The DOI matches its Crossref record; 210 of the 210 references it cites were found in a registry or an index; 4 of the 217 sources its claims cite were checked for support.
The molecular and cellular mechanisms of depression: a focus on reward circuitry
Open accessAbstract
Depression is a complex disorder that takes an enormous toll on individual health. As affected individuals display a wide variation in their clinical symptoms, the precise neural mechanisms underlying the development of depression remain elusive. Although it is impossible to phenocopy every symptom of human depression in rodents, the preclinical field has had great success in modeling some of the core affective and neurovegetative depressive symptoms, including social withdrawal, anhedonia, and weight loss. Adaptations in select cell populations may underlie these individual depressive symptoms and new tools have expanded our ability to monitor and manipulate specific cell types. This review outlines some of the most recent preclinical discoveries on the molecular and neurophysiological mechanisms in reward circuitry that underlie the expression of behavioral constructs relevant to depressive symptoms.
Overview
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Written from the paper’s full text.
TL;DR
This review synthesizes preclinical evidence on molecular and cellular adaptations in ventral tegmental area (VTA) and nucleus accumbens (NAc) reward circuitry that underlie depression-like behaviors, especially anhedonia and social withdrawal. It emphasizes cell-type-specific and sometimes bidirectional changes across stress models and calls for more work on non-neuronal cells, sex differences, and treatment-resistant depression.
Key findings
- Stress produces divergent VTA dopamine neuron activity: chronic social defeat stress (CSDS) increases VTA dopamine neuron firing, with increased Ih currents in NAc-projecting but not mPFC-projecting neurons; inhibiting NAc-projecting VTA dopamine neurons induces resilience, whereas inhibiting mPFC projections promotes susceptibility. Chronic mild or cold stress instead reduces VTA population activity, an effect more pronounced in females.
- In NAc, chronic stress causes opposing medium spiny neuron (MSN) subtype changes: excitatory input is weakened onto D1-MSNs and strengthened onto D2-MSNs; optogenetic D1-MSN stimulation reverses social and sucrose preference deficits, while D2-MSN stimulation enhances stress susceptibility. D1-MSN dendritic complexity is reduced in CSDS-susceptible mice, and D1-MSN RhoA/Egr3 signaling promotes susceptibility.
- Molecular adaptations include BDNF-TrkB, AKT, ERK2, Cdk5, Otx2, CREB/ΔFosB, β-catenin/Dicer1, Dnmt3a, Tet1, H3.3, and SIRT1, with cell-type-specific examples such as decreased Slc6a15 in D2-MSNs and decreased Nlgn2 in D1-MSNs of susceptible mice.
- Non-neuronal and neuroimmune mechanisms are implicated: at least 40% of cells in rodent and human brain are non-neuronal; chronic stress increases IL-6, IL-1β, and CXCL1, recruits monocytes/macrophages, and alters microglia, while anti-inflammatory treatments reduce depressive symptoms in humans. Approximately 95% of NAc neurons are MSNs, but cholinergic interneurons and glia also contribute.
Methods
- Design: narrative review of preclinical rodent models for depression-like behavior—chronic unpredictable stress (CUS; 8–12 weeks), learned helplessness, and CSDS (10 days; approximately 70% stress-susceptible, ~30% stress-resilient)—integrated with human functional imaging and postmortem MDD findings.
- Data or sample: no new experimental data; synthesizes cited rodent studies using male, female, and adolescent mice/rats, plus human postmortem MDD tissue and imaging studies.
- Main analysis: qualitative synthesis of electrophysiological, optogenetic, viral, transcriptomic, epigenetic, structural, and behavioral findings, with proposed remaining questions rather than a systematic or quantitative meta-analysis.
Limitations
- The paper states that many questions remain, including whether bidirectional VTA activity changes reflect stress paradigm, symptom type, or distinct cell populations; most NAc D1/D2-MSN work was done solely in male rodents; validation relies heavily on postmortem MDD tissue often from suicide completers; and new antidepressants have not been approved despite rodent progress.
- The paper states that preclinical models cannot phenocopy all human depression symptoms, that forced-swim/tail-suspension interpretations have been questioned, and that treatment-resistant populations are understudied.
- Evident from the text: as a narrative review, it lacks a systematic search or meta-analysis, and conclusions depend on cited studies with heterogeneous stress paradigms, housing conditions, sex inclusion, and cell-type specificity.
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Claims the paper makes
158 Not checked yet · 7 Own interpretation · 1 Supported · 1 Supported so far · 1 Partly supported · accuracy not yet measured
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In the paper
“The stress-mediated increases in VTA dopamine neuron firing are caused by increased Ih currents [29, 35]”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Partly supportedcites [29] Cao J-LJ-L, Covington HE, Friedman AK, Wilkinson MB, Walsh JJ, Cooper DC, et al. Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action. J Neurosci. 2010;30:16453–8. sourceExperimental — accuracy not yet measured
The Discussion says increased VTA dopamine-neuron firing after chronic social defeat is mediated at least partly by increased Ih current. The claim omits that qualification and presents increased Ih as the cause of stress-mediated firing increases generally, whereas the reported firing increase was in susceptible mice. (LLM, conf=0.88)
- Partly supportedcites [35] Wanat MJ, Hopf FW, Stuber GD, Phillips PEM, Bonci A. Corticotropin-releasing factor increases mouse ventral tegmental area dopamine neuron firing through a protein kinase C-dependent enhancement of I h. J Physiol. 2008;586:2157–70. sourceExperimental — accuracy not yet measured
The Results show that blocking Ih prevented CRF from increasing firing in mouse VTA neurons, and the Discussion concludes that CRF enhanced Ih to increase firing. The paper describes this as a potential mechanism linking stress and dopamine; it does not establish that stress-induced firing increases themselves are caused by increased Ih. (LLM, conf=0.87)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Increased VTA Cav1.3 channel activity enhances anhedonia and social-behavior deficits [56]”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Supportedcites [56] Martínez-Rivera A, Hao J, Tropea TF, Giordano TP, Kosovsky M, Rice RC, et al. Enhancing VTA Cav1.3 L-type Ca2+ channel activity promotes cocaine and mood-related behaviors via overlapping AMPA receptor mechanisms in the nucleus accumbens. Mol Psychiatry. 2017;22:1735–45. source
The Results section reports that repeated activation of VTA Cav1.3 channels induced anhedonia in a sucrose preference test and decreased social approach behavior in mice. These findings support the attributed claim; the paper reports these as mouse behavioral outcomes. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Supported
In the paper
“The remaining ~30% of mice retain preference for social interaction and are termed “stress-resilient.””
