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Cited by 40Treatment of Major DepressionNeurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology Research

Plasticity of synapses and reward circuit function in the genesis and treatment of depression

Open access
Thompson, Scott M.·2023·Neuropsychopharmacology
DOI 10.1038/s41386-022-01422-1PMC PMC9700729
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Abstract

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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Written from the paper’s full text.

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.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41386-022-01422-1

Cites

283 of 283 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 323 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Fluoxetine's restoration of synaptic strength and hedonic behavior is absent in mice with GluA1 subunits that cannot be phosphorylated by CaMK.

    “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).”
    Quote in the paperSubstantial claim
  • Premisecitation

    Chronic HPA axis overactivity and sustained high glucocorticoids damage excitatory synapses.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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  • Premisenone given

    Preclinical stress-based models of anhedonic states show dysfunction in cortico-mesolimbic and habenular circuits.

    “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”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    Excitatory synapse dysfunction weakens the circuits containing them, producing depression's mood, pleasure, and thought symptoms.

    “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.”
    Quote in the paperSubstantial claim
  • Interpretationnone given

    Long-term stress harms brain function largely by damaging excitatory synapses, which disrupts reward, aversion, cognitive, and mood circuits.

    “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.”
    Quote in the paperSubstantial claim
  • May combine two claims. 91
  • Classified as probably not a substantial claim. 15

  • May combine two claims.

    Findingcitation

    Chronic, but not acute, fluoxetine restores stress-weakened TA-CA1 excitatory synapse strength and normal hedonic behavior.

    “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].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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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    • cites [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

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  • May combine two claims.

    Interpretationreasoning

    Depression alters several synaptic circuits, and no single synapse or circuit accounts for the whole depressed phenotype.

    “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.”
    Quote in the paperSubstantial claim

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    Premisenone given

    Lateral habenula circuits preferentially process negative valence stimuli and project to the ventral tegmental area.

    “There are also circuits involving the lateral habenula that display a relatively selective processing of negative valence stimuli and feed forward to the VTA.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Chronic stress models produce depressive-like behavior resembling human depression symptom domains and alter brain circuits in parallel with human imaging findings.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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.

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    • cites [37] Strekalova T, Steinbusch HW. Measuring behavior in mice with chronic stress depression paradigm. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:348–61. source

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    • cites [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

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    All chronic stress protocols produce behavioral changes with face validity for human depression symptom domains.

    “All chronic stress protocols produce behavioral changes with face validity to the symptom domains of human depression.”
    Quote in the paperNot a substantial claim

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    Premisereasoning

    Reward and cognitive task impairments are consistently seen after chronic stress and are maladaptive.

    “Impairment in these tasks is consistently observed after chronic stress and is clearly maladaptive.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hippocampal ensemble firing helps animals predict the direction needed to reach a distant goal.

    “Hippocampal ensemble firing patterns also help animals correctly predict which direction they need to move in order to reach a chosen distant goal [62].”
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    • cites [62] Wikenheiser AM, Redish AD. Hippocampal theta sequences reflect current goals. Nat Neurosci. 2015;18:289–94. source

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    Premisecitation

    Reward receipt increases spike-wave ripples, which enhance place field stability and may promote learning of reward locations.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [63] Singer AC, Frank LM. Rewarded outcomes enhance reactivation of experience in the hippocampus. Neuron. 2009;64:910–21. source

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    • cites [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

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Impaired thinking and concentration, including memory, executive function, and attention deficits, is a major MDD symptom category and contributes substantially to depression disability.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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

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    • cites [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.

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    Premisenone given

    The hippocampus is essential for declarative and spatial memory formation.

    “The hippocampus is well known to be essential in declarative and spatial memory formation from both animal studies and humans.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The hippocampus regulates the hypothalamic-pituitary axis by mediating negative feedback on stress hormone secretion.

    “It is also known to be an important regulator of the hypothalamic-pituitary axis, mediating negative feedback of stress hormone secretion.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Prefrontal cortex and hippocampus decode stimulus and environmental features to guide adaptive reward responses, while lateral hypothalamus-lateral habenula circuits encode negative valence; both are integrated in nucleus accumbens and ventral tegmental area to regulate dopamine.

