites after chronic stress or corticosteroid exposure.
- Human and preclinical evidence converges on synaptic dysfunction in depression: hippocampal atrophy is a consistent imaging finding, and genetic studies implicate synaptic, axonal, and neurogenesis-related genes, though each gene contributes only a small amount of risk. Environmental factors are estimated to account for roughly 60% of depression risk, and depression affects about 5% of the US population.
- Classical antidepressants require chronic administration to restore stress-weakened synapses and behavior, paralleling the 3–8 week clinical delay and ineffectiveness in about one third of patients. Ketamine produces rapid antidepressant, antianhedonic, and antisuicidal effects within about two hours, sustained for at least seven days after a single dose, and preclinical work links this to rapid synapse restoration.
- Psilocybin shows rapid and persistent antidepressant effects in treatment-resistant patients; in mice, a single dose restored stress-impaired reward behavior by 24 hours and increased PFC dendritic spines for over one month, with preclinical evidence suggesting these effects may be independent of serotonin 2A receptor activation.
Methods
- Narrative review synthesizing human and preclinical literature; no primary experiments, systematic search strategy, or meta-analysis are described.
- Evidence includes rodent chronic stress models, electrophysiology, dendritic spine imaging, postmortem human tissue, functional imaging, and clinical trials of SSRIs, ketamine, and psilocybin.
- Main analysis is qualitative integration of findings across hippocampus, prefrontal cortex, nucleus accumbens, and lateral habenula to support an excitatory-synapse hypothesis of depression and antidepressant action.
Limitations
- Author-stated limitations include preclinical models using genetically homogeneous animals, which obscures genetic contributions to susceptibility and resilience; stress models also induce anxiety-related behaviors that may confound interpretation; some common tests such as the forced swim test are discouraged by NIMH and have unclear utility; human adult neurogenesis may be very limited or absent; and mechanisms of SSRI action in the nucleus accumbens remain largely unknown.
- The author notes that environmental factors explain only about 60% of depression risk, leaving genetic contributions underrepresented in animal work, and calls for more human before-and-after studies with fast-acting antidepressants.
- Evident from the text: as a narrative review, it does not systematically appraise study quality or quantify bias; causal claims rely heavily on animal models and correlational human imaging, and the highly interconnected reward circuits make it difficult to isolate a single synaptic cause of any symptom.
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187 Not checked yet · 40 Own interpretation · 14 No basis given · 4 Partly supported · 1 Supported · 1 Not supported · 1 Own result · accuracy not yet measured
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In the paper
“Activity in the human PFC is increased by 'happy' stimuli to a greater extent than it is for 'sad' stimuli and these responses are altered in depressed and anhedonic patients [180-182], consistent with alterations in PFC circuit function.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [180] Keedwell PA, Andrew C, Williams SC, Brammer MJ, Phillips ML. The neural correlates of anhedonia in major depressive disorder. Biol Psychiatry. 2005;58:843–53. source
- Partly supportedcites [181] Cheng W, Rolls ET, Qiu J, Liu W, Tang Y, Huang CC, et al. Medial reward and lateral non-reward orbitofrontal cortex circuits change in opposite directions in depression. Brain. 2016;139:3296–309. sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) relates depression and anhedonia to decreased effects of pleasant rewarding stimuli in the medial orbitofrontal cortex, and suggests altered processing of happy faces. But this resting-state study does not establish prefrontal responses to happy versus sad stimuli or study anhedonic patients as a separate group. (LLM, conf=0.85)
- Partly supportedcites [182] Green IW, Pizzagalli DA, Admon R, Kumar P. Anhedonia modulates the effects of positive mood induction on reward-related brain activation. Neuroimage. 2019;193:115–25. sourceExperimental — accuracy not yet measured
The Results (Imaging Results; page unavailable) report that anhedonia was associated with altered DLPFC–nucleus accumbens connectivity after positive mood induction. But the study compared responses to reward and neutral cues, not PFC responses to happy versus sad stimuli. Its Methods (Participants; page unavailable) describe groups defined by depressive symptoms and a dimensional analysis of anhedonia, rather than a finding specifically in depressed and anhedonic patients. (LLM, conf=0.87)
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In the paper
“Immunohistochemical analysis of interneurons and transcripts of interneuron-associated proteins are decreased within the PFC and anterior cingulate cortex in human MDD brain tissue and in chronically stressed rats, suggesting that deficits in GABA levels may contribute to the symptoms of depression [205][206][207][208].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Partly supportedcites [205] Rajkowska G, O’Dwyer G, Teleki Z, Stockmeier CA, Miguel-Hidalgo JJ. GABAergic neurons immunoreactive for calcium binding proteins are reduced in the prefrontal cortex in major depression. Neuropsychopharmacol. 2007;32:471–82. sourceExperimental — accuracy not yet measured
The Discussion reports reduced density and size of calbindin-immunoreactive interneurons in the dorsolateral prefrontal cortex of people with MDD. This paper did not measure interneuron-associated transcripts or study chronically stressed rats; its Discussion cites an earlier anterior cingulate study that found no change in the interneuron markers examined. (LLM, conf=0.91)
- Partly supportedcites [206] Sibille E, Morris H, Kota R, Lewis DA. GABA-related transcripts in the dorsolateral prefrontal cortex in mood disorders. J Neuropsychopharmacol. 2011;14:721–34. sourceExperimental — accuracy not yet measured
The Abstract (page unavailable) reports reduced somatostatin (SST) mRNA in the dorsolateral prefrontal cortex of human MDD subjects, but no change in the other transcripts measured. The Introduction (page unavailable) says calbindin-immunoreactive interneuron density was unchanged in cited cingulate-cortex studies. This paper does not establish the claimed decreases in chronically stressed rats. (LLM, conf=0.88)
- Partly supportedcites [207] Tripp A, Oh H, Guilloux J-P, Martinowich K, Lewis DA, Sibille E. Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder. Am J Psychiatry. 2012;169:1194–202. sourceExperimental — accuracy not yet measured
The Results report reduced transcripts for interneuron markers and GABA-related genes in postmortem human MDD tissue from the subgenual anterior cingulate cortex; the paper also mentions prior findings in the dorsolateral prefrontal cortex. The Methods describe PCR analysis and genetically modified mice, not immunohistochemical analysis or chronically stressed rats. Those parts of the attributed claim are not supported by this paper. (LLM, conf=0.88)
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In the paper
“Importantly, these effects persisted for up to a week after a single ketamine administration, strongly supporting an important role for plasticity in the cortico-mesolimbic circuitry in the genesis and treatment of depression.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Partly supportedcites [251] Sterpenich V, Vidal S, Hofmeister J, Michalopoulos G, Bancila V, Warrot D, et al. Increased reactivity of the mesolimbic reward system after ketamine injection in patients with treatment-resistant major depressive disorder. Anesthesiol. 2019;130:923–35. sourceExperimental — accuracy not yet measured
In “Ketamine and Depression” (page unavailable), the paper reports that ketamine-related changes in mesolimbic regions persisted for at least one week and suggests a lasting reorganization of neural networks. Its conclusion (under “Limitations,” page unavailable) says these findings point toward a role for ketamine in modulating neuronal plasticity. That supports a proposed role in treatment, but the paper does not establish that circuit plasticity has a role in the genesis of depression; it also cautions that the study cannot determine the molecular mechanisms. (LLM, conf=0.85)
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In the paper
“We observed that this restoration of synaptic strength and hedonic behavior was absent in mice with genetically modified GluA1 subunits that are incapable of being phosphorylated by calcium/calmodulin-dependent protein kinase (CaMK).”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
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“one of the most well-defined brain hallmarks of chronic hyperactivation of the HPA axis and chronic elevation of glucocorticoids is damage to excitatory synapses [16].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > STRESS, SYMPTOMS OF DEPRESSION, AND THE CIRCUITRY OF REWARD AND EMOTION
What the sources say
- Not checked yetcites [16] Sanacora G, Yan Z, Popoli M. The stressed synapse 2.0: pathophysiological mechanisms in stress-related neuropsychiatric disorders. Nat Rev Neurosci. 2022;23:86–103. source
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In the paper
“There is a great deal of evidence of dysfunction in both cortico-mesolimbic and habenular circuits in preclinical stress-based models of anhedonic states, as will be reviewed below”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > STRESS, SYMPTOMS OF DEPRESSION, AND THE CIRCUITRY OF REWARD AND EMOTION
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In the paper
“changes in the function of excitatory synapses impair the function of the circuits they are embedded in to give rise to the pathological changes in mood, hedonic state, and thought processes that characterize depression.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > Abstract
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In the paper
“chronic stress damages brain function, to a significant extent, through its deleterious effects on excitatory synapses, thereby impairing the circuits underlying the brain's responses to rewarding and aversive stimuli, cognitive demand, and mood.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > INTRODUCTION
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In the paper
“The nucleus accumbens (NAc) is a critical link in corticomesolimbic reward circuits, integrating information from the prefrontal cortices (PFC), amygdala, and hippocampus to control the release of dopamine from the ventral tegmental area (VTA) back to the telencephalon [19][20][21][22][23].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > STRESS, SYMPTOMS OF DEPRESSION, AND THE CIRCUITRY OF REWARD AND EMOTION
What the sources say
- Not checked yetcites [19] Nestler EJ, Carlezon WA. The mesolimbic dopamine reward circuit in depression. Biol Psychiatry. 2006;59:1151–9. source
- Not checked yetcites [20] Tye KM, Mirzabekov JJ, Warden MR, Ferenczi EA, Tsai HC, Finkelstein J, et al. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature. 2013;493:537–41. source
- Not checked yetcites [21] Burke CJ, Dreher J-C, Seymour B, Tobler PN. State-dependent value representation: evidence from the striatum. Front Neurosci. 2014;8:1481–9. source
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“Glucocorticoids normally regulate neuronal survival, excitability, proliferation, metabolism, and memory but persistently high glucocorticoid levels may promote depression by impairing these processes [17].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > STRESS, SYMPTOMS OF DEPRESSION, AND THE CIRCUITRY OF REWARD AND EMOTION
What the sources say
- Not checked yetcites [17] Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacol. 2000;23:477–501. source
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In the paper
“a critical mechanism underlying antidepressant efficacy is restoration of the function of stress-damaged synapses, particularly within these same reward circuits.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > INTRODUCTION
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In the paper
“classical and novel antidepressant drugs relieve the symptoms of depression by restoring the functions of these same synapses and circuits.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > Abstract
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In the paper
“Dysregulation of dopamine release in motivating responses to rewarding and aversive stimuli, as well as cognitive demand, is a plausible mechanistic cause that can explain a range of depression symptoms [24][25][26][27][28][29].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > STRESS, SYMPTOMS OF DEPRESSION, AND THE CIRCUITRY OF REWARD AND EMOTION
What the sources say
- Not checked yetcites [24] Floresco SB, Magyar O. Mesocortical dopamine modulation of executive functions: beyond working memory. Psychopharmacol. 2006;188:567–85. source
- Not checked yetcites [25] Treadway MT, Zald DH. Reconsidering anhedonia in depression: lessons from translational neuroscience. Neurosci Biobehav Rev. 2011;35:537–55. source
- Not checked yetcites [26] Schultz W. Neuronal reward and decision signals: from theories to data. Physiol Rev. 2015;95:853–951. source
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In the paper
“Importantly, these preclinical changes are reversed by chronic, but not acute, administration of classical monoaminergic antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) [36,[40][41][42][43][44]”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > STRESS, SYMPTOMS OF DEPRESSION, AND THE CIRCUITRY OF REWARD AND EMOTION
What the sources say
- Not checked yetcites [36] Kvarta MD, Bradbrook KE, Dantrassy HM, Bailey AM, Thompson SM. Corticosterone mediates the synaptic and behavioral effects of chronic stress at rat hippocampal temporoammonic synapses. J Neurophysiol. 2015;114:1713–24. source
- Not checked yetcites [40] Papp M, Moryl E, Willner P. Pharmacological validation of the chronic mild stress model of depression. Eur J Pharm. 1996;296:129–36. source
- Not checked yetcites [41] Grippo AJ, Beltz TG, Weiss RM, Johnson AK. The effects of chronic fluoxetine treatment on chronic mild stress-induced cardiovascular changes and anhedonia. Biol Psychiatry. 2006;59:309–16. source
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In the paper
“Chronic stress-based models in rodents come in several varieties, but the common factor is repeated (typically daily) exposure to psychological and physiological stress beyond a period lasting for several weeks [30][31][32].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > STRESS, SYMPTOMS OF DEPRESSION, AND THE CIRCUITRY OF REWARD AND EMOTION
What the sources say
- Not checked yetcites [30] Krishnan V, Nestler EJ. Animal models of depression: molecular perspectives. Curr Top Behav Neurosci. 2011;7:121–47. source
- Not checked yetcites [31] Willner P. The chronic mild stress (CMS) model of depression: history, evaluation and usage. Neurobiol Stress. 2017;6:78–93. source
- Not checked yetcites [32] Lopez J, Bagot RC. Defining valid chronic stress models for depression with female rodents. Biol Psychiatry. 2021;90:226–35. source
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In the paper
“They also respond quickly to acute administration of fast-acting antidepressant compounds like ketamine [45].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > STRESS, SYMPTOMS OF DEPRESSION, AND THE CIRCUITRY OF REWARD AND EMOTION
What the sources say
- Not checked yetcites [45] Zanos P, Thompson SM, Duman RS, Zarate CA, Gould TD. Convergent mechanisms underlying rapid antidepressant action. CNS Drugs. 2018;32:197–227. source
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In the paper
“These models thus demonstrate some degree of predictive validity.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > STRESS, SYMPTOMS OF DEPRESSION, AND THE CIRCUITRY OF REWARD AND EMOTION