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Social defeat stress
What the sources say
- Not checked yetcites [13] Krishnan V, Han M-HH, Graham DL, Berton O, Renthal W, Russo SJ, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131:391–404. source
plain- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Chronic physical or psychosocial stressors increase VTA dopamine neuron activity to elicit depression-like behavior.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [13] Krishnan V, Han M-HH, Graham DL, Berton O, Renthal W, Russo SJ, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131:391–404. source
- Not checked yetcites [23] Chaudhury D, Walsh JJ, Friedman AK, Juarez B, Ku SM, Koo JW, et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature. 2013;493:532–6. source
- Not checked yetcites [24] Wook Koo J, Labonté B, Engmann O, Calipari ES, Juarez B, Lorsch Z, et al. Essential role of mesolimbic brain-derived neurotrophic factor in chronic social stress–induced depressive behaviors. Biol Psychiatry. 2016;80:469–78. source
- Not checked yetcites [25] Friedman AK, Juarez B, Ku SM, Zhang H, Calizo RC, Walsh JJ, et al. KCNQ channel openers reverse depressive symptoms via an active resilience mechanism. Nat Commun. 2016;7:11671. source
- Not checked yetcites [26] Isingrini E, Perret L, Rainer Q, Amilhon B, Guma E, Tanti A, et al. Resilience to chronic stress is mediated by noradrenergic regulation of dopamine neurons. Nat Neurosci. 2016;19:560–3. source
- Not checked yetcites [27] Li L, Sun H, Ding J, Niu C, Su M, Zhang L, et al. Selective targeting of M-type potassium Kv 7.4 channels demonstrates their key role in the regulation of dopaminergic neuronal excitability and depression-like behaviour. Br J Pharmacol. 2017;174:4277–94. source
- Not checked yetcites [28] Razzoli M, Andreoli M, Michielin F, Quarta D, Sokal DM. Increased phasic activity of VTA dopamine neurons in mice 3 weeks after repeated social defeat. Behav Brain Res. 2011;218:253–7. source
- Not checked yetcites [29] Cao J-LJ-L, Covington HE, Friedman AK, Wilkinson MB, Walsh JJ, Cooper DC, et al. Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action. J Neurosci. 2010;30:16453–8. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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In the paper
“Compounds that produce acute behavioral effects in a forced-swim or tail-suspension test (i.e., increase struggling time) may not translate to meaningful therapeutics when administered chronically”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction
What the sources say
- Not checked yetcites [9] Anyan J, Amir S. Too depressed to swim or too afraid to stop? A reinterpretation of the forced swim test as a measure of anxiety-like behavior. Neuropsychopharmacology. 2018;43:931–3. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Stressed animals also tend to spend less time struggling against inescapable stressors such as forced swimming or tail suspension.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction
What the sources say
- Not checked yetcites [7] Czéh B, Fuchs E, Wiborg O, Simon M. Animal models of major depression and their clinical implications. Prog Neuropsychopharmacol Biol Psychiatry. 2016;64:293–310. source
- Not checked yetcites [8] Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. Nat Neurosci. 2010;13:1161–9. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“they also respond to aversive events [21, 22]”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [21] Matsumoto M, Hikosaka O. Two types of dopamine neuron distinctly convey positive and negative motivational signals. Nature. 2009;459:837–41. source
- Not checked yetcites [22] Cohen JY, Haesler S, Vong L, Lowell BB, Uchida N. Neuron-type-specific signals for reward and punishment in the ventral tegmental area. Nature. 2012;482:85–8. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Chronically stressed rodents have reduced reward preference, as measured by a loss of preference for sucrose solutions and time spent interacting with a novel con-specific.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction
What the sources say
- Not checked yetcites [7] Czéh B, Fuchs E, Wiborg O, Simon M. Animal models of major depression and their clinical implications. Prog Neuropsychopharmacol Biol Psychiatry. 2016;64:293–310. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“human functional imaging and postmortem tissue studies have identified abnormalities in several brain regions [2–6] including nuclei within the brain’s reward pathway.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction
What the sources say
- Not checked yetcites [2] Drevets WC. Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders. Curr Opin Neurobiol. 2001;11:240–9. source
- Not checked yetcites [3] Liotti M, Mayberg HS. The role of functional neuroimaging in the neuropsychology of depression. J Clin Exp Neuropsychol. 2001;23:121–36. source
- Not checked yetcites [4] Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron. 2002;34:13–25. source
- Not checked yetcites [5] Zhu M-Y, Klimek V, Dilley GE, Haycock JW, Stockmeier C, Overholser JC, et al. Elevated levels of tyrosine hydroxylase in the locus coeruleus in major depression. Biol Psychiatry. 1999;46:1275–86. source
- Not checked yetcites [6] Drysdale AT, Grosenick L, Downar J, Dunlop K, Mansouri F, Meng Y, et al. Resting-state connectivity biomarkers define neurophysiological subtypes of depression. Nat Med. 2017;23:28–38. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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In the paper
“burst firing is increased in vivo during an encounter with an aggressive rat [32].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [32] Anstrom KK, Miczek KA, Budygin EA. Increased phasic dopamine signaling in the mesolimbic pathway during social defeat in rats. Neuroscience. 2009;161:3–12. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Dendritic spine density, a proxy for excitatory synapse density and activity, is also increased in the VTA of CSDS-susceptible mice [33].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [33] Qu Y, Yang C, Ren Q, Ma M, Dong C, Hashimoto K. Regional differences in dendritic spine density confer resilience to chronic social defeat stress. Acta Neuropsychiatr. 2018;30:117–22. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“Following CSDS, stress-susceptible animals have increased VTA dopamine neuron firing [13, 23–29] that persists for several weeks after stress termination [28].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [13] Krishnan V, Han M-HH, Graham DL, Berton O, Renthal W, Russo SJ, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131:391–404. source
- Not checked yetcites [23] Chaudhury D, Walsh JJ, Friedman AK, Juarez B, Ku SM, Koo JW, et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature. 2013;493:532–6. source
- Not checked yetcites [24] Wook Koo J, Labonté B, Engmann O, Calipari ES, Juarez B, Lorsch Z, et al. Essential role of mesolimbic brain-derived neurotrophic factor in chronic social stress–induced depressive behaviors. Biol Psychiatry. 2016;80:469–78. source
- Not checked yetcites [25] Friedman AK, Juarez B, Ku SM, Zhang H, Calizo RC, Walsh JJ, et al. KCNQ channel openers reverse depressive symptoms via an active resilience mechanism. Nat Commun. 2016;7:11671. source
- Not checked yetcites [26] Isingrini E, Perret L, Rainer Q, Amilhon B, Guma E, Tanti A, et al. Resilience to chronic stress is mediated by noradrenergic regulation of dopamine neurons. Nat Neurosci. 2016;19:560–3. source
- Not checked yetcites [27] Li L, Sun H, Ding J, Niu C, Su M, Zhang L, et al. Selective targeting of M-type potassium Kv 7.4 channels demonstrates their key role in the regulation of dopaminergic neuronal excitability and depression-like behaviour. Br J Pharmacol. 2017;174:4277–94. source
- Not checked yetcites [28] Razzoli M, Andreoli M, Michielin F, Quarta D, Sokal DM. Increased phasic activity of VTA dopamine neurons in mice 3 weeks after repeated social defeat. Behav Brain Res. 2011;218:253–7. source
- Not checked yetcites [29] Cao J-LJ-L, Covington HE, Friedman AK, Wilkinson MB, Walsh JJ, Cooper DC, et al. Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action. J Neurosci. 2010;30:16453–8. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Chronic restraint stress also increases VTA firing [31]”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [31] Anstrom KK, Woodward DJ. Restraint increases dopaminergic burst firing in awake rats. Neuropsychopharmacology. 2005;30:1832. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“Through homeostatic adaptations, resilient mice upregulate K+ channels to reduce excitability as a consequence of the enhanced Ih [13, 30].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [13] Krishnan V, Han M-HH, Graham DL, Berton O, Renthal W, Russo SJ, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131:391–404. source
- Not checked yetcites [30] Friedman AK, Walsh JJ, Juarez B, Ku SM, Chaudhury D, Wang J, et al. Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience. Science. 2014;344:313–9. https://doi.org/10.1126/science.1249240 . source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“optogenetic stimulation of VTA dopamine neurons recapitulates stress susceptibility in previously resilient animals [23, 24, 30].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [23] Chaudhury D, Walsh JJ, Friedman AK, Juarez B, Ku SM, Koo JW, et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature. 2013;493:532–6. source
- Not checked yetcites [24] Wook Koo J, Labonté B, Engmann O, Calipari ES, Juarez B, Lorsch Z, et al. Essential role of mesolimbic brain-derived neurotrophic factor in chronic social stress–induced depressive behaviors. Biol Psychiatry. 2016;80:469–78. source