    “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”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [50] Sesack SR, Grace AA. Cortico-basal ganglia reward network: microcircuitry. Neuropsychopharmacol. 2010;2010:27–47. source

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    • cites [51] Russo SJ, Nestler EJ. The brain reward circuitry in mood disorders. Nat Rev Neurosci. 2013;14:609–25. source

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    • cites [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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    Premisecitation

    Early life trauma can cause lifelong decreases in hippocampal volume, suggesting preexisting atrophy may predispose some people to later depression.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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    Premisecitation

    Chronic stress and exogenous corticosteroids cause neuronal death, distal pyramidal dendrite atrophy, and dendritic spine loss in rodent hippocampus.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [69] Sapolsky R, Krey L, McEwen BS. Prolonged glucocorticoid exposure reduces hippocampal neuron number: implications for aging. J Neurosci. 1985;5:1222–27. source

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    • cites [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

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    • cites [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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    Premisecitation

    Human hippocampal atrophy can result solely from elevated corticosteroids, as in Cushing's syndrome, and is reversed by lowering cortisol.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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    Premisecitation

    These hippocampal effects occur across principal cell types and multiple physical and social stress forms.

    “These effects are consistent in all principal cell types and across multiple forms of physical and social stress [75][76][77].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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

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    • cites [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

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    • cites [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

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    Premisecitation

    Conventional antidepressants reduce hippocampal atrophy in human depression, including in previously drug-naïve patients, suggesting anatomical changes may underlie functional improvement.

    “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.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [84] Sheline YI, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. Am J Psychiatry. 2003;160:1516–8. source

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    • cites [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

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    • cites [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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    Premisecitation

    Conventional antidepressants promote BDNF expression and neurogenesis.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [87] Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59:1116–27. source

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    • cites [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

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    • cites [94] Malberg J, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult hippocampus. J Neurosci. 2000;20:9104–10. source

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    Premisecitation

    Adult dentate gyrus neurogenesis occurs at least in nonhuman animals, and new granule cells may contribute to depression and antidepressant actions.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    The neurotrophic hypothesis proposes that reduced neurotrophic factor signaling underlies dentate granule cell dysgenesis and dendritic and synaptic atrophy in depressed brain.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [87] Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59:1116–27. source

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    • cites [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

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    • cites [98] Castrén E, Monteggia LM. Brain-derived neurotrophic factor signaling in depression and antidepressant action. Biol Psychiatry. 2021;90:128–36. source

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    Premisecitation

    In CA3, chronic stress increases NMDAR-mediated synaptic currents but does not affect AMPARs.

    “In area CA3, chronic stress enhances synaptic currents mediated by NMDARs but has no effect on AMPARs [109].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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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    Premisecitation

    Stimulation of neurotrophic signaling and neurogenesis by antidepressants may explain their therapeutic actions.

    “This hypothesis is complementary to the suggestion that stimulation of neurotrophic signaling and neurogenesis by antidepressants explains their therapeutic actions [99][100][101].”
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    • cites [99] Dranovsky A, Hen R. Hippocampal neurogenesis: regulation by stress and antidepressants. Biol Psychiatry. 2006;59:1136–43. source

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    • cites [100] Sahay A, Hen R. Adult hippocampal neurogenesis in depression. Nat Neurosci. 2007;10:1110–5. source

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    • cites [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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    Premisecitation

    Chronic stress causes marked synaptic structural and functional changes in animal models, including altered synaptic currents, CA1 and DG plasticity deficits, and impaired local circuit function.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [104] Krugers HJ, Hoogenraad CC, Groc L. Stress hormones and AMPA plasticity and memory. Nat Rev Neurosci. 2010;11:675–81. source

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    • cites [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

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    • cites [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

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    Premisecitation

    Chronic stress does not change basal synaptic strength at SC-CA1 synapses but impairs SC-CA1 LTP.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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

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    • cites [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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    Premisecitation

    At TA-CA1 synapses, chronic stress or exogenous corticosteroids impair AMPAR-mediated basal transmission but leave LTP unaffected.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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

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    • cites [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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    Premisecitation

    Neurogenesis has limited explanatory power for depression and antidepressant effects because it occurs only in dentate gyrus and may be very limited or absent in humans.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    Acute stress effects are generally adaptive and differ from the maladaptive effects of chronic stress.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] Krugers HJ, Hoogenraad CC, Groc L. Stress hormones and AMPA plasticity and memory. Nat Rev Neurosci. 2010;11:675–81. source

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    Premisecitation

    Several chronic stress types cause loss of distal apical dendritic branches in CA3 and CA1 pyramidal cells and reduced dendritic spine size and number.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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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    • cites [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

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    • cites [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

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    Premisecitation

    Human data implicate AMPARs, and excitatory synaptic gene clusters are commonly found in genetic screens of suicide and depression and in preclinical studies.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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

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    • cites [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

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    • cites [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

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    Premisecitation

    Chronic adolescent stress in female rats reduces adult hippocampal SC-CA1 synaptic strength and impairs cognitive flexibility.