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“Excessive rumination on memories of emotionally significant negative events from the past is positively correlated with incidence of depression and anxiety [66].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [66] McEvoy PM, Watson H, Watkins ER, Nathan P. The relationship between worry, rumination, and comorbidity: evidence for repetitive negative thinking as a transdiagnostic construct. J Affect Disord. 2013;151:313–20. source
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“This is thought to result because the learning of reward locations results in the reorganization of place fields so that areas near those locations become overrepresented [61].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [61] Dupret D, O’Neill J, Pleydell-Bouverie B, Csicsvari J. The reorganization and reactivation of hippocampal maps predict spatial memory performance. Nat Neurosci. 2010;13:995–1002. source
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In the paper
“Numerous changes in the electrophysiological responses of hippocampal neurons related to various aspects of reward have been described, including an increase in firing rates as animals approach a reward location [59,60].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [59] Eichenbaum H, Kuperstein M, Fagan A, Nagode J. Cue- sampling and goal- approach correlates of hippocampal unit- activity in rats performing an odor- discrimination task. J Neurosci. 1987;7:716–32. source
- Not checked yetcites [60] Nyberg N, Duvelle É, Barry C, Spiers HJ. Spatial goal coding in the hippocampal formation. Neuron. 2022;110:394–422. source
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In the paper
“Dysfunction of the hippocampal-prefrontal circuits that underlie extinction of emotional memories is postulated to contribute to excessive negative rumination [67].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [67] Anderson MC, Floresco SB. Prefrontal-hippocampal interactions supporting the extinction of emotional memories: the retrieval stopping model. Neuropsychopharmacology. 2022;47:180–95. source
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In the paper
“These data suggest that chronic stress, either from traumatic life events or psychosocial stressors, like excessive negative rumination, is the cause of the hippocampal atrophy in depression.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
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In the paper
“Hippocampal atrophy is also one of the most consistent anatomical findings in imaging studies of human depression [78][79][80].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [78] Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci. 1996;93:3908–13. source
- Not checked yetcites [79] Sheline YI, Sanghavi M, Mintun MA, Gado MH. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci. 1999;19:5034–43. source
- Not checked yetcites [80] Videbech P, Ravnkilde B. Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry. 2004;161:1957–66. source
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In the paper
“Hippocampal volume loss in depressed patients is correlated with memory dysfunction [81].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [81] Hickie I, Naismith S, Ward PB, Turner K, Scott E, Mitchell, et al. Reduced hippocampal volumes and memory loss in patients with early- and late-onset depression. Br J Psychiatry. 2005;186:197–202. source
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In the paper
“Proper ventral hippocampus-to-mPFC signaling is also necessary to recall social memories [68].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [68] Phillips ML, Robinson HA, Pozzo-Miller L. Ventral hippocampal projections to the medial prefrontal cortex regulate social memory. Elife. 2019;8:e44182. source
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“Furthermore, hippocampal and prefrontal cortical BDNF and trkB levels are decreased in postmortem tissue taken from suicide victims compared to tissue obtained from non-suicidal control brains [88].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [88] Dwivedi Y, Rizavi HS, Conley RR, Roberts RC, Tamminga CA, Pandey GN. Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. Arch Gen Psychiatry. 2003;60:804–15. source
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In the paper
“Preclinical studies have shown that chronic stress and exogenous corticosteroid administration decrease the expression of several neurotrophic factors and their receptors, notably brain derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B (trkB)(for review see: [87].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [87] Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59:1116–27. source
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In the paper
“Preclinical studies have shown that the genesis of new neurons in the dentate gyrus from stem cells is impaired after chronic stress and exogenous corticosteroid administration [90][91][92].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [90] Gould E, McEwen BS, Tanapat P, Galea LA, Fuchs E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci. 1997;17:2492–8. source
- Not checked yetcites [91] Tanapat P, Galea LA, Gould E. Stress inhibits the proliferation of granule cell precursors in the developing dentate gyrus. Int J Dev Neurosci. 1998;16:235–9. source
- Not checked yetcites [92] Joëls M, Karst H, Alfarez D, Heine VM, Qin Y, van Riel E, et al. Effects of chronic stress on structure and cell function in rat hippocampus and hypothalamus. Stress 2004;7:221–31. source
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In the paper
“Nevertheless, the evidence of stressinduced changes in excitatory synaptic transmission in hippocampal pyramidal cells is somewhat mixed.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
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“Nevertheless, it is particularly exciting that several slowly and rapidly acting antidepressant compounds, including fluoxetine and other classical antidepressants, and ketamine and its metabolites, have recently been shown to bind directly to the trkB receptor and thereby promote its activation by BDNF [103].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [103] Casarotto PC, Girych M, Fred SM, Kovaleva V, Moliner R, Enkavi G, et al. Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. Cell. 2021;184:1299–313. source
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In the paper
“Chronic social defeat stress also induces dendritic spine atrophy in CA1 pyramidal cells [111].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [111] Iñiguez SD, Aubry A, Riggs LM, Alipio JB, Zanca RM, Flores-Ramirez, et al. Social defeat stress induces depression-like behavior and alters spine morphology in the hippocampus of adolescent male C57BL/6 mice. Neurobiol Stress. 2016;5:54–64. source
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In the paper
“The authors further examined genetic polymorphisms in genes encoding GluA1 subunits and found a single nucleotide polymorphism that correlated with vulnerability to stress.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [114] Schmidt MV, Trümbach D, Weber P, Wagner K, Scharf SH, Liebl C, et al. Individual stress vulnerability is predicted by short-term memory and AMPA receptor subunit ratio in the hippocampus. J Neurosci. 2010;30:16949–58. source
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In the paper
“The functional consequence of stress-weakened TA-CA1 synaptic transmission is an impairment of spatial memory consolidation [36,110].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [36] Kvarta MD, Bradbrook KE, Dantrassy HM, Bailey AM, Thompson SM. Corticosterone mediates the synaptic and behavioral effects of chronic stress at rat hippocampal temporoammonic synapses. J Neurophysiol. 2015;114:1713–24. source
- Not checked yetcites [110] Kallarackal AJ, Kvarta MD, Cammarata E, Jaberi L, Cai X, Bailey AM, et al. Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses. J Neurosci. 2013;33:15669–74. source
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In the paper
“For example, GluA1 expression is decreased by 50% in the distal dendrites of area CA1 by chronic stress and glucocorticoid elevation [36,110].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [36] Kvarta MD, Bradbrook KE, Dantrassy HM, Bailey AM, Thompson SM. Corticosterone mediates the synaptic and behavioral effects of chronic stress at rat hippocampal temporoammonic synapses. J Neurophysiol. 2015;114:1713–24. source
- Not checked yetcites [110] Kallarackal AJ, Kvarta MD, Cammarata E, Jaberi L, Cai X, Bailey AM, et al. Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses. J Neurosci. 2013;33:15669–74. source
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In the paper
“Mice in which the GluA1 gene cannot be phosphorylated by calcium/ calmodulin-dependent kinase (CaMK), thereby impairing their insertion into synapses, display altered behavior in the sucrose preference and novelty suppressed feeding tests, identical to those produced by chronic stress [44].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [44] Cai X, Kallarackal AJ, Kvarta MD, Goluskin S, Gaylor K, Bailey AM, et al. Local potentiation of excitatory synapses by serotonin and its alteration in rodent models of depression. Nat Neurosci. 2013;16:464–72. source
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In the paper
“In the chronic social defeat model, for example, stress susceptible mice had larger decreases in GluA1 expression in area CA1, compared to resilient mice [114].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [114] Schmidt MV, Trümbach D, Weber P, Wagner K, Scharf SH, Liebl C, et al. Individual stress vulnerability is predicted by short-term memory and AMPA receptor subunit ratio in the hippocampus. J Neurosci. 2010;30:16949–58. source
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In the paper
“Global deletion of the gene for the GluA1 subunit of the AMPAR, for example, results in a depressionlike phenotype in the learned helplessness test [113].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [113] Chourbaji S, Vogt MA, Fumagalli F, Sohr R, Frasca A, Brandwein C, et al. AMPA receptor subunit 1 (GluR-A) knockout mice model the glutamate hypothesis of depression. FASEB J. 2008;22:3129–34. source
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In the paper
“Restoration of stress-impaired excitatory synaptic function also appears to be a fundamental mechanism underlying the actions of known fast acting antidepressant drugs and potential therapeutic compounds.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
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In the paper
“Similarly, fluoxetine normalizes stress-induced changes in dendritic spine and glutamate receptor expression in the amygdala [127].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [127] Yi ES, Oh S, Lee JK, Leem YH. Chronic stress-induced dendritic reorganization and abundance of synaptosomal PKA-dependent CP-AMPA receptor in the basolateral amygdala in a mouse model of depression. Biochem Biophys Res Commun. 2017;486:671–8. source
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In the paper
“A common feature of all known antidepressants and many antidepressant treatments under development is their ability to reverse the effects of stress on synaptic structure and function, although they may produce this effect through various mechanisms.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
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In the paper
“These results suggest that chronic stress-induced changes in synaptic function impair local network function and thereby impair the neural computations underlying cognitive processing.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
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In the paper
“Ketamine's antidepressant effects compared to placebo controls are further supported by several thorough meta-analyses [134-136].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [134] Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry. 2015;172:950–66. source
- Not checked yetcites [135] Wilkinson ST, Ballard ED, Bloch MH, Mathew SJ, Murrough JW, Feder A, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psychiatry. 2018;175:150–8. source
- Not checked yetcites [136] Conley AA, Norwood AEQ, Hatvany TC, Griffith JD, Barber KE. Efficacy of ketamine for major depressive episodes at 2, 4, and 6-weeks post-treatment: A meta-analysis. Psychopharmacol (Berl). 2021;238:1737–52. source
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In the paper
“it is now known that ketamine produces increased synchronous neuronal activity in the prefrontal cortex and hippocampus, particularly in the gamma frequency band”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
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In the paper
“Based on early microdialysis measurements of increased extracellular glutamate release after a single administration of a therapeutic dose of ketamine [137]”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [137] Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci. 1997;17:2921–7. source
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In the paper
“Three classes of mechanism have been proposed to account for these therapeutic actions on the basis of preclinical work, all of which involve plasticity of excitatory synapses.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
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In the paper
“There is excellent evidence that these positively and negatively valenced functions take place within the PFC [168][169][170].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [168] Wilson RC, Takahashi YK, Schoenbaum G, Niv Y. Orbitofrontal cortex as a cognitive map of task space. Neuron. 2014;81:267–79. source
- Not checked yetcites [169] Howard JD, Kahnt T. To be specific: The role of orbitofrontal cortex in signaling reward identity. Behav Neurosci. 2021;135:210–7. source
- Not checked yetcites [170] Klein-Flügge MC, Bongioanni A, Rushworth MFS. Medial and orbital frontal cortex in decision-making and flexible behavior, Neuron 2022; https://doi.org/10.1016/j.neuron.2022.05.022 source
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In the paper
“Acute application of HNKs to hippocampal brain slices also produces a direct potentiation of SC-CA1 synaptic transmission [153], mediated by an increase in the probability of presynaptic glutamate release [161].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [153] Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533:481–6. source
- Not checked yetcites [161] Riggs LM, Aracava Y, Zanos P, Fischell J, Albuquerque EX, Pereira EFR, et al. (2R,6R)-hydroxynorketamine rapidly potentiates hippocampal glutamatergic transmission through a synapse-specific presynaptic mechanism. Neuropsychopharmacol. 2020;45:426–36. source
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In the paper
“Prefrontal cortical regions act in concert with the hippocampus, to which they are coupled by direct synaptic projections.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
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In the paper
“Perhaps the most direct evidence of the critical role that plasticity of excitatory synaptic transmission plays in the treatment of depression comes from preclinical studies of positive allosteric AMPAR modulators (i.e., AMPAkines) [162].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [162] Kadriu B, Musazzi L, Johnston JN, Kalynchuk LE, Caruncho HJ, Popoli M, et al. Positive AMPA receptor modulation in the treatment of neuropsychiatric disorders: A long and winding road. Drug Disco Today. 2021;26:2816–38. source
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In the paper
“One AMPAkine failed to restore sucrose preference in chronically stressed mice, however [165].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [165] Farley S, Apazoglou K, Witkin JM, Giros B, Tzavara ET. Antidepressant-like effects of an AMPA receptor potentiator under a chronic mild stress paradigm. Int J Neuropsychopharmacol. 2010;13:1207–18. source
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In the paper
“Modeling studies suggest that these comparisons are performed by two competing populations of neurons, each representing one option, which compete in a winner-take-all manner for choice via mutual recurrent excitatory synapses and reward-dependent synaptic plasticity [174,175].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [174] Wang XJ. Decision making in recurrent. Neuronal Circuits Neuron. 2008;60:215–34.