- Not checked yetcites [30] Friedman AK, Walsh JJ, Juarez B, Ku SM, Chaudhury D, Wang J, et al. Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience. Science. 2014;344:313–9. https://doi.org/10.1126/science.1249240 . source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“norepinephrine released from the locus coeruleus (LC) acts at adrenergic receptors expressed on dopamine neurons to regulate neuronal excitability and CSDS-susceptibility [26].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [26] Isingrini E, Perret L, Rainer Q, Amilhon B, Guma E, Tanti A, et al. Resilience to chronic stress is mediated by noradrenergic regulation of dopamine neurons. Nat Neurosci. 2016;19:560–3. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“ERK2 reduces inhibitory currents through GABAA receptors [48]”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [48] Bell-Horner CL, Dohi A, Nguyen Q, Dillon GH, Singh M. ERK/MAPK pathway regulates GABAA receptors. J Neurobiol. 2006;66:1467–74. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“the L-type voltage gated calcium channel Cav1.3, which decreases neuronal excitability [55].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [55] McKinney BC, Sze W, Lee B, Murphy GG. Impaired long-term potentiation and enhanced neuronal excitability in the amygdala of Ca(V)1.3 knockout mice. Neurobiol Learn Mem. 2009;92:519–28. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Enhanced VTA cholinergic tone increases forced-swim immobility and anhedonia through mAChRs [45]”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [45] Small KM, Nunes E, Hughley S, Addy NA. Ventral tegmental area muscarinic receptors modulate depression and anxiety-related behaviors in rats. Neurosci Lett. 2016;616:80–5. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Repeated activation of VTA projecting LC neurons promotes CSDS-resilience through α1 and β3 adrenergic receptors on VTA dopamine neurons [38].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [38] Zhang H, Chaudhury D, Nectow AR, Friedman AK, Zhang S, Juarez B, et al. Alpha1 and beta3 adrenergic receptor-mediated mesolimbic homeostatic plasticity confers resilience to social stress in susceptible mice. Biol Psychiatry. 2018;85:226–36. https://doi.org/10.1016/J.BIOPSYCH.2018.08.020 . source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Mice over-expressing CB2 have reduced vulnerability to CUS and depression-like behaviors at baseline [41, 42]”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [41] García-Gutiérrez M, Pérez-Ortiz J, Gutiérrez-Adán A, Manzanares J. Depression-resistant endophenotype in mice overexpressing cannabinoid CB2 receptors. Br J Pharmacol. 2010;160:1773. source
- Not checked yetcites [42] García-Gutiérrez MS, Manzanares J. Overexpression of CB2 cannabinoid receptors decreased vulnerability to anxiety and impaired anxiolytic action of alprazolam in mice. J Psychopharmacol. 2011;25:111–20. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“the M5-type muscarinic acetylcholine receptor (mAChR), which enhances tonic excitability of dopamine neurons [44].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [44] Picciotto MR, Higley MJ, Mineur YS. Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron. 2012;76:116–29. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Activation of these receptors balances Ih and K+ currents to reverse the hyperactivity of NAc projecting VTA neurons [38].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [38] Zhang H, Chaudhury D, Nectow AR, Friedman AK, Zhang S, Juarez B, et al. Alpha1 and beta3 adrenergic receptor-mediated mesolimbic homeostatic plasticity confers resilience to social stress in susceptible mice. Biol Psychiatry. 2018;85:226–36. https://doi.org/10.1016/J.BIOPSYCH.2018.08.020 . source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“CB2 knockout in dopaminergic cells enhances forced-swim and tail-suspension immobility [43].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [43] Liu Q-R, Canseco-Alba A, Zhang H-Y, Tagliaferro P, Chung M, Dennis E, et al. Cannabinoid type 2 receptors in dopamine neurons inhibits psychomotor behaviors, alters anxiety, depression and alcohol preference. Sci Rep. 2017;7:17410. source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“chronic mild or chronic cold stress instead reduce VTA population activity [50, 51].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [50] Valenti O, Gill KM, Grace AA. Different stressors produce excitation or inhibition of mesolimbic dopamine neuron activity: response alteration by stress pre-exposure. Eur J Neurosci. 2012;35:1312–21. source
- Not checked yetcites [51] Chang C, Grace AA. Amygdala-ventral pallidum pathway decreases dopamine activity after chronic mild stress in rats. Biol Psychiatry. 2014;76:223–30. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“mAChR or nicotinic acetylcholine receptor (nAChR) antagonism reduces forced-swim immobility [46].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [46] Addy NA, Nunes EJ, Wickham RJ. Ventral tegmental area cholinergic mechanisms mediate behavioral responses in the forced swim test. Behav Brain Res. 2015;288:54–62. source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“β-Cat signaling is down-regulated specifically in D2-MSNs of susceptible mice and excising β-cat from the NAc increases stress susceptibly [127].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [127] Dias C, Feng J, Sun H, Shao NY, Mazei-Robison MS, Damez-Werno D, et al. β-catenin mediates stress resilience through Dicer1/microRNA regulation. Nature. 2014;516:51–5. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“FosB and CREB can regulate BDNF expression, and BDNF upregulation induced by synaptic activity depends on Wnt secretion [125].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [125] Zhang W, Shi Y, Peng Y, Zhong L, Zhu S, Zhang W, et al. Neuron activity–induced Wnt signaling up-regulates expression of brain-derived neurotrophic factor in the pain neural circuit. J Biol Chem. 2018;293:15641–51. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Indeed, phospho-extracellular signaling regulated kinase is increased in the NAc shell of D1-MSNs in susceptible mice [24].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [24] Wook Koo J, Labonté B, Engmann O, Calipari ES, Juarez B, Lorsch Z, et al. Essential role of mesolimbic brain-derived neurotrophic factor in chronic social stress–induced depressive behaviors. Biol Psychiatry. 2016;80:469–78. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Two weeks of escitalopram reduces VTA firing rate and bursting activity [62]”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [62] Dremencov E, El Mansari M, Blier P. Effects of sustained serotonin reuptake inhibition on the firing of dopamine neurons in the rat ventral tegmental area. J Psychiatry Neurosci. 2009;34:223–9.
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Two weeks of fluoxetine normalizes Ih currents in dopaminergic neurons after CSDS [29]”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [29] Cao J-LJ-L, Covington HE, Friedman AK, Wilkinson MB, Walsh JJ, Cooper DC, et al. Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action. J Neurosci. 2010;30:16453–8. source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“both CSDS and CUS-induced firing changes are reversed by Ih current normalization after HCN2 overexpression [30, 61].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [30] Friedman AK, Walsh JJ, Juarez B, Ku SM, Chaudhury D, Wang J, et al. Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience. Science. 2014;344:313–9. https://doi.org/10.1126/science.1249240 . source
- Not checked yetcites [61] Zhong P, Vickstrom CR, Liu X, Hu Y, Yu L, Yu H-G, et al. HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress. Elife. 2018;7:pii: e32420. https://doi.org/10.7554/eLife.32420 . source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Mice that develop anhedonia after systemic lipopolysaccharide have reduced plasma membrane expression of AMPA receptor subunit GluR1 [60]”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [60] Sekio M, Seki K. Lipopolysaccharide-induced depressive-like behavior is associated with α1-adrenoceptor dependent downregulation of the membrane GluR1 subunit in the mouse medial prefrontal cortex and ventral tegmental area. Int J Neuropsychopharmacol. 2015;18:pyu005. https://doi.org/10.1093/ijnp/pyu005 . source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“DVL is downregulated in the NAc of postmortem MDD patients and GSK3β inhibition promotes CSDS-resilience [126].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [126] Wilkinson MB, Dias C, Magida J, Mazei-Robison M, Lobo M, Kennedy P, et al. A novel role of the WNT-dishevelled-GSK3 signaling cascade in the mouse nucleus accumbens in a social defeat model of depression. J Neurosci. 2011;31:9084–92. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“FosB and CREB can regulate BDNF expression, and BDNF upregulation induced by synaptic activity depends on Wnt secretion [125].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [125] Zhang W, Shi Y, Peng Y, Zhong L, Zhu S, Zhang W, et al. Neuron activity–induced Wnt signaling up-regulates expression of brain-derived neurotrophic factor in the pain neural circuit. J Biol Chem. 2018;293:15641–51. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“β2-nAChR signaling switches dopamine neurons to an excited state [57].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [57] Mameli-Engvall M, Evrard A, Pons S, Maskos U, Svensson TH, Changeux J-P, et al. Hierarchical control of dopamine neuron-firing patterns by nicotinic receptors. Neuron. 2006;50:911–21. source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“β-Cat signaling is down-regulated specifically in D2-MSNs of susceptible mice and excising β-cat from the NAc increases stress susceptibly [127].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [127] Dias C, Feng J, Sun H, Shao NY, Mazei-Robison MS, Damez-Werno D, et al. β-catenin mediates stress resilience through Dicer1/microRNA regulation. Nature. 2014;516:51–5. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
None of the sources cited for this claim have been checked yet.
In the paper
“other antidepressants or electroconvulsive therapy increase burst firing [63, 64].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [63] West CHK, Weiss JM. Effects of chronic antidepressant drug administration and electroconvulsive shock on activity of dopaminergic neurons in the ventral tegmentum. Int J Neuropsychopharmacol. 2011;14:201–10. source
- Not checked yetcites [64] Sekine Y, Suzuki K, Ramachandran PV, Blackburn TP, Ashby CR. Acute and repeated administration of fluoxetine, citalopram, and paroxetine significantly alters the activity of midbrain dopamine neurons in rats: an in vivo electrophysiological study. Synapse. 2007;61:72–7. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“DVL is downregulated in the NAc of postmortem MDD patients and GSK3β inhibition promotes CSDS-resilience [126].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [126] Wilkinson MB, Dias C, Magida J, Mazei-Robison M, Lobo M, Kennedy P, et al. A novel role of the WNT-dishevelled-GSK3 signaling cascade in the mouse nucleus accumbens in a social defeat model of depression. J Neurosci. 2011;31:9084–92. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Postmortem MDD brain tissue gene expression changes reflect antemortem MDD pathophysiology.