    “Chronic adolescent stress in female rats caused a decrease in hippocampal SC-CA1 synaptic strength in adults, accompanied by impaired cognitive flexibility [112].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    Serotonin increases AMPA receptor phosphorylation and surface delivery, an effect mimicked by imipramine.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    Gamma oscillation power contributes to working memory capacity, is reduced in MDD, and normalizes with symptomatic remission.

    “The power of gamma oscillations contributes to working memory capacity, is reduced in patients with MDD, and is normalized with symptomatic remission [121].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Interpretationreasoning

    Disruption of hippocampal glutamatergic transmission, specifically AMPAR function, accompanies and may cause the depression-like behavioral state in preclinical models.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    SSRI antidepressant actions are mediated in part by rapid AMPAR insertion into synapses via 5HT1BR-dependent CaMK activation and GluA1 serine 831 phosphorylation, plus slower restoration of GluA1 expression.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    GABAergic inhibition is affected by chronic stress and may contribute to altered excitation/inhibition balance and ensemble activity defects.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic stress reduces spatial tuning of hippocampal cell discharges and gamma oscillation power in local field potentials.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    Fluoxetine produces rapid disinhibition in hippocampal brain slices, which could contribute to net increased excitation in vivo.

    “Fluoxetine also produces rapid disinhibition in hippocampal brain slices [128], which could also contribute to a net increase in excitation in vivo.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    Ketamine produces rapid, robust antidepressant, antianhedonic, and antisuicidal effects within two hours, sustained at least seven days after a single infusion or intranasal dose in major depression.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

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  • May combine two claims.

    Premisecitation

    Deuterating ketamine to reduce its hydrolysis eliminates its behavioral actions in mice, suggesting NMDAR inhibition is not sufficient for antidepressant effects.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Interpretationreasoning

    The synaptic scaling hypothesis cannot be readily applied to fast-acting antidepressants that do not target NMDARs and is difficult to reconcile with other NMDAR antagonists lacking antidepressant activity.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Ketamine has strong antidepressant-like actions in preclinical models, including restoring reward behavior, promoting spine formation, restoring synaptic strength, and promoting pro-synaptic gene expression.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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  • May combine two claims.

    Premisecitation

    Acute eEF2K inhibition increases mEPSC amplitude in cultured hippocampal cells and occludes ketamine's actions on mEPSC amplitude.

    “As predicted, acute inhibition of eEF2K increases mEPSC amplitude in cultured hippocampal cells and occludes the actions of ketamine on mEPSC amplitude [159].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    Five days of citalopram did not produce antidepressant behavioral effects in mice but did decrease eEF2 phosphorylation.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    Ketamine may act through neuroactive metabolites, particularly hydroxynorketamines, rather than through NMDAR blockade.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The synaptic scaling hypothesis proposes that ketamine restores stress-impaired excitatory synapses by blocking spontaneously activated NMDARs, reducing Ca2+ influx and CaMK/eEF2K activity, de-suppressing eEF2 translation, increasing GluA1 and BDNF, and raising synaptic AMPAR expression.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [154] Kavalali ET, Monteggia LM. Targeting homeostatic synaptic plasticity for treatment of mood disorders. Neuron 2020;106:715–26. source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loneliness results from perceived social isolation and lack of companionship and is linked to higher risk of depression and suicide.

    “Loneliness, for example, is caused by perceived social isolation and absence of companionship and is associated with increased risk for depression and suicide [171].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AMPAkines have antidepressant-relevant effects including reduced FST immobility, BDNF expression, amplification of ketamine effects, and increased dentate neurogenesis.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Direct hydroxynorketamine administration mimics ketamine's behavioral actions in mice, promotes EEG gamma oscillations, increases AMPAR and BDNF expression, and decreases hippocampal eEF2 phosphorylation.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Prefrontal cortical subregions do not have identical functions and may show sex differences.