- Not checked yetcites [175] Wong KF, Wang XJ. A recurrent network mechanism of time integration in perceptual decisions. J Neurosci 2006;26:1314–28. source
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In the paper
“Activity in the human PFC is increased by 'happy' stimuli to a greater extent than it is for 'sad' stimuli and these responses are altered in depressed and anhedonic patients [180-182], consistent with alterations in PFC circuit function.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [180] Keedwell PA, Andrew C, Williams SC, Brammer MJ, Phillips ML. The neural correlates of anhedonia in major depressive disorder. Biol Psychiatry. 2005;58:843–53. source
- Not checked yetcites [181] Cheng W, Rolls ET, Qiu J, Liu W, Tang Y, Huang CC, et al. Medial reward and lateral non-reward orbitofrontal cortex circuits change in opposite directions in depression. Brain. 2016;139:3296–309. source
- Not checked yetcites [182] Green IW, Pizzagalli DA, Admon R, Kumar P. Anhedonia modulates the effects of positive mood induction on reward-related brain activation. Neuroimage. 2019;193:115–25. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The PFC is also an important site at which cognitive evaluations, such as the controllability of a stressor [176] or the valence of sensory stimuli [177], can influence affect and reward directly.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [176] Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, Maier SF. Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nat Neurosci. 2005;8:365–71. source
- Not checked yetcites [177] Berridge KC, Kringelbach ML. Pleasure systems in the brain. Neuron. 2015;86:646–64. source
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In the paper
“It appears that the PFC acts as a choice option comparator during reward-guided decision making.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [170] Klein-Flügge MC, Bongioanni A, Rushworth MFS. Medial and orbital frontal cortex in decision-making and flexible behavior, Neuron 2022; https://doi.org/10.1016/j.neuron.2022.05.022 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“For example, cognitive control of responses to emotionally laden stimuli activates lateral regions of the PFC in human subjects [179].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [179] Ochsner K, Gross JJ. The cognitive control of emotion. Trends Cogn Sci. 2005;9:242–9. source
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In the paper
“Compared to a group of unstressed control subjects, stress selectively impaired subjects' attention and disrupted functional connectivity within a frontoparietal cortical network.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [184] Liston C, McEwen BS, Casey BJ. Psychosocial stress reversibly disrupts prefrontal processing and attentional control. Proc Natl Acad Sci. 2009;106:912–7. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In animal models, chronic stress impairs attentional set-shifting tasks that are mediated by the PFC and decision making in reward-based tasks [185], mimicking the human deficits seen in MDD patients [184].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [185] Dias-Ferreira E, Sousa JC, Melo I, Morgado P, Mesquita AR, Cerqueira JJ, et al. Chronic stress causes frontostriatal reorganization and affects decision-making. Science. 2009;325:621–5. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In animal models, chronic stress impairs attentional set-shifting tasks that are mediated by the PFC and decision making in reward-based tasks [185], mimicking the human deficits seen in MDD patients [184].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [185] Dias-Ferreira E, Sousa JC, Melo I, Morgado P, Mesquita AR, Cerqueira JJ, et al. Chronic stress causes frontostriatal reorganization and affects decision-making. Science. 2009;325:621–5. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Hypoactivation of these regions is observed in MDD patients when performing tasks that require ignoring negative valence distracters [183].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [183] Fales CL, Barch DM, Rundle MM, Mintun MA, Snyder AZ, Cohen JD, et al. Altered emotional interference processing in affective and cognitive-control brain circuitry in major depression. Biol Psychiatry. 2008;63:377–84. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Activity in the human PFC is increased by 'happy' stimuli to a greater extent than it is for 'sad' stimuli and these responses are altered in depressed and anhedonic patients [180-182], consistent with alterations in PFC circuit function.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [180] Keedwell PA, Andrew C, Williams SC, Brammer MJ, Phillips ML. The neural correlates of anhedonia in major depressive disorder. Biol Psychiatry. 2005;58:843–53. source
- Not checked yetcites [181] Cheng W, Rolls ET, Qiu J, Liu W, Tang Y, Huang CC, et al. Medial reward and lateral non-reward orbitofrontal cortex circuits change in opposite directions in depression. Brain. 2016;139:3296–309. source
- Not checked yetcites [182] Green IW, Pizzagalli DA, Admon R, Kumar P. Anhedonia modulates the effects of positive mood induction on reward-related brain activation. Neuroimage. 2019;193:115–25. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“In animal models, chronic stress impairs attentional set-shifting tasks that are mediated by the PFC and decision making in reward-based tasks [185], mimicking the human deficits seen in MDD patients [184].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [184] Liston C, McEwen BS, Casey BJ. Psychosocial stress reversibly disrupts prefrontal processing and attentional control. Proc Natl Acad Sci. 2009;106:912–7. source
- Not checked yetcites [185] Dias-Ferreira E, Sousa JC, Melo I, Morgado P, Mesquita AR, Cerqueira JJ, et al. Chronic stress causes frontostriatal reorganization and affects decision-making. Science. 2009;325:621–5. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Compared to a group of unstressed control subjects, stress selectively impaired subjects' attention and disrupted functional connectivity within a frontoparietal cortical network.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [184] Liston C, McEwen BS, Casey BJ. Psychosocial stress reversibly disrupts prefrontal processing and attentional control. Proc Natl Acad Sci. 2009;106:912–7. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Indeed, consistent with spine loss, chronic stress decreases the synaptic excitation of pyramidal cells in the PFC [191].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [191] Yuen EY, Wei J, Liu W, Zhong P, Li X, Yan Z. Repeated Stress Causes Cognitive Impairment by Suppressing Glutamate Receptor Expression and Function in Prefrontal Cortex. Neuron. 2012;73:962–77. source
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In the paper
“Chronic stress also results in a ca.20% reduction in the length of apical dendrites in pyramidal neurons in the PFC and a ca.30% decrease in the density of axospinous synapses on apical dendrites, along with corresponding decreases in the expression of synaptic genes [186-189].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [186] Radley JJ, Sisti HM, Hao J, Rocher AB, McCall T, Hof PR, et al. Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex. Neuroscience. 2004;125:1–6. source
- Not checked yetcites [187] Radley JJ, Rocher AB, Miller M, Janssen WG, Liston C, Hof PR, et al. Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cereb Cortex. 2006;16:313–20. source
- Not checked yetcites [188] Liston C, Miller MM, Goldwater DS, Radley JJ, Rocher AB, Hof PR, et al. Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J Neurosci. 2006;26:7870–4. source
- Not checked yetcites [189] Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry. 2011a;69:754–61. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Longitudinal twophoton microscopic imaging of fluorescently labeled dendritic spines in the PFC revealed that chronic elevation of CORT leads to an increase in dendritic spine turnover and an abnormal loss of stable spines that had been formed early in life [190].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [190] Liston C, Gan WB. Glucocorticoids are critical regulators of dendritic spine development and plasticity in vivo. Proc Natl Acad Sci. 2011;108:16074–9. source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Loss of dendritic spines suggests a loss or dysfunction of excitatory synapses.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Longitudinal twophoton microscopic imaging of fluorescently labeled dendritic spines in the PFC revealed that chronic elevation of CORT leads to an increase in dendritic spine turnover and an abnormal loss of stable spines that had been formed early in life [190].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [190] Liston C, Gan WB. Glucocorticoids are critical regulators of dendritic spine development and plasticity in vivo. Proc Natl Acad Sci. 2011;108:16074–9. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Chronic stress also results in a ca.20% reduction in the length of apical dendrites in pyramidal neurons in the PFC and a ca.30% decrease in the density of axospinous synapses on apical dendrites, along with corresponding decreases in the expression of synaptic genes [186-189].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [186] Radley JJ, Sisti HM, Hao J, Rocher AB, McCall T, Hof PR, et al. Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex. Neuroscience. 2004;125:1–6. source
- Not checked yetcites [187] Radley JJ, Rocher AB, Miller M, Janssen WG, Liston C, Hof PR, et al. Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cereb Cortex. 2006;16:313–20. source
- Not checked yetcites [188] Liston C, Miller MM, Goldwater DS, Radley JJ, Rocher AB, Hof PR, et al. Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J Neurosci. 2006;26:7870–4. source
- Not checked yetcites [189] Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry. 2011a;69:754–61. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Chronic stress also results in a ca.20% reduction in the length of apical dendrites in pyramidal neurons in the PFC and a ca.30% decrease in the density of axospinous synapses on apical dendrites, along with corresponding decreases in the expression of synaptic genes [186-189].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [186] Radley JJ, Sisti HM, Hao J, Rocher AB, McCall T, Hof PR, et al. Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex. Neuroscience. 2004;125:1–6. source
- Not checked yetcites [187] Radley JJ, Rocher AB, Miller M, Janssen WG, Liston C, Hof PR, et al. Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cereb Cortex. 2006;16:313–20. source
- Not checked yetcites [188] Liston C, Miller MM, Goldwater DS, Radley JJ, Rocher AB, Hof PR, et al. Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J Neurosci. 2006;26:7870–4. source
- Not checked yetcites [189] Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry. 2011a;69:754–61. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Consistent with the decrease in excitation, expression of several immediate early genes and genes associated with synaptic function are decreased in the PFC of depressed humans and in rodent models [194,195].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [194] Covington HE 3rd, Lobo MK, Maze I, Vialou V, Hyman JM, Zaman S, et al. Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J Neurosci. 2010;30:16082–90. source
- Not checked yetcites [195] Newton DF, Oh H, Shukla R, Misquitta K, Fee C, Banasr M, et al. Chronic stress induces coordinated cortical microcircuit cell-type transcriptomic changes consistent with altered information processing. Biol Psychiatry. 2022;91:798–809. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There is also strong preclinical evidence that increases in PFC activity mimic the actions of antidepressants.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Ketamine and other fast-acting antidepressant candidates all produce a rapid restoration of dendritic spine density in the PFC in stressed and unstressed animals with the same rapid time course as its behavioral actions [145, 187, 202, 203], implying the restoration of synaptic and circuit function, too.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [145] Moda-Sava RN, Murdock MH, Parekh PK, Fetcho RN, Huang BS, Huynh TN, et al. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science. 2019;364:eaat8078. source
- Not checked yetcites [187] Radley JJ, Rocher AB, Miller M, Janssen WG, Liston C, Hof PR, et al. Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cereb Cortex. 2006;16:313–20. source
- Not checked yetcites [202] Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64. source
- Not checked yetcites [203] Phoumthipphavong V, Barthas F, Hassett S, Kwan AC. Longitudinal effects of ketamine on dendritic architecture in vivo in the mouse medial frontal cortex. eNeuro. 2016; 3:ENEURO.0133-15.2016. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Treatment of MDD patients with classical monoaminergic antidepressants also restores normal activation of the PFC in attention tasks and restores the volume of the PFC [197][198][199].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [197] Fales CL, Barch DM, Rundle MM, Mintun MA, Mathews J, Snyder AZ, et al. Antidepressant treatment normalizes hypoactivity in dorsolateral prefrontal cortex during emotional interference processing in major depression. J Affect Disord. 2009;112:206–11. source
- Not checked yetcites [198] Phillips ML, Chase HW, Sheline YI, Etkin A, Almeida JR, Deckersbach T, et al. Identifying predictors, moderators, and mediators of antidepressant response in major depressive disorder: neuroimaging approaches. Am J Psychiatry. 2015;172:124–38. source
- Not checked yetcites [199] Fonseka TM, MacQueen GM, Kennedy SH. Neuroimaging biomarkers as predictors of treatment outcome in major depressive disorder. J Affect Disord. 2018;233:21–35. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“For example, optogenetic stimulation of the mPFC in a bursting pattern, not unlike that occurring during ketamine-induced gamma oscillations, in mice subjected to chronic social defeat drives changes in immediate early gene expression like those seen in the PFC of human patients medicated with antidepressants and has an antidepressant-like effect in sucrose and social interaction preference tests”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [194] Covington HE 3rd, Lobo MK, Maze I, Vialou V, Hyman JM, Zaman S, et al. Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J Neurosci. 2010;30:16082–90. source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Treatment of MDD patients with classical monoaminergic antidepressants also restores normal activation of the PFC in attention tasks and restores the volume of the PFC [197][198][199].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [197] Fales CL, Barch DM, Rundle MM, Mintun MA, Mathews J, Snyder AZ, et al. Antidepressant treatment normalizes hypoactivity in dorsolateral prefrontal cortex during emotional interference processing in major depression. J Affect Disord. 2009;112:206–11. source
- Not checked yetcites [198] Phillips ML, Chase HW, Sheline YI, Etkin A, Almeida JR, Deckersbach T, et al. Identifying predictors, moderators, and mediators of antidepressant response in major depressive disorder: neuroimaging approaches. Am J Psychiatry. 2015;172:124–38. source
- Not checked yetcites [199] Fonseka TM, MacQueen GM, Kennedy SH. Neuroimaging biomarkers as predictors of treatment outcome in major depressive disorder. J Affect Disord. 2018;233:21–35. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“For example, optogenetic stimulation of the mPFC in a bursting pattern, not unlike that occurring during ketamine-induced gamma oscillations, in mice subjected to chronic social defeat drives changes in immediate early gene expression like those seen in the PFC of human patients medicated with antidepressants and has an antidepressant-like effect in sucrose and social interaction preference tests”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [194] Covington HE 3rd, Lobo MK, Maze I, Vialou V, Hyman JM, Zaman S, et al. Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J Neurosci. 2010;30:16082–90. source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There is strong evidence that treatments that reverse the symptoms of depression also reverse deficits in the PFC.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Both AMPAR-and NMDAR-components of the EPSP were equally affected, unlike in the NAc [192,193] and hippocampus [110].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [192] Kim U, Lee T. Topography of descending projections from anterior insular and medial prefrontal regions to the lateral habenula of the epithalamus in the rat. Eur J Neurosci. 2012;35:1253–69. source
- Not checked yetcites [193] LeGates TA, Kvarta MD, Tooley JR, Francis TC, Lobo MK, Creed MC, et al. Reward behaviour is regulated by the strength of hippocampus-nucleus accumbens synapses. Nature. 2018;564:258–62. source
- Not checked yetcites [110] Kallarackal AJ, Kvarta MD, Cammarata E, Jaberi L, Cai X, Bailey AM, et al. Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses. J Neurosci. 2013;33:15669–74. source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Ketamine and other fast-acting antidepressant candidates all produce a rapid restoration of dendritic spine density in the PFC in stressed and unstressed animals with the same rapid time course as its behavioral actions [145, 187, 202, 203], implying the restoration of synaptic and circuit function, too.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [145] Moda-Sava RN, Murdock MH, Parekh PK, Fetcho RN, Huang BS, Huynh TN, et al. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science. 2019;364:eaat8078. source
- Not checked yetcites [187] Radley JJ, Rocher AB, Miller M, Janssen WG, Liston C, Hof PR, et al. Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cereb Cortex. 2006;16:313–20. source
- Not checked yetcites [202] Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64. source
- Not checked yetcites [203] Phoumthipphavong V, Barthas F, Hassett S, Kwan AC. Longitudinal effects of ketamine on dendritic architecture in vivo in the mouse medial frontal cortex. eNeuro. 2016; 3:ENEURO.0133-15.2016. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Ketamine and other fast-acting antidepressant candidates all produce a rapid restoration of dendritic spine density in the PFC in stressed and unstressed animals with the same rapid time course as its behavioral actions [145, 187, 202, 203], implying the restoration of synaptic and circuit function, too.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [145] Moda-Sava RN, Murdock MH, Parekh PK, Fetcho RN, Huang BS, Huynh TN, et al. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science. 2019;364:eaat8078. source
- Not checked yetcites [187] Radley JJ, Rocher AB, Miller M, Janssen WG, Liston C, Hof PR, et al. Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cereb Cortex. 2006;16:313–20. source
- Not checked yetcites [202] Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64. source
- Not checked yetcites [203] Phoumthipphavong V, Barthas F, Hassett S, Kwan AC. Longitudinal effects of ketamine on dendritic architecture in vivo in the mouse medial frontal cortex. eNeuro. 2016; 3:ENEURO.0133-15.2016. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Immunohistochemical analysis of interneurons and transcripts of interneuron-associated proteins are decreased within the PFC and anterior cingulate cortex in human MDD brain tissue and in chronically stressed rats, suggesting that deficits in GABA levels may contribute to the symptoms of depression [205][206][207][208].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [205] Rajkowska G, O’Dwyer G, Teleki Z, Stockmeier CA, Miguel-Hidalgo JJ. GABAergic neurons immunoreactive for calcium binding proteins are reduced in the prefrontal cortex in major depression. Neuropsychopharmacol. 2007;32:471–82. source