In the paper
“Depressive behavior is mediated in part by increased NAc BDNF signaling (reviewed in ref. [66]).”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [66] Russo SJ, Nestler EJ. The brain reward circuitry in mood disorders. Nat Rev Neurosci. 2013;14:609–25. source
plainconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Egr3 is upregulated specifically in D1-MSNs of susceptible mice and its knockdown can prevent altered synaptic activity and stress susceptibility [88].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [88] 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;22:1512–9. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“The GTPase RhoA, which negatively regulates dendritic complexity, is increased specifically in D1-MSNs of susceptible mice [138].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [138] 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. 2018. https://doi.org/10.1038/s41380-018-0211-5 . [Epub ahead of print]. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
None of the sources cited for this claim have been checked yet.
In the paper
“For example, the mitochondrial biogenesis regulator PPAR-γ coactivator 1-α (PGC1α) is regulated by both CREB [128] and Egr3 [129].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [128] Herzig S, Long F, Jhala US, Hedrick S, Quinn R, Bauer A, et al. CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature. 2001;413:179–83. source
- Not checked yetcites [129] Chandra R, Engeln M, Francis TC, Konkalmatt P, Patel D, Lobo MK. A role for peroxisome proliferator-activated receptor gamma coactivator-1? in nucleus accumbens neuron subtypes in cocaine action. Biol Psychiatry. 2017;81:564–72. source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“For example, the MDD risk gene SLC6A15 [135] is decreased in postmortem MDD NAc.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [135] Kohli MA, Lucae S, Saemann PG, Schmidt MV, Demirkan A, Hek K, et al. The neuronal transporter gene SLC6A15 confers risk to major depression. Neuron. 2011;70:252–65. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Postmortem MDD brain tissue gene expression changes reflect antemortem MDD pathophysiology.
In the paper
“FNDC5 induces thermogenesis and elevates mitochondrial gene expression [131], and resilient mice have increased NAc metabolism [132].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [132] Larrieu T, Cherix A, Duque A, Rodrigues J, Lei H, Gruetter R, et al. Hierarchical status predicts behavioral vulnerability and nucleus accumbens metabolic profile following chronic social defeat stress. Curr Biol. 2017;27:2202–10. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“In mice susceptible to CSDS, Slc6a15 is decreased selectively in D2-MSNs and stress susceptibility is recapitulated by decreasing Slc6a15 specifically in D2-MSNs [136].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [136] Chandra R, Francis TC, Nam H, Riggs LM, Engeln M, Rudzinskas S, et al. Reduced Slc6a15 in nucleus accumbens D2-neurons underlies stress susceptibility. J Neurosci. 2017;37:6527–38. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
None of the sources cited for this claim have been checked yet.
In the paper
“Transcription factors downstream of BDNF, such as transforming growth factor β-inducible early gene-1 [102], and Early Growth Response 3 (Egr3) [88] are also upregulated after social defeat (Fig. 2, middle).”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [102] Coppens CM, Siripornmongcolchai T, Wibrand K, Alme MN, Buwalda B, de Boer SF, et al. Social defeat during adolescence and adulthood differentially induce BDNF-regulated immediate early genes. Front Behav Neurosci. 2011;5:72. source
- Not checked yetcites [88] 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;22:1512–9. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“D1-MSN Nlgn2 knockdown leads to susceptibility, whereas Nlgn2 knockdown in D2-MSNs confers resilience [137].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [137] Heshmati M, Aleyasin H, Menard C, Christoffel DJ, Flanigan ME, Pfau ML, et al. Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility. Proc Natl Acad Sci USA. 2018;115:1111–6. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“In mice susceptible to CSDS, Slc6a15 is decreased selectively in D2-MSNs and stress susceptibility is recapitulated by decreasing Slc6a15 specifically in D2-MSNs [136].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [136] Chandra R, Francis TC, Nam H, Riggs LM, Engeln M, Rudzinskas S, et al. Reduced Slc6a15 in nucleus accumbens D2-neurons underlies stress susceptibility. J Neurosci. 2017;37:6527–38. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“The GTPase RhoA, which negatively regulates dendritic complexity, is increased specifically in D1-MSNs of susceptible mice [138].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [138] 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. 2018. https://doi.org/10.1038/s41380-018-0211-5 . [Epub ahead of print]. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Social defeat increases NAc PGC1α and its downstream myokine FNDC5, and FNDC5 is upregulated more in resilient mice [130].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [130] Zhan G, Huang N, Li S, Hua D, Zhang J, Fang X, et al. PGC-1α–FNDC5–BDNF signaling pathway in skeletal muscle confers resilience to stress in mice subjected to chronic social defeat. Psychopharmacology (Berl). 2018;235:3351–8. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“RhoA is transcriptionally regulated by Egr3 [88] and in stress-naive mice, increased RhoA in D1-MSNs decreases sucrose preference in males, grooming behavior in females, and forced-swim immobility.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [88] 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;22:1512–9. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“NAc ERα overexpression in male mice also induces a transcriptional profile similar to that of resilient mice [133].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [133] Lorsch ZS, Loh Y-HE, Purushothaman I, Walker DM, Parise EM, Salery M, et al. Estrogen receptor α drives pro-resilient transcription in mouse models of depression. Nat Commun. 2018;9:1116. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“In female mice subject to chronic variable stress, NAc ERα is decreased in the nuclear fraction of both D1-and D2-MSNs.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [133] Lorsch ZS, Loh Y-HE, Purushothaman I, Walker DM, Parise EM, Salery M, et al. Estrogen receptor α drives pro-resilient transcription in mouse models of depression. Nat Commun. 2018;9:1116. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“D1-MSN Nlgn2 knockdown leads to susceptibility, whereas Nlgn2 knockdown in D2-MSNs confers resilience [137].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [137] Heshmati M, Aleyasin H, Menard C, Christoffel DJ, Flanigan ME, Pfau ML, et al. Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility. Proc Natl Acad Sci USA. 2018;115:1111–6. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Synaptic cell-adhesion molecule Neurologin 2 (Nlgn2) is decreased specifically in D1-MSNs of susceptible mice.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [137] Heshmati M, Aleyasin H, Menard C, Christoffel DJ, Flanigan ME, Pfau ML, et al. Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility. Proc Natl Acad Sci USA. 2018;115:1111–6. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“The repressive histone lysine methyl-transferase G9a decreases TrkB-CREB signaling and G9a expression is decreased in the NAc of CSDS-susceptible mice [140].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [140] Covington HE, Maze I, Sun H, Bomze HM, DeMaio KD, Wu EY, et al. A role for repressive histone methylation in cocaine-Iinduced vulnerability to stress. Neuron. 2011;71:656–70. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Dnmt3aoverexpression makes both sexes susceptible to 3 days of subchronic variable stress [144], indicating transcriptional repression is a shared mechanism of stress susceptibility between the sexes.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [144] Hodes GE, Pfau ML, Purushothaman I, Ahn HF, Golden SA, Christoffel DJ, et al. Sex differences in nucleus accumbens transcriptome profiles associated with susceptibility versus resilience to subchronic variable stress. J Neurosci. 2015;35:16362–76. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Tet1 is decreased in the NAc of susceptible mice.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [145] Feng J, Pena CJ, Purushothaman I, Engmann O, Walker D, Brown AN, et al. Tet1 in nucleus accumbens opposes depression- and anxiety-like behaviors. Neuropsychopharmacology. 2017;42:1657–69. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Permissive acetylation on the Rac1 promotor, a GTPase downregulated by CSDS, is significantly reduced in susceptible mice, and susceptible mice have enhanced methylation directly upstream of the promotor [141].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [141] Golden SA, Christoffel DJ, Heshmati M, Hodes GE, Magida J, Davis K, et al. Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression. Nat Med. 2013;19:337–44. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Stalling histone turnover with viral knockdown of H3.3 produces resilience after CSDS partly due to normalization of transcriptional dysregulation of genes associated with morphology and plasticity [146].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [146] Lepack AE, Bagot RC, Peña CJ, Loh Y-HE, Farrelly LA, Lu Y, et al. Aberrant H3.3 dynamics in NAc promote vulnerability to depressive-like behavior. Proc Natl Acad Sci USA. 2016;113:12562–7. source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
None of the sources cited for this claim have been checked yet.