    “but it is important to recognize that there is strong evidence that their functions are not identical and may display sex differences [167].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Animals learn to associate rewarding experiences with sensory cues and actions that predict future reward occurrence.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Cognitive maps of rewards underlie all goal-directed behaviors and permit flexible decision-making optimized for internal state and environmental availability.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The prefrontal cortex regulates negative ruminative thinking, which can indirectly harm cognition and mood.

    “It also regulates the negative ruminative thinking that can indirectly have an adverse impact on cognition and mood [178].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    Prefrontal electrophysiological activity encodes possible choices and compares them in the current environment, and prefrontal output converts these computations into actions.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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  • May combine two claims.

    Interpretationreasoning

    Deficits in prefrontal synaptic excitation and excitation-inhibition imbalance would affect these choice computations.

    “Deficits in PFC synaptic excitation and imbalances between excitation and inhibition would have obvious impact on these calculations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Social support is among the strongest predictors of resilience, and increasing it can be a beneficial part of effective therapy.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    In humans, brain activity increases as cues and stimuli become relevant to decisions, and the size of this increase tracks decision outcome and reliability.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Depressed patients show reduced prefrontal volume, activity, and connectivity on imaging.

    “Measured with fMRI, the PFC of depressed patients displays evidence of reduced volume, activity, and connectivity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Stress-induced decision-making deficits in MDD patients are reversible; after one month of reduced stress, subjects were indistinguishable from controls.

    “Stress induced decision-making deficits in MDD patients are reversible: after one month of reduced stress, subjects were indistinguishable from controls [196].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    Co-administration of the mTOR inhibitor rapamycin prevents ketamine-induced dendritic spine formation and ketamine's effects in the forced swim test and other behaviors.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Interpretationreasoning

    Interneuron inhibition may promote high-frequency oscillatory activity in pyramidal cells underlying gamma oscillations and thereby strengthen stress-impaired excitatory synapses through LTP and BDNF-trkB signaling.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The nucleus accumbens is an essential integrator of prefrontal, hippocampal, and amygdala inputs and is critical for motivating and reinforcing responses to rewards and avoidance of aversive stimuli.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [216] Floresco SB. The nucleus accumbens: an interface between cognition, emotion, and action. Annu Rev Psychol. 2015;66:25–52. source

      Not checked in the free run.

    • cites [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

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  • May combine two claims.

    Premisecitation

    Many forms of activity-dependent plasticity are likely NMDAR-dependent, supported by the antidepressant-like actions of GLYX-13 in preclinical models.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The nucleus accumbens is divided into core and shell subregions with distinct input and output patterns and likely distinct but similar functions.

    “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].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [177] Berridge KC, Kringelbach ML. Pleasure systems in the brain. Neuron. 2015;86:646–64. source

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  • May combine two claims.

    Premisecitation

    Ketamine's disinhibitory action in dendrites promotes dendritic Ca2+ influx, providing a mechanism for activity-dependent synaptic strengthening.

    “Ketamine's disinhibitory action in dendrites also promotes dendritic Ca 2+ influx [214], providing an additional mechanism to drive endogenous activitydependent synaptic strengthening mechanisms.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ketamine acutely inhibits interneuron discharge in the prefrontal cortex and reduces spontaneous IPSCs in pyramidal cells.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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  • May combine two claims.

    Premisecitation

    Activation of hippocampal and prefrontal inputs to the nucleus accumbens is rewarding and reinforces rewarding stimuli.

    “Activation of inputs to the NAc from the hippocampus and PFC is rewarding and reinforcing of rewarding stimuli [227,228].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

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  • May combine two claims.

    Premisecitation

    D1 medium spiny neuron activity is more associated with motivation, reward, positive responses, and stress resilience.

    “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].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [193,[223][224][225]

      Not checked in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    D2-type dopamine receptor-expressing medium spiny neurons of the indirect pathway project to ventral pallidum GABAergic cells that project to VTA interneurons; activating them inhibits dopamine projections by disinhibiting the interneurons that silence them.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [220] Watabe-Uchida M, Eshel N, Uchida N. Neural circuitry of reward prediction error. Annu Rev Neurosci. 2017;40:373–94. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    D1-type dopamine receptor-expressing medium spiny neurons of the direct pathway project to and inhibit VTA GABAergic interneurons that inhibit VTA dopamine cells; activating them disinhibits dopamine projections to the forebrain.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [220] Watabe-Uchida M, Eshel N, Uchida N. Neural circuitry of reward prediction error. Annu Rev Neurosci. 2017;40:373–94. source

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  • May combine two claims.