- Not checked yetcites [206] Sibille E, Morris H, Kota R, Lewis DA. GABA-related transcripts in the dorsolateral prefrontal cortex in mood disorders. J Neuropsychopharmacol. 2011;14:721–34. source
- Not checked yetcites [207] Tripp A, Oh H, Guilloux J-P, Martinowich K, Lewis DA, Sibille E. Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder. Am J Psychiatry. 2012;169:1194–202. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Ketamine triggers not only its activation, but also the activation of many of its downstream targets, within minutes-tohours, in unstressed rats.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [202] Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Use of synaptic vesicle PET ligands has recently revealed that ketamine produces similar synapsepromoting effects in the PFC in human depression [204].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [204] Holmes SE, Finnema SJ, Naganawa M, DellaGioia N, Holden D, Fowles K, et al. Imaging the effect of ketamine on synaptic density (SV2A) in the living brain. Mol Psychiatry. 2022;27:2273–81. https://doi.org/10.1038/s41380-022-01465-2 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“As in the hippocampus, ketamine inhibits the discharge of interneurons in the PFC and reduces spontaneous IPSCs in pyramidal cells acutely [210], while restoring inhibition at later timepoints corresponding to its behavioral actions [211].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [211] Ghosal S, Duman CH, Liu RJ, Wu M, Terwilliger R, Girgenti MJ, et al. Ketamine rapidly reverses stress-induced impairments in GABAergic transmission in the prefrontal cortex in male rodents. Neurobiol Dis. 2020;134:104669. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Similarly, chemogenetic inhibition of either somatostatin-and parvalbumin-expressing interneurons in the mPFC mimicked the effects produced by antidepressants in the FST and other tasks, suggesting that transient inhibition of GABAergic interneurons contributes to the actions of rapidly”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [212] Fogaça MV, Wu M, Li C, Li XY, Picciotto MR, Duman RS. Inhibition of GABA interneurons in the mPFC is sufficient and necessary for rapid antidepressant responses. Mol Psychiatry. 2021;26:3277–91. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Indeed, ketamine and GABA A receptor negative allosteric modulators share an ability to promote gamma oscillations in the PFC at doses that reverse the behavioral consequences of chronic stress [152,153].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [152] Troppoli TA, Zanos P, Georgiou P, Gould TD, Rudolph U, Thompson SM. Negative allosteric modulation of gamma-aminobutyric acid A receptors at α5 subunit-containing benzodiazepine sites reverses stress-induced anhedonia and weakened synaptic function in mice. Biol Psychiatry. 2022;92:216–26. source
- Not checked yetcites [153] Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533:481–6. source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There is also evidence that the antidepressant effects of ketamine occur via inhibition of GABA interneurons.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Similarly, chemogenetic inhibition of either somatostatin-and parvalbumin-expressing interneurons in the mPFC mimicked the effects produced by antidepressants in the FST and other tasks, suggesting that transient inhibition of GABAergic interneurons contributes to the actions of rapidly”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [212] Fogaça MV, Wu M, Li C, Li XY, Picciotto MR, Duman RS. Inhibition of GABA interneurons in the mPFC is sufficient and necessary for rapid antidepressant responses. Mol Psychiatry. 2021;26:3277–91. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Furthermore, knock-down and deletion of critical ketaminesensitive NMDARs from either somatostatin-or parvalbuminexpressing interneurons alters baseline behaviors in the FST and other tasks and eliminates the ability of ketamine to change these behaviors in unstressed mice [210].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [210] Gerhard DM, Pothula S, Liu RJ, Wu M, Li XY, Girgenti MJ, et al. GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions. J Clin Invest. 2020;130:1336–49. source
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“Furthermore, knock-down and deletion of critical ketaminesensitive NMDARs from either somatostatin-or parvalbuminexpressing interneurons alters baseline behaviors in the FST and other tasks and eliminates the ability of ketamine to change these behaviors in unstressed mice [210].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [210] Gerhard DM, Pothula S, Liu RJ, Wu M, Li XY, Girgenti MJ, et al. GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions. J Clin Invest. 2020;130:1336–49. source
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In the paper
“Somatostatin-and parvalbumin-expressing GABAergic interneurons are particularly affected in chronically stressed rats [209].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [209] Banasr M, Lepack A, Fee C, Duric V, Maldonado-Aviles J, DiLeone R, et al. Characterization of GABAergic marker expression in the chronic unpredictable stress model of depression. Chronic Stress (Thousand Oaks). 2017;1:2470547017720459. source
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In the paper
“Conversely, a decrease in the ability of D1 MSNs to drive dopamine release from the VTA, due to decreased excitation and/or increased activity of D2 MSNs, may contribute to the loss of the rewarding properties of normally rewarding stimuli characterizing anhedonia and lack of motivation in the depressed state.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
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In the paper
“Activity-dependent LTP in vivo was both necessary and sufficient to induce a conditioned place preference lasting for at least 24hrs [193].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [193] LeGates TA, Kvarta MD, Tooley JR, Francis TC, Lobo MK, Creed MC, et al. Reward behaviour is regulated by the strength of hippocampus-nucleus accumbens synapses. Nature. 2018;564:258–62. source
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In the paper
“More recent findings have established that these neat divisions do not apply as simplistically to the ventral striatum [221,222].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [221] Kupchik YM, Brown RM, Heinsbroek JA, Lobo MK, Schwartz DJ, Kalivas PW. Coding the direct/indirect pathways by D1 and D2 receptors is not valid for accumbens projections. Nat Neurosci. 2015;18:1230–2. source
- Not checked yetcites [222] Soares-Cunha C, de Vasconcelos N, Coimbra B, Domingues AV, Silva JM, Loureiro-Campos E, et al. Nucleus accumbens medium spiny neurons subtypes signal both reward and aversion. Mol Psychiatry 2019;25:3241–55.218. source
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In the paper
“Conversely, weakening inputs to the NAc can reverse previously established reward responses to addictive drugs [231,232].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [231] Ma YY, Lee BR, Wang X, Guo C, Liu L, Cui R, et al. Bidirectional modulation of incubation of cocaine craving by silent synapse-based remodeling of prefrontal cortex to accumbens projections. Neuron. 2014;83:1453–67. source
- Not checked yetcites [232] Creed M, Pascoli VJ, Lüscher C. Addiction therapy. Refining deep brain stimulation to emulate optogenetic treatment of synaptic pathology. Science. 2015;347:659–64. source
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In the paper
“Much like canonical hippocampal LTP, high frequency stimulation of hippocampal afferents to the NAc elicits a rapid and persistent NMDAR-triggered, Ca 2+ -and CaMKdependent increase in postsynaptic AMPAR responses in D1 and D2 MSNs [193].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [193] LeGates TA, Kvarta MD, Tooley JR, Francis TC, Lobo MK, Creed MC, et al. Reward behaviour is regulated by the strength of hippocampus-nucleus accumbens synapses. Nature. 2018;564:258–62. source
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In the paper
“In response to chronic stress, rodent NAc MSNs display an array of plastic changes that act in concert to alter forebrain dopaminergic release from the VTA and, thereby, alter the responses to rewarding and aversive stimuli [233].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [233] Francis TC, Lobo MK. Emerging role for nucleus accumbens medium spiny neuron subtypes in depression. Biol Psychiatry. 2017;81:645–53. source
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In the paper
“Similarly, establishment of cocaine place preferences is accompanied by a potentiation of hippocampal-NAc synaptic excitation [230].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [230] Sjulson L, Peyrache A, Cumpelik A, Cassataro D, Buzsáki G. Cocaine place conditioning strengthens location-specific hippocampal coupling to the nucleus accumbens. Neuron. 2018;98:926–34. source
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In the paper
“This differential effect suggests a possible stressinduced biasing of NAc responses from D1 MSN towards D2 MSN activation, hence favoring negative valence responses over positive valence.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
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In the paper
“Neuromodulators, including dopamine itself, serotonin, and enkephalins are also likely to play a significant role in gating synaptic strength and the balance between D1 and D2 MSN activity [217,233,237].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [217] Bayassi-Jakowicka M, Lietzau G, Czuba E, Steliga A, Waśkow M, Kowiański P. Neuroplasticity and multilevel system of connections determine the integrative role of nucleus accumbens in the brain reward system. Int J Mol Sci. 2021;22:9806. source
- Not checked yetcites [233] Francis TC, Lobo MK. Emerging role for nucleus accumbens medium spiny neuron subtypes in depression. Biol Psychiatry. 2017;81:645–53. source
- Not checked yetcites [237] Christoffel DJ, Walsh JJ, Heifets BD, Hoerbelt P, Neuner S, Sun G, et al. Input-specific modulation of murine nucleus accumbens differentially regulates hedonic feeding. Nat Commun. 2021;12:2135. source
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In the paper
“Similarly, evoked AMPA receptor-mediated excitatory synaptic currents are reduced by chronic stress in D1, but not D2, MSNs [236], including in response to afferents from the hippocampus [193].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [236] Lim BK, Huang KW, Grueter BA, Rothwell PE, Malenka RC. Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens. Nature 2012;487:183–9. source
- Not checked yetcites [193] LeGates TA, Kvarta MD, Tooley JR, Francis TC, Lobo MK, Creed MC, et al. Reward behaviour is regulated by the strength of hippocampus-nucleus accumbens synapses. Nature. 2018;564:258–62. source
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In the paper
“Susceptibility to chronic social defeat stress is accompanied by atrophy of MSN dendrites, specifically in D1 MSNs and not D2 MSNs, and a corresponding loss of dendritic spines [226,234,235].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [226] Francis TC, Chandra R, Friend DM, Finkel E, Dayrit G, Miranda J, et al. Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress. Biol Psychiatry. 2015;77:212–22. source
- Not checked yetcites [234] Francis TC, Chandra R, Gaynor A, Konkalmatt P, Metzbower SR, Evans B, et al. Molecular basis of dendritic atrophy and activity in stress susceptibility. Mol Psychiatry. 2017;22:1512–19. source
- Not checked yetcites [235] Fox ME, Chandra R, Menken MS, Larkin EJ, Nam H, Engeln M, et al. Dendritic remodeling of D1 neurons by RhoA/Rho-kinase mediates depression-like behavior. Mol Psychiatry. 2020;25:1022–34. source
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In the paper
“Although receiving less attention than cortical plasticity, there is evidence that known and novel potential antidepressant compounds exert some of their therapeutic benefits via actions within the NAc.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
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In the paper
“Susceptibility to social defeat stress is accompanied by an increase in input resistance and firing in response to depolarizing currents pulses in D1 MSNs, but not D2 MSNs [226,234].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [226] Francis TC, Chandra R, Friend DM, Finkel E, Dayrit G, Miranda J, et al. Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress. Biol Psychiatry. 2015;77:212–22. source
- Not checked yetcites [234] Francis TC, Chandra R, Gaynor A, Konkalmatt P, Metzbower SR, Evans B, et al. Molecular basis of dendritic atrophy and activity in stress susceptibility. Mol Psychiatry. 2017;22:1512–19. source
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In the paper
“As such they are heavily implicated as central players in the genesis of depression.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
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In the paper
“These decreases in the excitation of D1 MSNs may be sufficient, in and of themselves, to mediate an anhedonic loss of reward behavior.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
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In the paper
“Ketamine also restores the ability to induce LTP in the hippocampus-accumbens pathway in stressed animals [240].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [240] Belujon P, Grace AA. Restoring mood balance in depression: ketamine reverses deficit in dopamine-dependent synaptic plasticity. Biol Psychiatry. 2014;76:927–36. source
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In the paper
“Finally, local infusion of ketamine into the NAc reversed stress-induced decreases in the phosphorylation of GluA1 AMPARs at serines 831 and 845, which is known to promote their insertion into synapses, suggesting a direct mechanism for the potentiation of NAc synapses [244].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [244] Asim M, Hao B, Waris A, Liang YM, Wang XG. Ketamine attenuates the PTSD-like effect via regulation of glutamatergic signaling in the nucleus accumbens of mice. Mol Cell Neurosci. 2022;120:103723. source
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In the paper
“Ketamine restores a stress-induced decrease in VTA dopaminergic cell firing [240] and increases extracellular levels of dopamine in the nucleus accumbens [241].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [241] Witkin JM, Monn JA, Schoepp DD, Li X, Overshiner C, Mitchell SN, et al. The rapidly acting antidepressant ketamine and the mGlu2/3 receptor antagonist LY341495 rapidly engage dopaminergic mood circuits. J Pharm Exp Ther. 2016;358:71–82. source
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In the paper
“Consistent with these synaptic findings, the probability of action potential firing of neurons in the NAc in response to stimulation of hippocampal afferents is increased by escitalopram administration [238].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [238] Chakroborty S, Geisbush TR, Dale E, Pehrson AL, Sánchez C, West AR. Impact of vortioxetine on synaptic integration in prefrontal-subcortical circuits: comparisons with escitalopram. Front Pharm. 2017;8:764. source
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In the paper
“Ketamine restores a stress-induced decrease in VTA dopaminergic cell firing [240] and increases extracellular levels of dopamine in the nucleus accumbens [241].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [240] Belujon P, Grace AA. Restoring mood balance in depression: ketamine reverses deficit in dopamine-dependent synaptic plasticity. Biol Psychiatry. 2014;76:927–36. source
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In the paper
“As elsewhere in the brain, elevated BDNF -trkB signaling may be crucial within these mesolimbic circuits [243].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [243] Koo JW, Chaudhury D, Han MH, Nestler EJ. Role of Mesolimbic Brain-Derived Neurotrophic Factor in Depression. Biol Psychiatry. 2019;86:738–48. source
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In the paper
“Given the lack of local excitatory interactions within the NAc, it is likely that this high frequency synchronized activity is projected onto the NAc via afferents from the PFC and hippocampus.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
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In the paper
“Chronic treatment with escitalopram restores the ability of rewarding stimuli to trigger DA release within the NAc in chronically stressed rats [239].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [239] Minami S, Satoyoshi H, Ide S, Inoue T, Yoshioka M, Minami M. Suppression of reward-induced dopamine release in the nucleus accumbens in animal models of depression: Differential responses to drug treatment. Neurosci Lett. 2017;650:72–6. source
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In the paper
“Like the effects of ketamine in the cortex, ketamine increases the power of high-frequency oscillations of local field potentials in the NAc in unanesthetized mice [242], suggesting a potential role for activity-dependent synapse strengthening mechanisms.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [242] Hunt MJ, Olszewski M, Piasecka J, Whittington MA, Kasicki S. Effects of NMDA receptor antagonists and antipsychotics on high frequency oscillations recorded in the nucleus accumbens of freely moving mice. Psychopharmacol. 2015;232:4525–35. source
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In the paper
“The net effect of these synaptic changes is to restore the function of the NAc-VTA circuit.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
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In the paper
“Like the effects of ketamine in the cortex, ketamine increases the power of high-frequency oscillations of local field potentials in the NAc in unanesthetized mice [242], suggesting a potential role for activity-dependent synapse strengthening mechanisms.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [242] Hunt MJ, Olszewski M, Piasecka J, Whittington MA, Kasicki S. Effects of NMDA receptor antagonists and antipsychotics on high frequency oscillations recorded in the nucleus accumbens of freely moving mice. Psychopharmacol. 2015;232:4525–35. source
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In the paper
“Defects in hippocampal -NAc coupling have been observed to correlate with reward processing deficits [246].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [246] Schwarz K, Moessnang C, Schweiger JI, Harneit A, Schneider M, Chen J, et al. Ventral striatal-hippocampus coupling during reward processing as a stratification biomarker for psychotic disorders. Biol Psychiatry. 2022;91:216–25. source
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In the paper
“Importantly, these effects persisted for up to a week after a single ketamine administration, strongly supporting an important role for plasticity in the cortico-mesolimbic circuitry in the genesis and treatment of depression.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [251] Sterpenich V, Vidal S, Hofmeister J, Michalopoulos G, Bancila V, Warrot D, et al. Increased reactivity of the mesolimbic reward system after ketamine injection in patients with treatment-resistant major depressive disorder. Anesthesiol. 2019;130:923–35. source
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In the paper
“Similar increases in NAc-PFC connectivity correlate with reduced symptom severity and quality-of-life measurements in SSRI-responsive patients compared to unresponsive controls [250].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [250] Fischer AS, Holt-Gosselin B, Fleming SL, Hack LM, Ball TM, Schatzberg AF, et al. Intrinsic reward circuit connectivity profiles underlying symptom and quality of life outcomes following antidepressant medication: a report from the iSPOT-D trial. Neuropsychopharmacol. 2021;46:809–19. source