In the paper
“Upregulation of RhoA in D1-MSNs either by Egr3 overexpression or RhoA over-expression promotes stress susceptibility [88, 138].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [88] 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;22:1512–9. source
- Not checked yetcites [138] 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. 2018. https://doi.org/10.1038/s41380-018-0211-5 . [Epub ahead of print]. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“CSDS upregulates transcriptional repressor Dnmt3a in the NAc and chronic intra-NAc DNMT inhibition restores social interaction [143].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [143] LaPlant Q, Vialou V, Covington HE, Dumitriu D, Feng J, Warren BL, et al. Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens. Nat Neurosci. 2010;13:1137–43. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“After CSDS, inhibiting downstream effector Rho-kinase reverses social withdrawal and forced-swim immobility [138].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [138] 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. 2018. https://doi.org/10.1038/s41380-018-0211-5 . [Epub ahead of print]. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These cell-type-specific changes in gene expression are candidate mechanisms for bidirectional changes in activity (discussed above in “Bidirectional changes in D1-and D2-MSN activity”) and structure (discussed below in “Structural plasticity”).”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Epigenetic modifications are a candidate mechanism for how stress alters gene expression to convey the risk for depression.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“The repressive histone lysine methyl-transferase G9a decreases TrkB-CREB signaling and G9a expression is decreased in the NAc of CSDS-susceptible mice [140].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [140] Covington HE, Maze I, Sun H, Bomze HM, DeMaio KD, Wu EY, et al. A role for repressive histone methylation in cocaine-Iinduced vulnerability to stress. Neuron. 2011;71:656–70. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Paradoxically, NAc Tet1 knockout increases sucrose preference and social interaction in stressed mice.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [145] Feng J, Pena CJ, Purushothaman I, Engmann O, Walker D, Brown AN, et al. Tet1 in nucleus accumbens opposes depression- and anxiety-like behaviors. Neuropsychopharmacology. 2017;42:1657–69. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“CSDS upregulates transcriptional repressor Dnmt3a in the NAc and chronic intra-NAc DNMT inhibition restores social interaction [143].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [143] LaPlant Q, Vialou V, Covington HE, Dumitriu D, Feng J, Warren BL, et al. Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens. Nat Neurosci. 2010;13:1137–43. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Similarly, there is increased repressive trimethylation along the promoter region of Rac1 after social isolation stress [142].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [142] Wilkinson MB, Xiao G, Kumar A, LaPlant Q, Renthal W, Sikder D, et al. Imipramine treatment and resiliency exhibit similar chromatin regulation in the mouse nucleus accumbens in depression models. J Neurosci. 2009;29:7820–32. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“However, Tet1 overexpression induces a resilience-like NAc gene expression profile [145].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [145] Feng J, Pena CJ, Purushothaman I, Engmann O, Walker D, Brown AN, et al. Tet1 in nucleus accumbens opposes depression- and anxiety-like behaviors. Neuropsychopharmacology. 2017;42:1657–69. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Dnmt3aoverexpression makes both sexes susceptible to 3 days of subchronic variable stress [144], indicating transcriptional repression is a shared mechanism of stress susceptibility between the sexes.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [144] Hodes GE, Pfau ML, Purushothaman I, Ahn HF, Golden SA, Christoffel DJ, et al. Sex differences in nucleus accumbens transcriptome profiles associated with susceptibility versus resilience to subchronic variable stress. J Neurosci. 2015;35:16362–76. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Permissive acetylation on the Rac1 promotor, a GTPase downregulated by CSDS, is significantly reduced in susceptible mice, and susceptible mice have enhanced methylation directly upstream of the promotor [141].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [141] Golden SA, Christoffel DJ, Heshmati M, Hodes GE, Magida J, Davis K, et al. Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression. Nat Med. 2013;19:337–44. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“DNA methyltransferases (DNMTs), histone methyltransferases, and histone deacetylases (HDAC) alter the structure and function of chromatin to regulate gene expression [139].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [139] Klengel T, Pape J, Binder EB, Mehta D. The role of DNA methylation in stress-related psychiatric disorders. Neuropharmacology. 2014;80:115–32. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Permissive acetylation on the Rac1 promotor, a GTPase downregulated by CSDS, is significantly reduced in susceptible mice, and susceptible mice have enhanced methylation directly upstream of the promotor [141].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [141] Golden SA, Christoffel DJ, Heshmati M, Hodes GE, Magida J, Davis K, et al. Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression. Nat Med. 2013;19:337–44. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
None of the sources cited for this claim have been checked yet.
In the paper
“Reduced D1-MSN complexity is sufficient to drive CSDS-susceptibility [88, 138].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [88] 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;22:1512–9. source
- Not checked yetcites [138] 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. 2018. https://doi.org/10.1038/s41380-018-0211-5 . [Epub ahead of print]. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Indeed, the deacetylase SIRT1 promotes CSDS-susceptibility through D1-MSNs [147].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [147] Kim H-D, Hesterman J, Call T, Magazu S, Keeley E, Armenta K, et al. SIRT1 mediates depression-like behaviors in the nucleus accumbens. J Neurosci. 2016;36:8441–52. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
None of the sources cited for this claim have been checked yet.
In the paper
“Reduced dendritic complexity largely agrees with changes in other brain regions [151, 152] and is associated with reduced excitatory input but increased intrinsic excitability [88, 89], which may reflect homeostatic self-tuning [153].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [151] Shansky RM, Hamo C, Hof PR, McEwen BS, Morrison JH. Stress-induced dendritic remodeling in the prefrontal cortex is circuit specific. Cereb Cortex. 2009;19:2479–84. source
- Not checked yetcites [152] McEwen BS. Stress and hippocampal plasticity. Annu Rev Neurosci. 1999;22:105–22. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“NAc MSN spine density, dendritic length, and branch points are decreased after stress hormone corticosterone [149] or gestational stress [150].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [149] Morales-Medina JC, Sanchez F, Flores G, Dumont Y, Quirion R. Morphological reorganization after repeated corticosterone administration in the hippocampus, nucleus accumbens and amygdala in the rat. J Chem Neuroanat. 2009;38:266–72. source
- Not checked yetcites [150] Haim A, Sherer M, Leuner B. Gestational stress induces persistent depressive-like behavior and structural modifications within the postpartum nucleus accumbens. Eur J Neurosci. 2014;40:3766–73. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
None of the sources cited for this claim have been checked yet.
In the paper
“In the NAc, dendritic complexity of D1-, but not D2-MSNs, is reduced in CSDS-susceptible mice.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [88] 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;22:1512–9. source
- Not checked yetcites [138] 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. 2018. https://doi.org/10.1038/s41380-018-0211-5 . [Epub ahead of print]. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“MSN spine density is also increased in rats susceptible to learned helplessness [155].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [155] Yang C, Shirayama Y, Zhang J-c, Ren Q, Hashimoto K. Regional differences in brain-derived neurotrophic factor levels and dendritic spine density confer resilience to inescapable stress. Int J Neuropsychopharmacol. 2015;18:pyu121–pyu121. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Spine density is unchanged in D1-MSNs [88, 89], yet there is evidence MSNs from susceptible mice have more stubby spines [156].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [156] Christoffel DJ, Golden SA, Dumitriu D, Robison AJ, Janssen WG, Ahn HF, et al. IκB kinase regulates social defeat stress-induced synaptic and behavioral plasticity. J Neurosci. 2011;31:314–21. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
None of the sources cited for this claim have been checked yet.
In the paper
“The mechanism underlying structural plasticity of MSNs in CSDS is altered expression and activity of Rho GTPases [88, 89, 138, 141].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [88] 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;22:1512–9. source
- Not checked yetcites [89] Francis TC, Gaynor A, Chandra R, Fox ME, Lobo MK. The selective RhoA inhibitor Rhosin promotes stress resiliency through enhancing D1-MSN plasticity and reducing hyperexcitability. Biol Psychiatry. 2019. https://doi.org/10.1016/j.biopsych.2019.02.007 . source
- Not checked yetcites [138] 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. 2018. https://doi.org/10.1038/s41380-018-0211-5 . [Epub ahead of print]. source
- Not checked yetcites [141] Golden SA, Christoffel DJ, Heshmati M, Hodes GE, Magida J, Davis K, et al. Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression. Nat Med. 2013;19:337–44. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Indeed, social avoidance correlates with reductions in volume of the cingulate cortex, NAc, thalamus, raphe, and bed nucleus of the stria terminalis, suggesting the neurons in these regions may undergo structural atrophy [148].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [148] Anacker C, Scholz J, O’Donnell KJ, Allemang-Grand R, Diorio J, Bagot RC, et al. Neuroanatomic differences associated with stress susceptibility and resilience. Biol Psychiatry. 2016;79:840–9. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
None of the sources cited for this claim have been checked yet.