    Premisecitation

    Dopamine receptor activation is not required for this potentiation but may modulate it under physiological conditions.

    “Dopamine receptor activation is not required for this potentiation but may be modulatory under physiological conditions [229].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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. source

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  • May combine two claims.

    Premisecitation

    Chronic, but not acute, fluoxetine in stressed mice restores hippocampal excitatory synapse strength in D1 medium spiny neurons and their ability to undergo LTP, alongside restored sucrose preference.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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  • May combine two claims.

    Premisecitation

    Preventing stress-induced AMPA receptor loss in D1 medium spiny neurons prevents stress-induced loss of hedonic responses in sucrose preference and cocaine-induced place preference, but not in the forced swim test.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Susceptibility to chronic social defeat stress is accompanied by atrophy of D1 medium spiny neuron dendrites, but not D2 dendrites.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The nucleus accumbens is activated by reward anticipation and by motivational and hedonic aspects of reward processing.

    “There is evidence that the NAc is activated by reward anticipation and both motivational and hedonic aspects of reward processing [245].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ketamine increases responses in a reward task and activity in the orbitofrontal cortex, ventral striatum, and ventral tegmental area.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Excitatory synapses onto lateral habenula cells have a high AMPAR-to-NMDAR ratio, indicating low NMDAR expression.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Chronic SSRI administration in depressed patients improves self-reported depression severity and negative affective bias, and these improvements strongly correlate with increases in nucleus accumbens activity and nucleus accumbens-prefrontal connectivity.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Unmedicated MDD patients show deficits in reward learning, reduced ventral striatum responses for positive prediction errors, and reduced nucleus accumbens-VTA connectivity.

    “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].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The lateral habenula is a key node in regulating reward behaviors and has been implicated in depressive symptoms and reward dysregulation.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lateral habenula neurons fire in response to aversive stimuli and the absence of an expected reward.

    “LHb neurons fire in response to both aversive stimuli and the absence of an expected reward [257-260].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [257] Matsumoto M, Hikosaka O. Representation of negative motivational value in the primate lateral habenula. Nat Neurosci. 2009;12:77–84. source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Optogenetic activation of lateral habenula neurons via lateral hypothalamic projections triggers avoidance and escape behaviors, whereas optogenetic or pharmacological inhibition of lateral habenula discharge impairs avoidance and escape in response to aversive stimuli.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Acute physical restraint, foot shock, tail suspension, forced swimming, and social defeat are all accompanied by strong lateral habenula activation.

    “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].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    RMTg neurons project to the VTA and largely mediate the inhibitory action of lateral habenula projections onto VTA dopaminergic neurons.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased numbers of burst-firing lateral habenula neurons were observed in vitro and in vivo in a congenital learned helplessness rat strain and in wild-type rats after chronic restraint stress, with no overall change in membrane potential.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Lesioning or pharmacologically silencing the lateral habenula can normalize learned helplessness responses, including inhibition of NMDAR-mediated lateral habenula bursting.

    “Lesioning or pharmacologically silencing the LHb can normalize learned helplessness responses [266,268], including inhibition of NMDAR-mediated LHb bursting [264].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Selective activity-dependent potentiation of synapses formed by lateral hypothalamic axons onto lateral habenula neurons promotes lateral habenula discharge and is sufficient to mimic chronic stress behavioral effects in the forced swim and sucrose preference tests.

    “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].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Optogenetically induced increases in burst firing in lateral habenula neurons increased mobility in the forced swim test and decreased sucrose preference, like the effects of chronic stress.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Increased burst discharges are attributed to dysregulation of astrocytic K+ channels that regulate extracellular K+ concentrations, promoting hyperpolarization of lateral habenula neurons.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The evidence is plentiful and strong that the lateral habenula is an important mediator of aversive behavioral responses via its outputs to the VTA and that its activity is profoundly increased in chronic stress conditions used to model depression-relevant behaviors in rodents.