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In the paper
“Finally, local infusion of ketamine into the NAc reversed stress-induced decreases in the phosphorylation of GluA1 AMPARs at serines 831 and 845, which is known to promote their insertion into synapses, suggesting a direct mechanism for the potentiation of NAc synapses [244].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [244] Asim M, Hao B, Waris A, Liang YM, Wang XG. Ketamine attenuates the PTSD-like effect via regulation of glutamatergic signaling in the nucleus accumbens of mice. Mol Cell Neurosci. 2022;120:103723. source
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In the paper
“It integrates glutamatergic inputs from the lateral hypothalamus [253] and from the anterior cingulate and medial prefrontal cortices [254].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE LATERAL HABENULA
What the sources say
- Not checked yetcites [253] Poller WC, Madai VI, Bernard R, Laube G, Veh RW. A glutamatergic projection from the lateral hypothalamus targets VTA-projecting neurons in the lateral habenula of the rat. Brain Res. 2013;1507:45–60. source
- Not checked yetcites [254] Kim U, Lee T. Topography of descending projections from anterior insular and medial prefrontal regions to the lateral habenula of the epithalamus in the rat. Eur J Neurosci. 2012;35:1253–69. source
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In the paper
“The consequences of LHb activity are largely mediated by its output to the RMTg [261].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE LATERAL HABENULA
What the sources say
- Not checked yetcites [261] Jhou TC. The rostromedial tegmental (RMTg) “brake” on dopamine and behavior: A decade of progress but also much unfinished work. Neuropharmacol. 2021;198:108763. source
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In the paper
“LHb neurons also receive feed-forward and feedback GABAergic inhibition [253,255].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE LATERAL HABENULA
What the sources say
- Not checked yetcites [253] Poller WC, Madai VI, Bernard R, Laube G, Veh RW. A glutamatergic projection from the lateral hypothalamus targets VTA-projecting neurons in the lateral habenula of the rat. Brain Res. 2013;1507:45–60. source
- Not checked yetcites [255] Li B, Piriz J, Mirrione M, Chung C, Proulx CD, Schulz D, et al. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature. 2011;470:535–9. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Conversely, reward delivery decreases LHb discharge [257].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE LATERAL HABENULA
What the sources say
- Not checked yetcites [257] Matsumoto M, Hikosaka O. Representation of negative motivational value in the primate lateral habenula. Nat Neurosci. 2009;12:77–84. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Importantly, activation of LHb inputs to the RMTg reduced motivation to work for a rewarding sucrose solution in an operant task, without reducing its rewarding hedonic properties [262].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE LATERAL HABENULA
What the sources say
- Not checked yetcites [262] Proulx CD, Aronson S, Milivojevic D, Molina C, Loi A, Monk B, et al. A neural pathway controlling motivation to exert effort. Proc Natl Acad Sci 2018;115:5792–7. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Stress-induced increases in firing are attributed to decreased function of G-protein coupled K + channels in LHb neurons [263].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE LATERAL HABENULA
What the sources say
- Not checked yetcites [263] Lecca S, Pelosi A, Tchenio A, Moutkine I, Lujan R, Hervé D, et al. Rescue of GABAB and GIRK function in the lateral habenula by protein phosphatase 2A inhibition ameliorates depression-like phenotypes in mice. Nat Med. 2016;22:254–61. source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“An increased probability of presynaptic glutamate release in the LHb accompanies learned helplessness and chronic restraint stress [255,260].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE LATERAL HABENULA
What the sources say
- Not checked yetcites [255] Li B, Piriz J, Mirrione M, Chung C, Proulx CD, Schulz D, et al. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature. 2011;470:535–9. source
- Not checked yetcites [260] Zheng Z, Guo C, Li M, Yang L, Liu P, Zhang X, et al. Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset. Neuron. 2022;110:1400–15. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Some forms of chronic stress also increase the amplitude of spontaneous excitatory synaptic responses [260].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE LATERAL HABENULA
What the sources say
- Not checked yetcites [260] Zheng Z, Guo C, Li M, Yang L, Liu P, Zhang X, et al. Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset. Neuron. 2022;110:1400–15. source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Viral knockdown of beta-CaMK, the enzyme underlying the stress-induced presynaptic potentiation of LHb excitatory synapses, prevented forced swim and learned helplessness behaviors in congenitally learned helpless rats [267].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE LATERAL HABENULA
What the sources say
- Not checked yetcites [267] Li K, Zhou T, Liao L, Yang Z, Wong C, Henn F, et al. βCaMKII in lateral habenula mediates core symptoms of depression. Science. 2013;341:1016–20. source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The work cited above, describing results from both preclinical and human studies, provides compelling evidence, first, that prolonged stress, both physical and psychosocial, affects the structure, protein composition, and function of excitatory synapses in every area of the brain devoted to the processing of reward related stimuli and cognitive, learning, and memory processes.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“One of the most exciting developments in the treatment of depression and other psychiatric disorders has been the recent findings that a single administration of psilocybin produces a rapid and persistent improvement in self-reported depression symptoms in patients resistant to conventional antidepressants (e.g., [274]).”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
What the sources say
- Not checked yetcites [274] Davis AK, Barrett FS, May DG, Cosimano MP, Sepeda ND, Johnson MW, et al. Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2021;78:481–9. source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As summarized above, there is strong evidence from imaging and functional connectivity studies of human patients to suggest that analogous changes occur in human MDD.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Further supporting this hypothesis of antidepressant action, these substances do not necessarily share the same mechanisms of action.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
hedged- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Supporting the hypothesis that synaptic and circuit dysfunction is a major cause of depression, there is increasing evidence that restoration of the function of synapses and circuits is a common mechanism of action underlying a wide range of known and novel antidepressants.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In the hippocampus, stress-impaired reward behaviors are restored to baseline levels 24 h after a single administration of psilocybin [275], exactly as seen with other fast-acting antidepressants.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
What the sources say
- Not checked yetcites [275] Hesselgrave N, Troppoli TA, Wulff AB, Cole AB, Thompson SM. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proc Natl Acad Sci. 2021;118:e2022489118. source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The distributed nature of these changes also complicates experimental efforts to identify a single synapse or circuit as the unique 'cause' of a given behavioral deficit, given their highly interconnected nature.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Nevertheless, all strengthen synapse function.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Subsequent preclinical experiments supported this hypothesis [152,273].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
What the sources say
- Not checked yetcites [152] Troppoli TA, Zanos P, Georgiou P, Gould TD, Rudolph U, Thompson SM. Negative allosteric modulation of gamma-aminobutyric acid A receptors at α5 subunit-containing benzodiazepine sites reverses stress-induced anhedonia and weakened synaptic function in mice. Biol Psychiatry. 2022;92:216–26. source
- Not checked yetcites [273] Fischell J, Van Dyke AM, Kvarta MD, LeGates TA, Thompson SM. Rapid Antidepressant Action and Restoration of Excitatory Synaptic Strength After Chronic Stress by Negative Modulators of Alpha5-Containing GABAA Receptors. Neuropsychopharmacol. 2015;40:2499–509. source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These plastic changes appear maladaptive.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
hedged- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“These oscillations are likely to result from disinhibition produced by a selective block of NMDARs on GABAergic interneurons [142, 143].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
What the sources say
- Not checked yetcites [142] Homayoun H, Moghaddam B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci. 2007;27:11496–500. source
- Not checked yetcites [143] Widman AJ, McMahon LL. Disinhibition of CA1 pyramidal cells by low-dose ketamine and other antagonists with rapid antidepressant efficacy. Proc Natl Acad Sci. 2018;115:E3007–E3016. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Chronic, but not acute, administration of conventional antidepressants also reverses stress-induced dendritic atrophy in rodents[126]”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
What the sources say
- Not checked yetcites [126] Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA, et al. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol Psychiatry. 2009;14:764–73. source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“which is accompanied by an increase in the frequency of spontaneous mEPSCs [276]”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
What the sources say
- Not checked yetcites [276] Shao LX, Liao C, Gregg I, Davoudian PA, Savalia NK, Delagarza K, et al. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron 2021;109:2535–.e4. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“These preclinical findings are paralleled by human functional imaging findings that psychedelics change connectivity in reward-and emotionrelevant brain regions in a persistent manner [277].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
What the sources say
- Not checked yetcites [277] Barrett FS, Doss MK, Sepeda ND, Pekar JJ, Griffiths RR. Emotions and brain function are altered up to one month after a single high dose of psilocybin. Sci Rep. 2020;10:2214.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“both studies suggested that the actions of psilocybin were independent of the serotonin 2 A receptor that mediates the mind-altering properties of psychedelics, raising the possibility of dissociating the 'trip' from the antidepressant benefits of psychedelics.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
What the sources say
- Not checked yetcites [275] Hesselgrave N, Troppoli TA, Wulff AB, Cole AB, Thompson SM. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proc Natl Acad Sci. 2021;118:e2022489118. source
- Not checked yetcites [276] Shao LX, Liao C, Gregg I, Davoudian PA, Savalia NK, Delagarza K, et al. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron 2021;109:2535–.e4. source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The serotonin 2A receptor mediates the mind-altering effects of psychedelics.
- It may state two separate claims as one. 91
- Probably not a substantial claim. 15
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“Dopamine receptor activation is not required for this potentiation but may be modulatory under physiological conditions [229].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Disputedcites [229] Yagishita S, Hayashi-Takagi A, Ellis-Davies GC, Urakubo H, Ishii S, Kasai H. A critical time window for dopamine actions on the structural plasticity of dendritic spines. Science. 2014;345:1616–20. sourceExperimental — accuracy not yet measured
The paper’s Abstract states that the studied structural plasticity depended on the D1 dopamine receptor and PKA, contrary to the claim that dopamine receptor activation is not required. It reports only weak spine enlargement without dopamine, compared with robust enlargement when dopamine was applied; it also describes dopamine as regulating the gain of plasticity. (LLM, conf=0.85)
Checked by a reasoning model — may be wrong.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Disputed
Every source the paper cites for this claim was checked and supports it.
In the paper
“For example, Sterpinich et al. [251] observed that ketamine increased responses in a reward task and caused an accompanying increase in activity in the orbitofrontal cortex, ventral striatum, and the ventral tegmental area.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Supportedcites [251] Sterpenich V, Vidal S, Hofmeister J, Michalopoulos G, Bancila V, Warrot D, et al. Increased reactivity of the mesolimbic reward system after ketamine injection in patients with treatment-resistant major depressive disorder. Anesthesiol. 2019;130:923–35. source
The Perioperative Medicine passage reports better performance on reward-task trials associated with potential gain, alongside increased recruitment of the orbitofrontal cortex and ventral striatum. A second passage in that section reports increased medial substantia nigra/ventral tegmental area activity during positively cued trials. Page numbers are not provided in our copy. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Nevertheless, the evidence is plentiful and strong that the LHb is an important mediator of aversive behavioral responses via its outputs to the VTA and that its behavior is profoundly increased in a variety of chronic stress conditions used to model depression relevant behaviors in rodents (for excellent further reviews, see: [252, 269, 270]).”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE LATERAL HABENULA
What the sources say
- Not checked yetcites [252] Lecca S, Meye FJ, Mameli M. The lateral habenula in addiction and depression: an anatomical, synaptic and behavioral overview. Eur J Neurosci. 2014;39:1170–8. source
- Partly supportedcites [269] Yang Y, Wang H, Hu J, Hu H. Lateral habenula in the pathophysiology of depression. Curr Opin Neurobiol. 2018b;48:90–6. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked yetcites [270] Mondoloni S, Mameli M, Congiu M. Reward and aversion encoding in the lateral habenula for innate and learned behaviours. Transl Psychiatry. 2022;12:3.
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“We have observed that chronic, but not acute, administration of fluoxetine restores the strength of stress-weakened TA-CA1 excitatory synapses, concomitant with the recovery of normal hedonic behavior [44,120].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [44] Cai X, Kallarackal AJ, Kvarta MD, Goluskin S, Gaylor K, Bailey AM, et al. Local potentiation of excitatory synapses by serotonin and its alteration in rodent models of depression. Nat Neurosci. 2013;16:464–72. source
- Not checked yetcites [120] Tomar A, Polygalov D, McHugh TJ. Differential impact of acute and chronic stress on CA1 spatial coding and gamma oscillations. Front Behav Neurosci. 2021;15:710725. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The range of behaviors altered in depression suggests that multiple synaptic circuits are adversely affected, with no one synapse or circuit likely to be uniquely responsible for generating the entirety of the depressed phenotype.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > STRESS, SYMPTOMS OF DEPRESSION, AND THE CIRCUITRY OF REWARD AND EMOTION
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“There are also circuits involving the lateral habenula that display a relatively selective processing of negative valence stimuli and feed forward to the VTA.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > STRESS, SYMPTOMS OF DEPRESSION, AND THE CIRCUITRY OF REWARD AND EMOTION
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“These chronic stress models induce depressive-like behavioral states, resembling the symptom domains of human depression, and alter the putative underlying brain circuits in parallel with functional imaging findings in depressed humans [18,[37][38][39].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > STRESS, SYMPTOMS OF DEPRESSION, AND THE CIRCUITRY OF REWARD AND EMOTION
What the sources say
- Not checked yetcites [18] Xia CH, Ma Z, Ciric R, Gu S, Betzel RF, Kaczkurkin AN, et al. Linked dimensions of psychopathology and connectivity in functional brain networks. Nat Commun. 2018;9:3003.
- Not checked yetcites [37] Strekalova T, Steinbusch HW. Measuring behavior in mice with chronic stress depression paradigm. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:348–61. source
- Not checked yetcites [38] Lammel S, Tye KM, Warden MR. Progress in understanding mood disorders: optogenetic dissection of neural circuits. Genes Brain Behav. 2014;13:38–51. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“All chronic stress protocols produce behavioral changes with face validity to the symptom domains of human depression.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > STRESS, SYMPTOMS OF DEPRESSION, AND THE CIRCUITRY OF REWARD AND EMOTION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Impairment in these tasks is consistently observed after chronic stress and is clearly maladaptive.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > STRESS, SYMPTOMS OF DEPRESSION, AND THE CIRCUITRY OF REWARD AND EMOTION
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Hippocampal ensemble firing patterns also help animals correctly predict which direction they need to move in order to reach a chosen distant goal [62].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [62] Wikenheiser AM, Redish AD. Hippocampal theta sequences reflect current goals. Nat Neurosci. 2015;18:289–94. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Importantly, receipt of a reward triggers an increase in the rate of spike-wave ripples [63], which are known to enhance place field stability, and may thereby promote learning of reward locations [64].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [63] Singer AC, Frank LM. Rewarded outcomes enhance reactivation of experience in the hippocampus. Neuron. 2009;64:910–21. source
- Not checked yetcites [64] Roux L, Hu B, Eichler R, Stark E, Buzsaki G. Sharp wave ripples during learning stabilize the hippocampal spatial map. Nat Neurosci. 2017;20:845–53. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“An impaired ability to think and concentrate, which encompasses deficits in memory, executive function, and attention, is one of the major symptom categories used to diagnose MDD and contributes significantly to the overall disability associated with depression [56,57].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [56] Ottowitz WE, Dougherty DD, Savage CR. The neural network for abnormalities of attention and executive function in major depressive disorder: implications for application of the medical disease model to psychiatric disorders. Harv Rev Psychiatry. 2002;10:86–99. source
- Not checked yetcites [57] Frodl T, Schaub A, Banac S, Charypar M, Jäger M, Kümmler P, et al. Reduced hippocampal volume correlates with executive dysfunctioning in major depression. J Psych Neurosci. 2006;31:316–23.