In the paper
“Spine density is unchanged in D1-MSNs [88, 89], yet there is evidence MSNs from susceptible mice have more stubby spines [156].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [88] 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;22:1512–9. source
- Not checked yetcites [89] Francis TC, Gaynor A, Chandra R, Fox ME, Lobo MK. The selective RhoA inhibitor Rhosin promotes stress resiliency through enhancing D1-MSN plasticity and reducing hyperexcitability. Biol Psychiatry. 2019. https://doi.org/10.1016/j.biopsych.2019.02.007 . source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“IL-6 drives production of inflammatory T-helper 17 (Th17) cells, which promote learned helplessness and social avoidance, and mice unable to produce Th17 are resilient to learned helplessness [178].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [178] Beurel E, Harrington LE, Jope RS. Inflammatory T helper 17 cells promote depression-like behavior in mice. Biol Psychiatry. 2013;73:622–30. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“There is particular interest in how inflammatory cell types in the brain cause depressive symptoms, as anti-inflammatory treatments reduce depressive symptoms in humans [173] and chronic stress enhances inflammation in animal models [174].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [174] Kubera M, Obuchowicz E, Goehler L, Brzeszcz J, Maes M. In animal models, psychosocial stress-induced (neuro)inflammation, apoptosis and reduced neurogenesis are associated to the onset of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:744–59. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“In the PFC, reduced p11 is associated with increased repressive methylation on the p11 promotor [164], but it is unclear if this also occurs in NAc ChIs.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [164] Melas PA, Rogdaki M, Lennartsson A, Björk K, Qi H, Witasp A, et al. Antidepressant treatment is associated with epigenetic alterations in the promoter of P11 in a genetic model of depression. Int J Neuropsychopharmacol. 2012;15:669–79. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Further, prolonged restraint stress decreases anti-inflammatory IL-4 and IL-10 [176].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [176] Voorhees JL, Tarr AJ, Wohleb ES, Godbout JP, Mo X, Sheridan JF, et al. Prolonged restraint stress increases IL-6, reduces IL-10, and causes persistent depressive-like behavior that is reversed by recombinant IL-10. PLoS ONE. 2013;8:e58488. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“In the brain, cytokines such as interferon-α promote depressive behaviors [179] and serotonin reuptake inhibitors have anti-inflammatory properties [180].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [179] Hayley S, Scharf J, Anisman H. Central administration of murine interferon-α induces depressive-like behavioral, brain cytokine and neurochemical alterations in mice: A mini-review and original experiments. Brain Behav Immun. 2013;31:115–27. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
None of the sources cited for this claim have been checked yet.
In the paper
“In the periphery, chronically stressed mice upregulate the pro-inflammatory cytokine interleukin 6 (IL-6) [175–177].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [175] Hodes GE, Pfau ML, Leboeuf M, Golden SA, Christoffel DJ, Bregman D, et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc Natl Acad Sci USA. 2014;111:16136–41. source
- Not checked yetcites [176] Voorhees JL, Tarr AJ, Wohleb ES, Godbout JP, Mo X, Sheridan JF, et al. Prolonged restraint stress increases IL-6, reduces IL-10, and causes persistent depressive-like behavior that is reversed by recombinant IL-10. PLoS ONE. 2013;8:e58488. source
- Not checked yetcites [177] Monje FJ, Cabatic M, Divisch I, Kim E-J, Herkner KR, Binder BR, et al. Constant darkness induces IL-6-dependent depression-like behavior through the NF- B signaling pathway. J Neurosci. 2011;31:9075–83. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Decreased ChI activity may modulate local MSN activity to cause depressive behaviors, as optogenetic inhibition of ChI enhances MSN spiking [159].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [159] Witten IB, Lin S-C, Brodsky M, Prakash R, Diester I, Anikeeva P, et al. Cholinergic interneurons control local circuit activity and cocaine conditioning. Science (80-). 2010;330:1677–81. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“There is particular interest in how inflammatory cell types in the brain cause depressive symptoms, as anti-inflammatory treatments reduce depressive symptoms in humans [173] and chronic stress enhances inflammation in animal models [174].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [173] Köhler O, Benros ME, Nordentoft M, Farkouh ME, Iyengar RL, Mors O, et al. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects. JAMA Psychiatry. 2014;71:1381. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Decreased ChI activity may modulate local MSN activity to cause depressive behaviors, as optogenetic inhibition of ChI enhances MSN spiking [159].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [159] Witten IB, Lin S-C, Brodsky M, Prakash R, Diester I, Anikeeva P, et al. Cholinergic interneurons control local circuit activity and cocaine conditioning. Science (80-). 2010;330:1677–81. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Thus, we believe the stress-related changes to spine density occur on D2-MSNs, as D2-MSNs do not undergo dendritic atrophy but have enhanced excitatory input [82].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [82] 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
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
None of the sources cited for this claim have been checked yet.
In the paper
“CSDS promotes recruitment of circulating monocytes and macrophages into the brain perivascular space via complement 3 receptor and CX3C chemokine receptor 1 signaling [181–183].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [181] Wohleb ES, Powell ND, Godbout JP, Sheridan JF. Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior. J Neurosci. 2013;33:13820–33. source
- Not checked yetcites [182] Wohleb ES, McKim DB, Shea DT, Powell ND, Tarr AJ, Sheridan JF, et al. Re-establishment of anxiety in stress-sensitized mice is caused by monocyte trafficking from the spleen to the brain. Biol Psychiatry. 2014;75:970–81. source
- Not checked yetcites [183] Crider A, Feng T, Pandya CD, Davis T, Nair A, Ahmed AO, et al. Complement component 3a receptor deficiency attenuates chronic stress-induced monocyte infiltration and depressive-like behavior. Brain Behav Immun. 2018;70:246–56. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“IL-6 drives production of inflammatory T-helper 17 (Th17) cells, which promote learned helplessness and social avoidance, and mice unable to produce Th17 are resilient to learned helplessness [178].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [178] Beurel E, Harrington LE, Jope RS. Inflammatory T helper 17 cells promote depression-like behavior in mice. Biol Psychiatry. 2013;73:622–30. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“In the brain, cytokines such as interferon-α promote depressive behaviors [179] and serotonin reuptake inhibitors have anti-inflammatory properties [180].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [180] Walker FR. A critical review of the mechanism of action for the selective serotonin reuptake inhibitors: do these drugs possess anti-inflammatory properties and how relevant is this in the treatment of depression? Neuropharmacology. 2013;67:304–17. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“However, in mice previously exposed to CUS, LPS decreases forced-swim immobility [188].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [188] Kreisel T, Frank MG, Licht T, Reshef R, Ben-Menachem-Zidon O, Baratta MV, et al. Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis. Mol Psychiatry. 2014;19:699–709. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“The “stress programmed” lymphocytes alter the microglia in Rag2−/− mice, causing them to skew toward a more neuroprotective, M2-like profile [193].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [193] Brachman RA, Lehmann ML, Maric D, Herkenham M. Lymphocytes from chronically stressed mice confer antidepressant-like effects to naive mice. J Neurosci. 2015;35:1530–8. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Chronic stress alters microglia density, morphology, and function dependent on stress duration and brain region [188].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [188] Kreisel T, Frank MG, Licht T, Reshef R, Ben-Menachem-Zidon O, Baratta MV, et al. Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis. Mol Psychiatry. 2014;19:699–709. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
None of the sources cited for this claim have been checked yet.