    “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]).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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

      Not checked in the free run.

    • cites [269] Yang Y, Wang H, Hu J, Hu H. Lateral habenula in the pathophysiology of depression. Curr Opin Neurobiol. 2018b;48:90–6. source

      Not checked in the free run.

    • cites [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.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationreasoning

    Hypoactive prefrontal circuits might be more heavily affected in patients with more prevalent cognitive and decision-making symptoms.

    “In contrast, hypoactive PFC circuits might be more heavily affected in patients with more prevalent cognitive and decision-making symptoms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Preclinical evidence supports that psilocybin can restore reward-related behaviors and synaptic structure and function.

    “There is also robust preclinical evidence that psilocybin can restore both reward behaviors and synapse structure and function.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Driving the lateral habenula may overpower counterbalancing nucleus accumbens inputs to the VTA regardless of whether those inputs are fully functional or dysfunctional.

    “Driving the LHb may overpower counterbalancing NAc inputs to the VTA, for example, regardless of whether they are fully functional or dysfunctional.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The synaptic changes weaken pathways that promote dopamine release by activating VTA cells, including direct and indirect weakening of D1 medium spiny neuron excitatory drive in the nucleus accumbens, and potentiate pathways inhibiting dopamine secretion, such as the lateral hypothalamus-lateral habenula-RMTg pathway.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Some antidepressants favor activity-dependent synaptic strengthening mechanisms, such as ketamine and ketamine metabolites, whereas others, such as SSRIs, favor neurotrophic growth factor signaling.

    “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.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationcitation

    An overactive lateral habenula circuit may favor an increase in negative affect in emotional dysregulation.

    “Considering emotional dysregulation [271], for example, an overactive LHb circuit may favor an increase in negative affect.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [271] Hofmann SG, Sawyer AT, Fang A, Asnaani A. Emotion dysregulation model of mood and anxiety disorders. Depress Anxiety. 2012;29:409–16. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Concerted synaptic changes after chronic stress occur in essentially every circuit in every reward pathway, providing a mechanistic explanation for the wide range of symptoms that constitute clinical depression.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Antidepressants that restore synaptic strength slowly, such as SSRIs, do so slowly, whereas fast-acting antidepressants do so rapidly.

    “Those antidepressants that restore synaptic strength slowly, such as SSRIs, restore synaptic strength slowly, whereas fast acting antidepressants do so rapidly.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Excitatory synapses generally become reduced in number and weaker in areas for attention and decision making and stronger in pathways processing negative-valence stimuli.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    These synapses are working elements of their circuits and could cause significant changes in circuit function.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the prefrontal cortex of unstressed mice, psilocybin increases net formation of new dendritic spines in pyramidal cells, and this increase lasts more than one month.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In hippocampal slices from those same stressed mice, psilocybin restores the strength of stress-sensitive TA-CA1 synapses at the same time as reward behavior recovers.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    AZD6765, mGluR2/3 antagonists, alpha5 subunit-selective GABA A receptor negative allosteric modulators, and the ketamine metabolite (2R,6R)-HNK all increase EEG power in the gamma frequency band.

    “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.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Several processes described earlier, such as neurotrophin signaling and enzymatic cascades that promote receptor trafficking and process outgrowth, are probably involved in the lasting increases in synaptic strength.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

103 of 103

  • 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”
4 of 4

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?

  • Ketamine rapidly alters structural and functional connectivity in reward, emotion, and cognition regions, probably via glutamate-driven excitation of underactive areas.

    “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.

  • Forced-swim result is described as both stress-like and antidepressant-like

    Minor

    The lateral habenula section calls increased mobility in the forced swim test a chronic-stress-like effect. Elsewhere, the paper identifies decreased immobility-the corresponding direction of change-as an antidepressant-relevant effect.

  • Patent disclosure conflicts with the no-competing-interests statement

    Minor

    The paper states that there are no competing interests, but elsewhere discloses that the author's institution has filed patents on antidepressant approaches for which the author is an inventor.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. 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.
  2. 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

Related

Authors
Thompson, S. M.
Affiliations
University of Colorado Anschutz (US)
Corresponding author
Thompson, Scott M.
ORCID
Thompson, Scott M.
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2022-09-03
Volume
48
Issue
1
Pages
90-103
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/s41386-022-01422-1
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
Licence
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 › 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

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