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The hippocampus is well known to be essential in declarative and spatial memory formation from both animal studies and humans.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“It is also known to be an important regulator of the hypothalamic-pituitary axis, mediating negative feedback of stress hormone secretion.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
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In the paper
“A grossly oversimplified overview of these circuits is that the prefrontal cortices and hippocampus are devoted to detecting and decoding specific features of stimuli and the environment, including the social environment, to guide decision-making and ensure adaptive, flexible, and predictive responses to rewarding stimuli, whereas the lateral hypothalamus-lateral habenula circuits predominantly En”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > STRESS, SYMPTOMS OF DEPRESSION, AND THE CIRCUITRY OF REWARD AND EMOTION
What the sources say
- Not checked yetcites [50] Sesack SR, Grace AA. Cortico-basal ganglia reward network: microcircuitry. Neuropsychopharmacol. 2010;2010:27–47. source
- Not checked yetcites [51] Russo SJ, Nestler EJ. The brain reward circuitry in mood disorders. Nat Rev Neurosci. 2013;14:609–25. source
- Not checked yetcites [52] Lammel S, Lim BK, Malenka RC. Reward and aversion in a heterogeneous midbrain dopamine system. Neuropharmacol. 2014a;76:351–9. source
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In the paper
“There is also evidence that early life trauma can cause lifelong decreases in hippocampal volume [83], suggesting that preexisting hippocampal atrophy may predispose some people to the onset of depression later in life.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [83] Opel N, Redlich R, Zwanzger P, Grotegerd D, Arolt V, Heindel W, et al. Hippocampal atrophy in major depression: a function of childhood maltreatment rather than diagnosis? Neuropsychopharmacol. 2014;39:2723–31. source
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In the paper
“McEwen and colleagues first discovered that chronic stress and administration of exogenous corticosteroids lead to neuronal death in the hippocampus in rodents, as well as atrophy of the distal pyramidal cell dendrites and loss of dendritic spines [69][70][71][72][73][74].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [69] Sapolsky R, Krey L, McEwen BS. Prolonged glucocorticoid exposure reduces hippocampal neuron number: implications for aging. J Neurosci. 1985;5:1222–27. source
- Not checked yetcites [70] Woolley C, Gould E, McEwen BS. Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res. 1990;531:225–31. source
- Not checked yetcites [71] Watanabe Y, Gould E, McEwen BS. Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res. 1992;588:341–5. source
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In the paper
“As in animal models, human hippocampal atrophy can result solely from elevated corticosteroid levels.Selective atrophy of the hippocampus is observed in patients with Cushing's Syndrome and other diseases with chronically elevated cortisol levels, and these morphological changes are reversed by treatments that lower cortisol levels [82].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [82] Starkman MN, Giordani B, Gebarski SS, Berent S, Schork MA, Schteingart DE. Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing’s disease. Biol Psychiatry. 1999;46:1595–602. source
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In the paper
“These effects are consistent in all principal cell types and across multiple forms of physical and social stress [75][76][77].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [75] Silva-Gómez AB, Rojas D, Juárez I, Flores G. Decreased dendritic spine density on prefrontal cortical and hippocampal pyramidal neurons in postweaning social isolation rats. Brain Res. 2003;983:128–36. source
- Not checked yetcites [76] Donohue HS, Gabbott PL, Davies HA, Rodríguez JJ, Cordero MI, Sandi C, et al. Chronic restraint stress induces changes in synapse morphology in stratum lacunosum-moleculare CA1 rat hippocampus: a stereological and three-dimensional ultrastructural study. Neuroscience. 2006;140:597–606. source
- Not checked yetcites [77] Maras PM, Molet J, Chen Y, Rice C, Ji SG, Solodkin A, et al. Preferential loss of dorsal-hippocampus synapses underlies memory impairments provoked by short, multimodal stress. Mol Psychiatry. 2014;19:811–22. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Treatment with conventional antidepressants diminishes the atrophy in human depression [84], including recent longitudinal studies in previously drug naïve patients [85,86], suggesting that the anatomical changes may underlie functional improvements.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [84] Sheline YI, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. Am J Psychiatry. 2003;160:1516–8. source
- Not checked yetcites [85] Katsuki A, Watanabe K, Nguyen L, Otsuka Y, Igata R, Ikenouchi A, et al. Structural changes in hippocampal subfields in patients with continuous remission of drug-naive major depressive disorder. Int J Mol Sci. 2020;21:3032. source
- Not checked yetcites [86] Zarate-Garza PP, Ortega-Balderas JA, Ontiveros-Sanchez de la Barquera JA, Lugo-Guillen RA, Marfil-Rivera A, Quiroga-Garza A, et al. Hippocampal volume as treatment predictor in antidepressant naïve patients with major depressive disorder. J Psychiatr Res. 2021;140:323–8. source
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In the paper
“The link between these phenomena and the genesis of depression was considerably strengthened with the finding that conventional antidepressants promote BDNF expression [87,93] and neurogenesis [94][95][96].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [87] Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59:1116–27. source
- Not checked yetcites [93] Nibuya M, Morinobu S, Duman RS. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci. 1995;15:7539–47. source
- Not checked yetcites [94] Malberg J, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult hippocampus. J Neurosci. 2000;20:9104–10. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The dentate gyrus is a unique source of ongoing neurogenesis in the adult brain, at least in nonhuman animals, and there is preclinical evidence that the birth and maturation of new granule cells may play a role in depression and antidepressant drug actions [89].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [89] Tartt AN, Mariani MB, Hen R, Mann JJ, Boldrini M Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications. Mol Psychiatry. 2022;27:2689-99; https://doi.org/10.1038/s41380-022-01520-y. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“A neurotrophic hypothesis of depression has been proposed, which posits that a decrease in neurotrophic factor signaling as the root of dysgenesis of dentate granule cells and atrophy of dendrites and synapses in depressed brain [87,97,98].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [87] Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59:1116–27. source
- Not checked yetcites [97] Duman RS, Li N. A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists. Philos Trans R Soc Lond B Biol Sci. 2012;367:2475–84. source
- Not checked yetcites [98] Castrén E, Monteggia LM. Brain-derived neurotrophic factor signaling in depression and antidepressant action. Biol Psychiatry. 2021;90:128–36. source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“In area CA3, chronic stress enhances synaptic currents mediated by NMDARs but has no effect on AMPARs [109].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [109] Kole MHP, Swan L, Fuchs E. The antidepressant tianeptine persistently modulates glutamate receptor currents of the hippocampal CA3 commissural associational synapse in chronically stressed rats. Eur J Neurosci. 2002;16:807–16. source
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In the paper
“This hypothesis is complementary to the suggestion that stimulation of neurotrophic signaling and neurogenesis by antidepressants explains their therapeutic actions [99][100][101].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [99] Dranovsky A, Hen R. Hippocampal neurogenesis: regulation by stress and antidepressants. Biol Psychiatry. 2006;59:1136–43. source
- Not checked yetcites [100] Sahay A, Hen R. Adult hippocampal neurogenesis in depression. Nat Neurosci. 2007;10:1110–5. source
- Not checked yetcites [101] Anacker C, Zunszain PA, Cattaneo A, Carvalho LA, Garabedian MJ, Thuret S, et al. Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor. Mol Psychiatry. 2011;16:738–50. source
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Beyond dendritic atrophy, there are dramatic alterations in synaptic structure and function in animal models based on chronic stress [104], including altered synaptic currents [105], deficits in synaptic plasticity in CA1 and DG [106], and impaired local circuit function [107].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [104] Krugers HJ, Hoogenraad CC, Groc L. Stress hormones and AMPA plasticity and memory. Nat Rev Neurosci. 2010;11:675–81. source
- Not checked yetcites [105] Karst H, Joëls M. Effect of chronic stress on synaptic currents in rat hippocampal dentate gyrus neurons. J Neurophysiol. 2003;89:625–33. source
- Not checked yetcites [106] Alfarez DN, Joëls M, Krugers HJ. Chronic unpredictable stress impairs long-term potentiation in rat hippocampal CA1 area and dentate gyrus in vitro. Eur J Neurosci. 2003;17:1928–34. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In contrast, chronic stress has no effect on basal synaptic strength at Schaffer collateral (SC) synapses in area CA1, although it does impair SC-CA1 long-term potentiation (LTP) [106,110].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [106] Alfarez DN, Joëls M, Krugers HJ. Chronic unpredictable stress impairs long-term potentiation in rat hippocampal CA1 area and dentate gyrus in vitro. Eur J Neurosci. 2003;17:1928–34. source
- Not checked yetcites [110] Kallarackal AJ, Kvarta MD, Cammarata E, Jaberi L, Cai X, Bailey AM, et al. Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses. J Neurosci. 2013;33:15669–74. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In contrast, at the temporoammonic (TA) synapses formed by entorhinal cortical afferents to the distal dendrites of CA1 pyramidal cells, where atrophy is most apparent, AMPARmediated basal synaptic transmission is impaired by chronic stress or exogenous corticosteroid administration, but LTP is unaffected [36,110].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [36] Kvarta MD, Bradbrook KE, Dantrassy HM, Bailey AM, Thompson SM. Corticosterone mediates the synaptic and behavioral effects of chronic stress at rat hippocampal temporoammonic synapses. J Neurophysiol. 2015;114:1713–24. source
- Not checked yetcites [110] Kallarackal AJ, Kvarta MD, Cammarata E, Jaberi L, Cai X, Bailey AM, et al. Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses. J Neurosci. 2013;33:15669–74. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“The explanatory power of neurogenesis in depression and antidepressant drug effects is complicated by the fact that neurogenesis is only observed in the dentate gyrus, putting a severe limit on the possible depression symptom domains it can impact, and by recent findings that neurogenesis may be very limited or absent in humans [102].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [102] Franjic D, Skarica M, Ma S, Arellano JI, Tebbenkamp ATN, Choi J, et al. Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells. Neuron. 2022;110:452–69. source
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“In this regard, it is important to recognize that the effects of acute stress are generally adaptive and very different from the maladaptive consequences of chronic stress [104].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [104] Krugers HJ, Hoogenraad CC, Groc L. Stress hormones and AMPA plasticity and memory. Nat Rev Neurosci. 2010;11:675–81. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In the hippocampus, several types of chronic stress cause a loss of distal apical dendritic branches in CA3 and CA1 pyramidal cells and a loss in the size and number of dendritic spines [71,74,108].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [71] Watanabe Y, Gould E, McEwen BS. Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res. 1992;588:341–5. source
- Not checked yetcites [74] Magariños AM, McEwen BS, Flügge G, Fuchs E. Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews. J Neurosci. 1996;16:3534–40. source
- Not checked yetcites [108] Sousa N, Lukoyanov NV, Madeira MD, Almeida OFX, Paula-Barbosa MM. Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement. Neuroscience. 2000;97:253–66. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“How this compares to human GluA1 gene SNPs was not described, but this evidence converges with human data implicating AMPARs [115].Gene clusters associated with excitatory synaptic function are also commonly identified in genetic screens in suicide and depression [116][117][118] and in preclinical studies [119].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [115] Freed WJ, Dillon-Carter O, Kleinman JE. Properties of [3H]AMPA binding in postmortem human brain from psychotic subjects and controls: increases in caudate nucleus associated with suicide. Exp Neurol. 1993;121:48–56. source
- Not checked yetcites [116] Sequeira A, Mamdani F, Ernst C, Vawter MP, Bunney WE, Lebel V, et al. Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PLoS One. 2009;4:e6585. source
- Not checked yetcites [117] Sokolowski M, Wasserman J, Wasserman D. Gene-level associations in suicide attempter families show overrepresentation of synaptic genes and genes differentially expressed in brain development. Am J Med Genet B Neuropsychiatr Genet. 2018;177:774–84. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Chronic adolescent stress in female rats caused a decrease in hippocampal SC-CA1 synaptic strength in adults, accompanied by impaired cognitive flexibility [112].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [112] Hyer MM, Shaw GA, Goswamee P, Dyer SK, Burns CM, Soriano E, et al. Chronic adolescent stress causes sustained impairment of cognitive flexibility and hippocampal synaptic strength in female rats. Neurobiol Stress. 2021;14:100303. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Serotonin increases phosphorylation of AMPA receptors and increases their delivery to the cell surface [123], an effect that is mimicked by the tricyclic antidepressant imipramine”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [123] Andreetta F, Carboni L, Grafton G, Jeggo R, Whyment AD, van den Top M, et al. Hippocampal 5-HT7 receptors signal phosphorylation of the GluA1 subunit to facilitate AMPA receptor mediated-neurotransmission in vitro and in vivo. Br J Pharm. 2016;173:1438–51. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The power of gamma oscillations contributes to working memory capacity, is reduced in patients with MDD, and is normalized with symptomatic remission [121].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [121] Arikan MK, Metin B, Tarhan N. EEG gamma synchronization is associated with response to paroxetine treatment. J Affect Disord. 2018;235:114–6. source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together these data make a strong argument that disruption of hippocampal glutamatergic transmission, specifically AMPAR function, accompanies and may cause the depression-like behavioral state seen in preclinical models.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We concluded that the antidepressant actions of SSRIs are mediated, in part, by a rapid insertion of AMPARs into synapses, due to 5HT 1B R-dependent activation of CaMK and phosphorylation of GluA1 subunits at serine 831, a mechanism shared with canonical NMDAR-dependent long-term potentiation, as well as a slower restoration in GluA1 expression levels.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“GABAergic inhibition is also affected by chronic stress [122] and may contribute to the altered balance of excitation and inhibition as well as defects in ensemble activity.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [122] Alaiyed S, McCann M, Mahajan G, Rajkowska G, Stockmeier CA, Kellar KJ, et al. Venlafaxine stimulates an MMP-9-dependent increase in excitatory/inhibitory balance in a stress model of depression. J Neurosci. 2020;40:4418–31. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“On a network level, chronic stress deceases the spatial tuning of hippocampal cell discharges, as well as the power of gamma oscillations in local field potentials [120].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [120] Tomar A, Polygalov D, McHugh TJ. Differential impact of acute and chronic stress on CA1 spatial coding and gamma oscillations. Front Behav Neurosci. 2021;15:710725. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Fluoxetine also produces rapid disinhibition in hippocampal brain slices [128], which could also contribute to a net increase in excitation in vivo.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [128] Méndez P, Pazienti A, Szabo G, Bacci A. Direct alteration of a specific inhibitory circuit of the hippocampus by antidepressants. J Neurosci. 2012;32:16616–28. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Extensive experience with human patients has established that ketamine exerts rapid, robust antidepressant, antianhedonic, and antisuicidal actions within two hours of administration that are sustained for at least seven days in patients with major depression following a single infusion or intranasal administration [129-133].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [129] Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351–4. source
- Not checked yetcites [130] Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856–64. source
- Not checked yetcites [131] DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA, et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry. 2010;71:1605–11. source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Zanos et al. [153] reported that the behavioral actions of ketamine in mice could be eliminated by deuterating the molecule to greatly reduce its rate of hydrolysis, suggesting that ketamine's inhibition of NMDARs is not sufficient for its antidepressant actions.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [153] Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533:481–6. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This hypothesis cannot be readily applied to other fast acting antidepressant compounds that do not target NMDARs.It is also difficult to reconcile with findings that other NMDAR antagonists that do not appear to have antidepressant activity.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Ketamine also exerts strong antidepressant-like actions in preclinical models, including restoration of reward behavior in chronically stressed animals, promotion of dendritic spine formation, restoration of synaptic strength, and promotion of expression of pro-synaptic genes [45].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [45] Zanos P, Thompson SM, Duman RS, Zarate CA, Gould TD. Convergent mechanisms underlying rapid antidepressant action. CNS Drugs. 2018;32:197–227. source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“As predicted, acute inhibition of eEF2K increases mEPSC amplitude in cultured hippocampal cells and occludes the actions of ketamine on mEPSC amplitude [159].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [159] Suzuki K, Kim JW, Nosyreva E, Kavalali ET, Monteggia LM. Convergence of distinct signaling pathways on synaptic scaling to trigger rapid antidepressant action. Cell Rep. 2021;37:109918. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Finally, it was observed that five days of treatment with the monoaminergic antidepressant citalopram failed to produce antidepressant behavioral effects in mice but did decrease phosphorylation of eEF2 levels [160].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [160] Opal MD, Klenotich SC, Morais M, Bessa J, Winkle J, Doukas D, et al. Serotonin 2C receptor antagonists induce fast-onset antidepressant effects. Mol Psychiatry. 2014;19:1106–14. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Lastly, there is an exciting recent hypothesis that ketamine may exert its antidepressant actions not by blocking NMDARs, but rather by its neuroactive metabolites, particularly the hydroxynorketamines (HNKs).”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [153] Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533:481–6. source
hedgedconditional- Asserted: fails — The authors may not put it forward as true.
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Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“This hypothesis posits that ketamine restores stress-impaired excitatory synapses by blocking a subset of NMDARs that are preferentially activated by spontaneous glutamate release.”