In the paper
“Anhedonia caused by high-fat diet or restraint stress is associated with increased ionized calcium-binding adaptor molecule 1-positive microglia in several brain regions including the NAc [189, 190].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [189] Tynan RJ, Naicker S, Hinwood M, Nalivaiko E, Buller KM, Pow DV, et al. Chronic stress alters the density and morphology of microglia in a subset of stress-responsive brain regions. Brain Behav Immun. 2010;24:1058–68. source
- Not checked yetcites [190] Décarie-Spain L, Sharma S, Hryhorczuk C, Issa-Garcia V, Barker PA, Arbour N, et al. Nucleus accumbens inflammation mediates anxiodepressive behavior and compulsive sucrose seeking elicited by saturated dietary fat. Mol Metab. 2018;10:1–13. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Cytokines can also be released by neurons and in a spinal nerve ligation model of anhedonia, cytokine CCL2 is upregulated in both NAc D1-and D2-MSNs.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [192] Wu X-B, Jing P-B, Zhang Z-J, Cao D-L, Gao M-H, Jiang B-C, et al. Chemokine receptor CCR2 contributes to neuropathic pain and the associated depression via increasing NR2B-mediated currents in both D1 and D2 dopamine receptor-containing medium spiny neurons in the nucleus accumbens shell. Neuropsychopharmacology. 2018;43:2320–30. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“As microglia are the resident immune cells of the central nervous system (CNS) and microglial transcripts are upregulated after stress [185], they are an attractive linker between inflammation and depression in the brain.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [185] Wohleb ES, Terwilliger R, Duman CH, Duman RS. Stress-induced neuronal colony stimulating factor 1 provokes microglia-mediated neuronal remodeling and depressive-like behavior. Biol Psychiatry. 2018;83:38–49. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Further, severe combined immunodeficiency mice have impaired social preference [195].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [195] Filiano AJ, Xu Y, Tustison NJ, Marsh RL, Baker W, Smirnov I, et al. Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature. 2016;535:425–9. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Viral inhibition of IKK and NF-κB in NAc also prevents neuroinflammation and forced-swim immobility caused by high-fat diet [190].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [190] Décarie-Spain L, Sharma S, Hryhorczuk C, Issa-Garcia V, Barker PA, Arbour N, et al. Nucleus accumbens inflammation mediates anxiodepressive behavior and compulsive sucrose seeking elicited by saturated dietary fat. Mol Metab. 2018;10:1–13. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Chronic stress also increases the leakiness of the blood-brain barrier to permit infiltration of peripheral immune cells and cytokines such as IL-6 [184].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [184] Menard C, Pfau ML, Hodes GE, Kana V, Wang VX, Bouchard S, et al. Social stress induces neurovascular pathology promoting depression. Nat Neurosci. 2017;20:1752–60. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Dysregulation of the brain’s reward circuitry is heavily implicated in the symptomology of depression and the use of genetic and viral tools has enabled us to define the precise cell types that contribute to anhedonia.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Concluding remarks
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This subset of patients certainly does not represent the entirety of individuals suffering from MDD and we must try to identify biomarkers that are more readily accessible in living humans with MDD.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Concluding remarks
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Postmortem MDD brain tissue gene expression changes reflect antemortem MDD pathophysiology.
In the paper
“As glutamate clearance modulates neuronal excitability [200] and glutamatergic synapse strength contributes to depression [202], how astrocytic glutamate clearance contributes to excitatory synapse strength and subsequent depressive behavior is also worth further investigation in the reward circuit.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [200] Cui W, Mizukami H, Yanagisawa M, Aida T, Nomura M, Isomura Y, et al. Glial dysfunction in the mouse habenula causes depressive-like behaviors and sleep disturbance. J Neurosci. 2014;34:16273–85. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Indeed, CUS can downregulate myelin and oligodendrocyte-specific transcripts in the NAc [199].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [199] Liu J, Dietz K, Hodes GE, Russo SJ, Casaccia P. Widespread transcriptional alternations in oligodendrocytes in the adult mouse brain following chronic stress. Dev Neurobiol. 2018;78:152–62. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“As glutamate clearance modulates neuronal excitability [200] and glutamatergic synapse strength contributes to depression [202], how astrocytic glutamate clearance contributes to excitatory synapse strength and subsequent depressive behavior is also worth further investigation in the reward circuit.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [202] Thompson SM, Kallarackal AJ, Kvarta MD, Van Dyke AM, LeGates TA, Cai X. An excitatory synapse hypothesis of depression. Trends Neurosci. 2015;38:279–94. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Dysregulation of the brain’s reward circuitry is heavily implicated in the symptomology of depression and the use of genetic and viral tools has enabled us to define the precise cell types that contribute to anhedonia.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Concluding remarks
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“The gut microbiome controls gut permeability and inflammation, and may thus participate in the neuroimmune mechanisms of depression [197].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [197] Foster JA, McVey Neufeld K-A. Gut–brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36:305–12. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Mice with reduced glutamate transporter GLT-1 expression in habenular astrocytes are more stress-susceptible and exhibit increased tail-suspension immobility at baseline [200], in agreement with reduced glutamate transporter expression in learned helpless rats [201].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [201] Zink M, Vollmayr B, Gebicke-Haerter PJ, Henn FA. Reduced expression of glutamate transporters vGluT1, EAAT2 and EAAT4 in learned helpless rats, an animal model of depression. Neuropharmacology. 2010;58:465–73. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
- It may state two separate claims as one. 49
- Probably not a substantial claim. 4
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“CB2 activation reduces VTA dopamine neuron firing [39] and immobility in forced-swim and tail-suspension tests [40].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Supportedcites [39] Zhang H-Y, Gao M, Liu Q-R, Bi G-H, Li X, Yang H-J, et al. Cannabinoid CB2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice. Proc Natl Acad Sci USA. 2014;111:E5007–15. source
Citation [39] is attached only to the claim about VTA dopamine neuron firing; the immobility claim is attributed to [40]. In “CB2R Activation Inhibits VTA DA Neuronal Firing” (page not provided), the paper reports that CB2 receptor agonists inhibited VTA dopamine neuronal firing. (LLM, conf=0.94)
- Not checked yetcites [40] Bahi A, Al Mansouri S, Al Memari E, Al Ameri M, Nurulain SM, Ojha S. β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice. Physiol Behav. 2014;135:119–24. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
In the paper
“The stress-induced behavioral phenotypes are reversed by chronic, but not acute antidepressant treatment, and are thus posited to have both face and predictive validity [8].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction
What the sources say
- Not checked yetcites [8] Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. Nat Neurosci. 2010;13:1161–9. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Reward learning and connectivity between the VTA and striatum is impaired in MDD patients [18, 19].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [18] 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. Neuropsychopharmacology. 2018;43:1581–8. source
- Not checked yetcites [19] Blood AJ, Iosifescu DV, Makris N, Perlis RH, Kennedy DN, Dougherty DD, et al. Microstructural abnormalities in subcortical reward circuitry of subjects with major depressive disorder. PLoS ONE. 2010;5:e13945. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“dopaminergic neurons in the VTA fire in response to unpredicted reward and in anticipation of impending reward [20]”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [20] Schultz W. Reward prediction error. Curr Biol. 2017;27:R369–R371. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“rodents are exposed to a series of stressors such as cage tilting and disrupted lights for 8–12 weeks [10], after which animals show reduced sucrose preference.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Chronic unpredictable stress
What the sources say
- Not checked yetcites [10] Willner P. The chronic mild stress (CMS) model of depression: history, evaluation and usage. Neurobiol Stress. 2017;6:78–93. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Approximately 70% of mice that undergo CSDS are termed “stress-susceptible,” displaying a robust depression-like phenotype marked by reduced social interaction, increased anhedonia, and significant body-weight changes [13].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Social defeat stress
What the sources say
- Not checked yetcites [13] Krishnan V, Han M-HH, Graham DL, Berton O, Renthal W, Russo SJ, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131:391–404. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“inhibiting VTA dopamine neurons that project to the NAc induces resilience but inhibiting VTA dopamine projections to medial prefrontal cortex (mPFC) promotes CSDS susceptibility [23].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [23] Chaudhury D, Walsh JJ, Friedman AK, Juarez B, Ku SM, Koo JW, et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature. 2013;493:532–6. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Increased Ih currents occur specifically in NAc, but not mPFC projecting VTA dopamine neurons [30]”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [30] Friedman AK, Walsh JJ, Juarez B, Ku SM, Chaudhury D, Wang J, et al. Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience. Science. 2014;344:313–9. https://doi.org/10.1126/science.1249240 . source
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In the paper