- Also stated in: § THE HIPPOCAMPUS · plain
“As a result, synaptic AMPAR expression is increased [154, 159].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [154] Kavalali ET, Monteggia LM. Targeting homeostatic synaptic plasticity for treatment of mood disorders. Neuron 2020;106:715–26. source
- Not checked yetcites [155] Sutton MA, Taylor AM, Ito HT, Pham A, Schuman EM. Postsynaptic decoding of neural activity: eEF2 as a biochemical sensor coupling miniature synaptic transmission to local protein synthesis. Neuron. 2007;55:648–61. source
- Not checked yetcites [159] Suzuki K, Kim JW, Nosyreva E, Kavalali ET, Monteggia LM. Convergence of distinct signaling pathways on synaptic scaling to trigger rapid antidepressant action. Cell Rep. 2021;37:109918. source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
- Also stated in: § THE HIPPOCAMPUS · plain
In the paper
“Loneliness, for example, is caused by perceived social isolation and absence of companionship and is associated with increased risk for depression and suicide [171].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [171] McClelland H, Evans JJ, Nowland R, Ferguson E, O’Connor RC. Loneliness as a predictor of suicidal ideation and behaviour: a systematic review and meta-analysis of prospective studies. J Affect Disord. 2020;274:880–96. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“Antidepressant relevant effects reported for AMPAkines include decreased immobility in the FST, promotion of BDNF expression, amplification of ketamine effects, and increased neurogenesis in the dentate gyrus [163][164][165][166].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [163] Li X, Tizzano JP, Griffey K, Clay M, Lindstrom T, Skolnick P. Antidepressant-like actions of an AMPA receptor potentiator (LY392098). Neuropharmacol. 2001;40:1028–33. source
- Not checked yetcites [164] Bai F, Bergeron M, Nelson DL. Chronic AMPA receptor potentiator (LY451646) treatment increases cell proliferation in adult rat hippocampus. Neuropharmacol. 2003;44:1013–21. source
- Not checked yetcites [165] Farley S, Apazoglou K, Witkin JM, Giros B, Tzavara ET. Antidepressant-like effects of an AMPA receptor potentiator under a chronic mild stress paradigm. Int J Neuropsychopharmacol. 2010;13:1207–18. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Direct administration of HNKs mimicked the behavioral actions of ketamine in mice, promoted EEG gamma oscillations, promoted expression of AMPARs and BDNF, and decreased phosphorylation of eEF2 levels in the hippocampus, providing plenty of mechanisms that could be triggered independently from NMDAR inhibition.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
What the sources say
- Not checked yetcites [153] Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533:481–6. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“but it is important to recognize that there is strong evidence that their functions are not identical and may display sex differences [167].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [167] Wallace T, Myers B. Effects of Biological Sex and Stress Exposure on Ventromedial Prefrontal Regulation of Mood-Related Behaviors. Front Behav Neurosci. 2021;15:737960. source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“An essential adaptive skill of all animals is to learn to associate a rewarding experience with the sensory cues and actions in the environment that can be used to predict their future occurrence.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“These cognitive maps of rewards underlie all goaldirected behaviors, providing an adaptive benefit of permitting flexible decision-making optimized for both interoceptive state and environmental availability.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“It also regulates the negative ruminative thinking that can indirectly have an adverse impact on cognition and mood [178].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [178] Lewis EJ, Blanco I, Raila H, Joormann J. Does repetitive negative thinking affect attention? Differential effects of worry and rumination on attention to emotional stimuli. Emotion. 2019;19:1450–62. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Electrophysiological activity in the PFC encodes potential choice options and computes their comparison in the currently relevant environment.PFC output then turns these computations into actual actions [170].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [170] Klein-Flügge MC, Bongioanni A, Rushworth MFS. Medial and orbital frontal cortex in decision-making and flexible behavior, Neuron 2022; https://doi.org/10.1016/j.neuron.2022.05.022 source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Deficits in PFC synaptic excitation and imbalances between excitation and inhibition would have obvious impact on these calculations.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“On the other hand, social support is one of the strongest predictors of resilience and increasing social support can provide a beneficial component of effective therapeutic approaches [172].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [172] Pearce E, Myles-Hooton P, Johnson S, Hards E, Olsen S, Clisu D, et al. Loneliness as an active ingredient in preventing or alleviating youth anxiety and depression: a critical interpretative synthesis incorporating principles from rapid realist reviews. Transl Psychiatry. 2021;11:628. source
plainconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In the human brain, activity increases as cues and stimuli become relevant to decisions, with the magnitude of this increase directly proportional to the outcome and reliability of the decision [173].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [173] Grueschow M, Polania R, Hare TA, Ruff CC. Automatic versus choice-dependent value representations in the human brain. Neuron. 2015;85:874–85. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Measured with fMRI, the PFC of depressed patients displays evidence of reduced volume, activity, and connectivity.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Stress induced decision-making deficits in MDD patients are reversible: after one month of reduced stress, subjects were indistinguishable from controls [196].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [196] Soares JM, Sampaio A, Ferreira LM, Santos NC, Marques F, Palha JA, et al. Stress-induced changes in human decision-making are reversible. Transl Psychiatry. 2012;2:e131. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Furthermore, co-administration of the mTOR inhibitor rapamycin prevented the induction of dendritic spines by ketamine, as well as ketamine's actions in the FST and other behaviors [202].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [202] Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As discussed above, inhibition of interneurons may promote the kinds of high frequency oscillatory activity in pyramidal cells that underlies gamma oscillations, as seen in human and rodent EEGs, and, in turn, promotes endogenous activity-dependent mechanisms that strengthen stress-impaired excitatory synapses, such as LTP and BDNF-trkB signaling.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The nucleus accumbens in the ventral striatum is an essential integrator of input pathways from the prefrontal cortex, hippocampus, and amygdala and is critical for determining motivating and reinforcing responses to rewarding stimuli and avoidance responses to aversive stimuli [215][216][217].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [215] Volkow ND, Wise RA, Baler R. The dopamine motive system: implications for drug and food addiction. Nat Rev Neurosci. 2017;18:741–52. source
- Not checked yetcites [216] Floresco SB. The nucleus accumbens: an interface between cognition, emotion, and action. Annu Rev Psychol. 2015;66:25–52. source
- Not checked yetcites [217] Bayassi-Jakowicka M, Lietzau G, Czuba E, Steliga A, Waśkow M, Kowiański P. Neuroplasticity and multilevel system of connections determine the integrative role of nucleus accumbens in the brain reward system. Int J Mol Sci. 2021;22:9806. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Many of these forms of activity-dependent plasticity are likely to be NMDAR-dependent, as supported by the antidepressant-like actions of the NMDAR positive allosteric modulator GLYX-13 (rapastinel) in preclinical models [213].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [213] Liu RJ, Duman C, Kato T, Hare B, Lopresto D, Bang E, et al. GLYX-13 produces rapid antidepressant responses with key synaptic and behavioral effects distinct from ketamine. Neuropsychopharmacol. 2017;42:1231–42. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The NAc is divided into two histologically distinct subregions, the core and the shell, which have unique patterns of inputs and outputs [218,219] and are thought to serve distinct, but similar functions [177].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [218] Heimer L, Zahm DS, Churchill L, Kalivas PW, Wohltmann C. Specificity in the projection patterns of accumbal core and shell in the rat. Neurosci. 1991;41:89–125. source
- Not checked yetcites [219] Brog JS, Salyapongse A, Deutch AY, Zahm DS. The patterns of afferent innervation of the core and shell in the “accumbens” part of the rat ventral striatum: immunohistochemical detection of retrogradely transported fluoro-gold. J Comp Neurol. 1993;338:255–78. source
- Not checked yetcites [177] Berridge KC, Kringelbach ML. Pleasure systems in the brain. Neuron. 2015;86:646–64. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Ketamine's disinhibitory action in dendrites also promotes dendritic Ca 2+ influx [214], providing an additional mechanism to drive endogenous activitydependent synaptic strengthening mechanisms.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [214] Ali F, Gerhard DM, Sweasy K, Pothula S, Pittenger C, Duman RS, et al. Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines. Nat Commun. 2020;11:72.
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“As in the hippocampus, ketamine inhibits the discharge of interneurons in the PFC and reduces spontaneous IPSCs in pyramidal cells acutely [210], while restoring inhibition at later timepoints corresponding to its behavioral actions [211].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE PREFRONTAL CORTICES
What the sources say
- Not checked yetcites [210] Gerhard DM, Pothula S, Liu RJ, Wu M, Li XY, Girgenti MJ, et al. GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions. J Clin Invest. 2020;130:1336–49. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Activation of inputs to the NAc from the hippocampus and PFC is rewarding and reinforcing of rewarding stimuli [227,228].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [227] Britt JP, Benaliouad F, McDevitt RA, Stuber GD, Wise RA, Bonci A. Synaptic and behavioral profile of multiple glutamatergic inputs to the nucleus accumbens. Neuron. 2012;76:790–803. source
- Not checked yetcites [228] Otis JM, Namboodiri VM, Matan AM, Voets ES, Mohorn EP, Kosyk O, et al. Prefrontal cortex output circuits guide reward seeking through divergent cue encoding. Nature. 2017;543:103–7. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Nevertheless, activity in D1 MSNs is more likely to be associated with motivation, reward, and positive responses [193,[223][224][225] and resilience to stress [226].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [193,[223][224][225]
- Not checked yetcites [226] Francis TC, Chandra R, Friend DM, Finkel E, Dayrit G, Miranda J, et al. Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress. Biol Psychiatry. 2015;77:212–22. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In contrast, MSNs expressing D2-type dopamine receptors, canonically considered the 'indirect' pathway, project to GABAergic cells within the ventral pallidum, that then project to the interneurons within the VTA.Activation of D2-expressing MSNs thereby inhibits activation of dopamine projections back to the forebrain by disinhibiting the interneurons that silence them.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [220] Watabe-Uchida M, Eshel N, Uchida N. Neural circuitry of reward prediction error. Annu Rev Neurosci. 2017;40:373–94. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“As originally described in the dorsal striatum, MSNs expressing D1-type dopamine receptors, canonically considered the 'direct' pathway, project to and inhibit GABAergic interneurons within the VTA that, in turn, inhibit VTA dopamine releasing cells.Activation of D1-expressing MSNs thereby promotes activation of dopamine projections back to the forebrain by disinhibiting them [220].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [220] Watabe-Uchida M, Eshel N, Uchida N. Neural circuitry of reward prediction error. Annu Rev Neurosci. 2017;40:373–94. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Chronic, but not acute, administration of fluoxetine to stressed mice restores the strength of hippocampal excitatory synapses in D1 MSNs and their ability to undergo LTP, concomitant with restoration of sucrose preference [193].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [193] LeGates TA, Kvarta MD, Tooley JR, Francis TC, Lobo MK, Creed MC, et al. Reward behaviour is regulated by the strength of hippocampus-nucleus accumbens synapses. Nature. 2018;564:258–62. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Lim et al. [236] demonstrated that preventing stress-induced AMPA receptor loss in D1 MSNs was sufficient to prevent stress-induced loss of hedonic responses in sucrose preference and cocaine-induced place preference (although not the FST).”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [236] Lim BK, Huang KW, Grueter BA, Rothwell PE, Malenka RC. Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens. Nature 2012;487:183–9. source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Susceptibility to chronic social defeat stress is accompanied by atrophy of MSN dendrites, specifically in D1 MSNs and not D2 MSNs, and a corresponding loss of dendritic spines [226,234,235].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [226] Francis TC, Chandra R, Friend DM, Finkel E, Dayrit G, Miranda J, et al. Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress. Biol Psychiatry. 2015;77:212–22. source
- Not checked yetcites [234] Francis TC, Chandra R, Gaynor A, Konkalmatt P, Metzbower SR, Evans B, et al. Molecular basis of dendritic atrophy and activity in stress susceptibility. Mol Psychiatry. 2017;22:1512–19. source
- Not checked yetcites [235] Fox ME, Chandra R, Menken MS, Larkin EJ, Nam H, Engeln M, et al. Dendritic remodeling of D1 neurons by RhoA/Rho-kinase mediates depression-like behavior. Mol Psychiatry. 2020;25:1022–34. source
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In the paper
“There is evidence that the NAc is activated by reward anticipation and both motivational and hedonic aspects of reward processing [245].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [245] Pool ER, Munoz Tord D, Delplanque S, Stussi Y, Cereghetti D, Vuilleumier P, et al. Differential contributions of ventral striatum subregions to the motivational and hedonic components of the affective processing of reward. J Neurosci. 2022;42:2716–28. source
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In the paper
“Excitatory synapses onto LHb cells are characterized by a high ratio of AMPAR-to NMDAR-mediated synaptic responses [255], indicative of low levels of NMDAR expression.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE LATERAL HABENULA
What the sources say
- Not checked yetcites [255] Li B, Piriz J, Mirrione M, Chung C, Proulx CD, Schulz D, et al. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature. 2011;470:535–9. source
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In the paper
“There is limited evidence of the effect of antidepressants on these measures of reward circuit function, but it has been shown that improvements in self-reported depression severity and negative affective bias are improved with chronic SSRI administration in depressed patients and are strongly correlated with increases in NAc activity and NAc-PFC connectivity [249].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [249] Heller AS, Johnstone T, Light SN, Peterson MJ, Kolden GG, Kalin NH, et al. Davidson RJ. Relationships between changes in sustained fronto-striatal connectivity and positive affect in major depression resulting from antidepressant treatment. Am J Psychiatry. 2013;170:197–206. source
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In the paper
“Unmedicated MDD patients show deficits in reward learning, reduced responses in the ventral striatum for positive prediction errors in a reward task, and reduced NAc-VTA connectivity [247,248].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE NUCLEUS ACCUMBENS
What the sources say
- Not checked yetcites [247] Kumar P, Goer F, Murray L, Dillon DG, Beltzer ML, Cohen AL, et al. Impaired reward prediction error encoding and striatal-midbrain connectivity in depression. Neuropsychopharmacol. 2018;43:1581–8. source
- Not checked yetcites [248] Reinen JM, Whitton AE, Pizzagalli DA, Slifstein M, Abi-Dargham A, McGrath PJ, et al. Differential reinforcement learning responses to positive and negative information in unmedicated individuals with depression. Eur Neuropsychopharmacol. 2021;53:89–100. source
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In the paper
“The lateral habenula (LHb) is another key node in regulation of reward behaviors that has been implicated in the genesis of depressive symptoms and reward dysregulation [252].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE LATERAL HABENULA
What the sources say
- Not checked yetcites [252] Lecca S, Meye FJ, Mameli M. The lateral habenula in addiction and depression: an anatomical, synaptic and behavioral overview. Eur J Neurosci. 2014;39:1170–8. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“LHb neurons fire in response to both aversive stimuli and the absence of an expected reward [257-260].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE LATERAL HABENULA
What the sources say
- Not checked yetcites [257] Matsumoto M, Hikosaka O. Representation of negative motivational value in the primate lateral habenula. Nat Neurosci. 2009;12:77–84. source
- Not checked yetcites [258] Lecca S, Meye FJ, Trusel M, Tchenio A, Harris J, Schwarz MK, et al. Aversive stimuli drive hypothalamus-to-habenula excitation to promote escape behavior. Elife. 2017;6:1–16. source
- Not checked yetcites [259] Cerniauskas I, Winterer J, de Jong JW, Lukacsovich D, Yang H, Khan F, et al. Chronic Stress Induces Activity, Synaptic, and Transcriptional Remodeling of the Lateral Habenula Associated with Deficits in Motivated Behaviors. Neuron. 2019;104:899–915. source
- Not checked yetcites [260] Zheng Z, Guo C, Li M, Yang L, Liu P, Zhang X, et al. Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset. Neuron. 2022;110:1400–15. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Optogenetic activation of LHb neurons via projections from the lateral hypothalamic nucleus (LH) triggers avoidance and escape behaviors, whereas optogenetic or pharmacological inhibition of LHb cell discharge impairs avoidance and escape in response to aversive stimuli [258][259][260].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE LATERAL HABENULA
What the sources say
- Not checked yetcites [258] Lecca S, Meye FJ, Trusel M, Tchenio A, Harris J, Schwarz MK, et al. Aversive stimuli drive hypothalamus-to-habenula excitation to promote escape behavior. Elife. 2017;6:1–16. source
- Not checked yetcites [259] Cerniauskas I, Winterer J, de Jong JW, Lukacsovich D, Yang H, Khan F, et al. Chronic Stress Induces Activity, Synaptic, and Transcriptional Remodeling of the Lateral Habenula Associated with Deficits in Motivated Behaviors. Neuron. 2019;104:899–915. source
- Not checked yetcites [260] Zheng Z, Guo C, Li M, Yang L, Liu P, Zhang X, et al. Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset. Neuron. 2022;110:1400–15. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“With regard to behaviors typically used to study depression and antidepressant drugs, acute physical restraint, foot shock, tail suspension, forced swimming, and social defeat are all accompanied by strong LHb activation [258,260].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE LATERAL HABENULA
What the sources say
- Not checked yetcites [258] Lecca S, Meye FJ, Trusel M, Tchenio A, Harris J, Schwarz MK, et al. Aversive stimuli drive hypothalamus-to-habenula excitation to promote escape behavior. Elife. 2017;6:1–16. source
- Not checked yetcites [260] Zheng Z, Guo C, Li M, Yang L, Liu P, Zhang X, et al. Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset. Neuron. 2022;110:1400–15. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“RMTg neurons, in turn, project to the VTA and are largely responsible for the predominantly inhibitory action of LHb projections onto VTA dopaminergic neurons [256].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE LATERAL HABENULA
What the sources say
- Not checked yetcites [256] Ji H, Shepard PD. Lateral habenula stimulation inhibits rat midbrain dopamine neurons through a GABA(A) receptor-mediated mechanism. J Neurosci. 2007;27:6923–30. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Increased numbers of burst-firing LHb neurons were observed in vitro and in vivo in both a rat strain with congenital learned helplessness and in wild type rats after chronic restraint stress, although no overall change in membrane potential was reported [266].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE LATERAL HABENULA
What the sources say
- Not checked yetcites [266] Yang LM, Hu B, Xia YH, Zhang BL, Zhao H. Lateral habenula lesions improve the behavioral response in depressed rats via increasing the serotonin level in dorsal raphe nucleus. Behav Brain Res. 2008;188:84–90. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Lesioning or pharmacologically silencing the LHb can normalize learned helplessness responses [266,268], including inhibition of NMDAR-mediated LHb bursting [264].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE LATERAL HABENULA
What the sources say
- Not checked yetcites [266] Yang LM, Hu B, Xia YH, Zhang BL, Zhao H. Lateral habenula lesions improve the behavioral response in depressed rats via increasing the serotonin level in dorsal raphe nucleus. Behav Brain Res. 2008;188:84–90. source
- Not checked yetcites [268] Winter C, Vollmayr B, Djodari-Irani A, Klein J, Sartorius A. Pharmacological inhibition of the lateral habenula improves depressive-like behavior in an animal model of treatment resistant depression. Behav Brain Res. 2011;216:463–5. source
- Not checked yetcites [264] Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature. 2018a;554:317–22. source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Selective activity-dependent potentiation of synapses formed by axons of LH neurons with LHb neurons promoted LHb discharge and was sufficient to induce mimic the behavioral effects of chronic stress in the forced swim and sucrose preference tests [260, 267].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE LATERAL HABENULA
What the sources say
- Not checked yetcites [260] Zheng Z, Guo C, Li M, Yang L, Liu P, Zhang X, et al. Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset. Neuron. 2022;110:1400–15. source
- Not checked yetcites [267] Li K, Zhou T, Liao L, Yang Z, Wong C, Henn F, et al. βCaMKII in lateral habenula mediates core symptoms of depression. Science. 2013;341:1016–20. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Optogenetically induced increases in burst firing in LHb neurons increased mobility in the FST and decreased sucrose preference [266], like the effects of chronic stress.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE LATERAL HABENULA
What the sources say
- Not checked yetcites [266] Yang LM, Hu B, Xia YH, Zhang BL, Zhao H. Lateral habenula lesions improve the behavioral response in depressed rats via increasing the serotonin level in dorsal raphe nucleus. Behav Brain Res. 2008;188:84–90. source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Increased burst discharges [264] are attributed to dysregulation of the astrocytic K + channels that regulate extracellular K + concentrations, thereby promoting hyperpolarization of LHb neurons [265], although this hyperpolarization was not shown.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE LATERAL HABENULA
What the sources say
- Not checked yetcites [264] Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature. 2018a;554:317–22. source
- Not checked yetcites [265] Cui Y, Yang Y, Ni Z, Dong Y, Cai G, Foncelle A, et al. Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression. Nature. 2018;554:323–7. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, hypoactive PFC circuits might be more heavily affected in patients with more prevalent cognitive and decision-making symptoms.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
hedgedcorrelational- Asserted: fails — The authors may not put it forward as true.
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Probably not a substantial claim. The authors may not put it forward as true.
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In the paper
“There is also robust preclinical evidence that psilocybin can restore both reward behaviors and synapse structure and function.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
What the sources say
- Not checked yetcites [275] Hesselgrave N, Troppoli TA, Wulff AB, Cole AB, Thompson SM. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proc Natl Acad Sci. 2021;118:e2022489118. source
- Not checked yetcites [276] Shao LX, Liao C, Gregg I, Davoudian PA, Savalia NK, Delagarza K, et al. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron 2021;109:2535–.e4. source
boosteddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Driving the LHb may overpower counterbalancing NAc inputs to the VTA, for example, regardless of whether they are fully functional or dysfunctional.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In general, the synaptic changes result in a weakening of pathways that promote dopamine release by activating cells in the VTA, such as the direct and indirect weakening of excitatory drive of D1 MSNs in the NAc, and potentiation of pathways inhibiting dopamine secretion, such as those within the LH-LHb-RMTg.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although there is overlap, some favor activity-dependent synaptic strengthening mechanisms, such as ketamine and ketamine metabolites, whereas others, such as SSRIs, favor neurotrophic growth factor signaling.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Considering emotional dysregulation [271], for example, an overactive LHb circuit may favor an increase in negative affect.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
What the sources say
- Not checked yetcites [271] Hofmann SG, Sawyer AT, Fang A, Asnaani A. Emotion dysregulation model of mood and anxiety disorders. Depress Anxiety. 2012;29:409–16. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These concerted changes in synapses in response to chronic stress have been found in essentially every circuit in every reward pathway, providing a mechanistic explanation for the wide range of symptoms that together constitute the clinical definition of depression.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Those antidepressants that restore synaptic strength slowly, such as SSRIs, restore synaptic strength slowly, whereas fast acting antidepressants do so rapidly.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Excitatory synapses generally become reduced in number and weaker in areas devoted to directing attention and making decisions about cues and stimuli and stronger in the pathways processing negative valence stimuli.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These synapses are the working elements of the circuits they are embedded in and hence are could be the cause of significant changes in the function of those circuits.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Similarly, in the PFC, psilocybin administration to unstressed mice leads to an increase in the net formation of new dendritic spines in pyramidal cells, persisting for over one month, which is accompanied by an increase in the frequency of spontaneous mEPSCs [276].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
What the sources say
- Not checked yetcites [276] Shao LX, Liao C, Gregg I, Davoudian PA, Savalia NK, Delagarza K, et al. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron 2021;109:2535–.e4. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Taking hippocampal brain slices from these same mice revealed that psilocybin also restored the strength of the stress-sensitive TA-CA1 synapses, concurrent with the restoration of reward behavior, again much like other fastacting antidepressants.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
What the sources say
- Not checked yetcites [275] Hesselgrave N, Troppoli TA, Wulff AB, Cole AB, Thompson SM. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proc Natl Acad Sci. 2021;118:e2022489118. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“such as AZD6765 [149], mGluR 2/3 antagonists [150], alpha5 subunit-selective GABA A R-NAMs [151, 152], and the ketamine metabolite (2 R,6 R)-HNK [153], all of which enhance EEG power in the gamma frequency band.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
What the sources say
- Not checked yetcites [149] Sanacora G, Smith MA, Pathak S, Su HL, Boeijinga PH, McCarthy DJ, et al. Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects. Mol Psychiatry. 2014;19:978–85. source
- Not checked yetcites [150] Ahnaou A, Ver Donck L, Drinkenburg WH. Blockade of the metabotropic glutamate (mGluR2) modulates arousal through vigilance states transitions: evidence from sleep-wake EEG in rodents. Behav Brain Res. 2014;270:56–67. source
- Not checked yetcites [153] Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533:481–6. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Many of the same processes described above are likely to be involved, including neurotrophin signaling and enzymatic cascades promoting receptor trafficking and process outgrowth [278].”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > FUTURE RESEARCH DIRECTIONS: PUTTING IT ALL TOGETHER
What the sources say
- Not checked yetcites [278] Ly C, Greb AC, Cameron LP, Wong JM, Barragan EV, Wilson PC, et al. Psychedelics Promote Structural and Functional Neural Plasticity. Cell Rep. 2018;23:3170–3182. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The authors state this as an assumption.
Chronic stress produced experimentally in animals provides a realistic model of human depression.
“An underlying assumption of all preclinical models is that the forms of chronic stress we produce experimentally in our animals provides a realistic model of human depression.”
The paper relies on this without support.
Environmental factors account for only about 60% of the risk for major depressive disorder.
“On the other hand, environmental factors are believed to account for only 60% of risk for MDD.”
The paper relies on this without support.
Overall genetic risk for major depressive disorder arises from small differences in many genes, each contributing a small amount to overall risk.
“Given the likelihood that overall genetic risk results from small differences in large numbers of genes, each with small contributions to overall risk, this blind spot represents a particular short coming in our current understanding and significant experimental challenge for future progress.”
The paper relies on this without support.
The serotonin 2A receptor mediates the mind-altering effects of psychedelics.
“the serotonin 2 A receptor that mediates the mind-altering properties of psychedelics”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Ketamine produces rapid changes in structural and functional connectivity within many regions associated with reward, emotion, and cognitive function, likely by acting on glutamate and increasing excitation in hypoactive regions of the brain, as previously reviewed [44, 111].”
From Beyond the serotonin deficit hypothesis: Communicating a neuroplasticity framework of major depressive disorder (2024) · cites this paper as [44]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE LATERAL HABENULA
“Optogenetically induced increases in burst firing in LHb neurons increased mobility in the FST and decreased sucrose preference [266], like the effects of chronic stress.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > THE HIPPOCAMPUS
“Antidepressant relevant effects reported for AMPAkines include decreased immobility in the FST, promotion of BDNF expression, amplification of ketamine effects, and increased neurogenesis in the dentate gyrus [163][164][165][166].”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > Conflict
“The authors declare no competing interests.”
§ Plasticity of synapses and reward circuit function in the genesis and treatment of depression > Contribution
“The University of Maryland, Baltimore, has filed multiple patents for novel antidepressant therapeutic approaches on which the author is listed as an inventor.”
Citations
Cites
Molecular Mechanisms of Depression: Perspectives on New Treatment Strategies
Lang, U. E., & Borgwardt, S. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350094 · Cited by 8,526
The cognitive control of emotion
OCHSNER, K., & GROSS, J. (2005) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2005.03.010 · Cited by 4,495
Antidepressant effects of ketamine in depressed patients
Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00230-9 · Cited by 3,856
A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
Zarate, C. A., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., Charney, D. S., & Manji, H. K. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.8.856 · Cited by 3,766
The Neuroendocrinology of Stress: A Never Ending Story
Lightman, S. L. (2008) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2008.01711.x · Cited by 3,588
A Neurotrophic Model for Stress-Related Mood Disorders
Duman, R. S., & Monteggia, L. M. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.02.013 · Cited by 3,375
Nestler, E. J., Barrot, M., DiLeone, R. J., Eisch, A. J., Gold, S. J., & Monteggia, L. M. (2002) · Neuron · doi:10.1016/s0896-6273(02)00653-0 · Cited by 3,217
Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus
Malberg, J. E., Eisch, A. J., Nestler, E. J., & Duman, R. S. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-24-09104.2000 · Cited by 3,111
eQTLGen, Wray, N. R., 23andMe, the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Ripke, S., Mattheisen, M., Trzaskowski, M., Byrne, E. M., Abdellaoui, A., Adams, M. J., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0090-3 · Cited by 3,005
mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists
Li, N., Lee, B., Liu, R.-J., Banasr, M., Dwyer, J. M., Iwata, M., Li, X.-Y., Aghajanian, G., & Duman, R. S. (2010) · Science · doi:10.1126/science.1190287 · Cited by 2,881
Research works printed but not linked: 2
- Gourley SL, Kiraly DD, Howell JL, Olausson P, Jane R, Taylor JR. Acute hippocampal BDNF restores motivational and forced swim performance after corticosterone. J Neurosci. 2009;64:884–90.
- Kim U, Lee T. Topography of descending projections from anterior insular and medial prefrontal regions to the lateral habenula of the epithalamus in the rat. Eur J Neurosci. 2012;35:1253–69. · DOI · Paper page
Cited by
Sorted by citations
Zanos, P., Brown, K. A., Georgiou, P., Yuan, P., Zarate, C. A., Thompson, S. M., & Gould, T. D. (2023) · The Journal of Neuroscience · doi:10.1523/jneurosci.1316-22.2022 · Cited by 115
Self-citationThompson, S. M. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-023-01728-8 · Cited by 101
Self-citationDuan, W., Cao, D., Wang, S., & Cheng, J. (2023) · Chemical Reviews · doi:10.1021/acs.chemrev.3c00375 · Cited by 81
Page, C. E., Epperson, C. N., Novick, A. M., Duffy, K. A., & Thompson, S. M. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02625-2 · Cited by 80
Self-citationTargeting metaplasticity mechanisms to promote sustained antidepressant actions
Brown, K. A., & Gould, T. D. (2024) · Molecular Psychiatry · doi:10.1038/s41380-023-02397-1 · Cited by 49
Metadata
- Authors
- Thompson, S. M.
- Affiliations
- University of Colorado Anschutz (US)
- Corresponding author
- Thompson, Scott M.
- ORCID
- Thompson, Scott M.
- Venue
- Neuropsychopharmacology
- Published
- 2022-09-03
- Volume
- 48
- Issue
- 1
- Pages
- 90-103
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC9700729
- OpenAlex
- W4294433359
- Cited by
- 40
- References
- 281
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 13 · 2023: 7
- FWCI
- 1.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Health & Human Services | National Institutes of Health (R01 MH086828)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- depression, synaptic plasticity, excitatory synapses, reward systems, antidepressants, antidepressant drug development, mood, synaptic dysfunction
- MeSH terms
- Antidepressive Agents, Depression, Humans, Neuronal Plasticity, Reward, Synapses
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-05, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-05 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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