“Ih and intrinsic excitability are upregulated in CSDS-susceptible mice [30], but somewhat paradoxically, Ih is upregulated to a greater extent in resilient mice.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [30] Friedman AK, Walsh JJ, Juarez B, Ku SM, Chaudhury D, Wang J, et al. Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience. Science. 2014;344:313–9. https://doi.org/10.1126/science.1249240 . source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“KCNQ channel Kv7.4 is an attractive target in depression, as this subtype is more selectively expressed in VTA (not substantia nigra) dopamine neurons and Kv7.4 currents are reduced in susceptible mice [27].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [27] Li L, Sun H, Ding J, Niu C, Su M, Zhang L, et al. Selective targeting of M-type potassium Kv 7.4 channels demonstrates their key role in the regulation of dopaminergic neuronal excitability and depression-like behaviour. Br J Pharmacol. 2017;174:4277–94. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“KCNQ overexpression or administration of KCNQ-openers rescues depressive behavior [25, 27] by reducing firing of NAc projecting, but not PFC projecting VTA dopamine neurons [25].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [25] Friedman AK, Juarez B, Ku SM, Zhang H, Calizo RC, Walsh JJ, et al. KCNQ channel openers reverse depressive symptoms via an active resilience mechanism. Nat Commun. 2016;7:11671. source
- Not checked yetcites [27] Li L, Sun H, Ding J, Niu C, Su M, Zhang L, et al. Selective targeting of M-type potassium Kv 7.4 channels demonstrates their key role in the regulation of dopaminergic neuronal excitability and depression-like behaviour. Br J Pharmacol. 2017;174:4277–94. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Ih potentiation with repeated lamotrigine increases K+ currents and decreases neuronal excitability in previously susceptible mice to reverse social and sucrose preference deficits [25].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [25] Friedman AK, Juarez B, Ku SM, Zhang H, Calizo RC, Walsh JJ, et al. KCNQ channel openers reverse depressive symptoms via an active resilience mechanism. Nat Commun. 2016;7:11671. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Sucrose preference deficits, social avoidance, and VTA excitability are reduced by opening Kv7.4 channels with fasudil [27]”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [27] Li L, Sun H, Ding J, Niu C, Su M, Zhang L, et al. Selective targeting of M-type potassium Kv 7.4 channels demonstrates their key role in the regulation of dopaminergic neuronal excitability and depression-like behaviour. Br J Pharmacol. 2017;174:4277–94. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“chronic stress increases extracellular signal-regulated kinase 2 (ERK2) activity in the VTA and inhibiting VTA ERK2 rescues CSDS-susceptibility and reduces forced-swim and tail-suspension immobility by reducing dopamine neuron excitability [47].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [47] Iñiguez SD, Vialou V, Warren BL, Cao J-L, Alcantara LF, Davis LC, et al. Extracellular signal-regulated kinase-2 within the ventral tegmental area regulates responses to stress. J Neurosci. 2010;30:7652–63. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Rats exposed to chronic mild stress have fewer spontaneously active dopamine neurons [52, 53], an effect more pronounced in females [53].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [52] Moreines JL, Owrutsky ZL, Gagnon KG, Grace AA. Divergent effects of acute and repeated quetiapine treatment on dopamine neuron activity in normal vs. chronic mild stress induced hypodopaminergic states. Transl Psychiatry. 2017;7:1275. source
- Not checked yetcites [53] Rincón-Cortés M, Grace AA. Sex-dependent effects of stress on immobility behavior and VTA dopamine neuron activity: modulation by ketamine. Int J Neuropsychopharmacol. 2017;20:823–32. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“VTA firing is also reduced in mice exposed to CUS and optogenetic stimulation in this context reverses, instead of promotes, stress-induced behavioral deficits [54].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [54] Tye KM, Mirzabekov JJ, Warden MR, Ferenczi EA, Tsai H-C, Finkelstein J, et al. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature. 2013;493:537–41. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“long-term activation of PPARα decreases β2-nAChR phosphorylation, increases dopamine neuron bursting, and rescues sucrose self-administration after stress [59].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [59] Scheggi S, Melis M, De Felice M, Aroni S, Muntoni AL, Pelliccia T, et al. PPARα modulation of mesolimbic dopamine transmission rescues depression-related behaviors. Neuropharmacology. 2016;110:251–9. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Peroxisome proliferator-activated receptor α (PPARα) signaling increases β2-nAChR phosphorylation, which subsequently decreases VTA dopamine neuron firing [58].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Ventral tegmental area
What the sources say
- Not checked yetcites [58] Melis M, Carta S, Fattore L, Tolu S, Yasar S, Goldberg SR, et al. Peroxisome proliferator-activated receptors-alpha modulate dopamine cell activity through nicotinic receptors. Biol Psychiatry. 2010;68:256–64. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“β-Cat regulates Dicer1, a microRNA regulator that, in turn, modulates other known pro-susceptibility genes such as Arc and Npas4 [127].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [127] Dias C, Feng J, Sun H, Shao NY, Mazei-Robison MS, Damez-Werno D, et al. β-catenin mediates stress resilience through Dicer1/microRNA regulation. Nature. 2014;516:51–5. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“FNDC5 induces thermogenesis and elevates mitochondrial gene expression [131], and resilient mice have increased NAc metabolism [132].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [131] Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481:463–8. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In both male and female mice, NAc ERα overexpression increases sucrose preference and promotes CSDS-resilience in males [133].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [133] Lorsch ZS, Loh Y-HE, Purushothaman I, Walker DM, Parise EM, Salery M, et al. Estrogen receptor α drives pro-resilient transcription in mouse models of depression. Nat Commun. 2018;9:1116. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Egr3 is upregulated specifically in D1-MSNs of susceptible mice and its knockdown can prevent altered synaptic activity and stress susceptibility [88].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [88] 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;22:1512–9. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Social defeat increases NAc PGC1α and its downstream myokine FNDC5, and FNDC5 is upregulated more in resilient mice [130].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [130] Zhan G, Huang N, Li S, Hua D, Zhang J, Fang X, et al. PGC-1α–FNDC5–BDNF signaling pathway in skeletal muscle confers resilience to stress in mice subjected to chronic social defeat. Psychopharmacology (Berl). 2018;235:3351–8. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“RhoA is transcriptionally regulated by Egr3 [88] and in stress-naive mice, increased RhoA in D1-MSNs decreases sucrose preference in males, grooming behavior in females, and forced-swim immobility.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [138] 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. 2018. https://doi.org/10.1038/s41380-018-0211-5 . [Epub ahead of print]. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Intra-NAc HDAC inhibition reverses social avoidance induced by CSDS, likely caused by increased Rac1 expression [141].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [141] Golden SA, Christoffel DJ, Heshmati M, Hodes GE, Magida J, Davis K, et al. Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression. Nat Med. 2013;19:337–44. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Repressive histone modifications are both up-and downregulated after social defeat stress, and these changes are linked to genes with known roles in CSDS-susceptibility.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [140] Covington HE, Maze I, Sun H, Bomze HM, DeMaio KD, Wu EY, et al. A role for repressive histone methylation in cocaine-Iinduced vulnerability to stress. Neuron. 2011;71:656–70. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Subchronic stress also upregulates NAc Dnmt3a, but to a greater extent in stressed females.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [144] Hodes GE, Pfau ML, Purushothaman I, Ahn HF, Golden SA, Christoffel DJ, et al. Sex differences in nucleus accumbens transcriptome profiles associated with susceptibility versus resilience to subchronic variable stress. J Neurosci. 2015;35:16362–76. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“G9a overexpression promotes resilience, thought to occur by normalization of TrkB-CREB signaling [140].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [140] Covington HE, Maze I, Sun H, Bomze HM, DeMaio KD, Wu EY, et al. A role for repressive histone methylation in cocaine-Iinduced vulnerability to stress. Neuron. 2011;71:656–70. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Expression of activity-dependent histone variant H3.3 (H3f3b) is increased in the NAc in postmortem MDD tissue, after early life stress, and in CSDS-susceptible mice, an effect prevented in mice by environmental enrichment [146].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [146] Lepack AE, Bagot RC, Peña CJ, Loh Y-HE, Farrelly LA, Lu Y, et al. Aberrant H3.3 dynamics in NAc promote vulnerability to depressive-like behavior. Proc Natl Acad Sci USA. 2016;113:12562–7. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: Postmortem MDD brain tissue gene expression changes reflect antemortem MDD pathophysiology.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
None of the sources cited for this claim have been checked yet.
In the paper
“Pro-susceptibility Dnmt3a overexpression [143] or constitutively active IκB kinase (IKK) [156, 157] both increase MSN spine density.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [143] LaPlant Q, Vialou V, Covington HE, Dumitriu D, Feng J, Warren BL, et al. Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens. Nat Neurosci. 2010;13:1137–43. source
- Not checked yetcites [156] Christoffel DJ, Golden SA, Dumitriu D, Robison AJ, Janssen WG, Ahn HF, et al. IκB kinase regulates social defeat stress-induced synaptic and behavioral plasticity. J Neurosci. 2011;31:314–21. source
- Not checked yetcites [157] Christoffel DJ, Golden SA, Heshmati M, Graham A, Birnbaum S, Neve RL, et al. Effects of inhibitor of κB kinase activity in the nucleus accumbens on emotional behavior. Neuropsychopharmacology. 2012;37:2615–23. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Histone acetylation on the Fosb promotor drives resilience in D1-MSNs, but susceptibility in D2-MSNs [124].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [124] Hamilton PJ, Burek DJ, Lombroso SI, Neve RL, Robison AJ, Nestler EJ, et al. Cell-type-specific epigenetic editing at the Fosb gene controls susceptibility to social defeat stress. Neuropsychopharmacology. 2018;43:272–84. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“In contrast, CUS increases dendritic length of NAc core MSNs, which is reversed by imipramine or fluoxetine treatment [154].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [154] Bessa JM, Morais M, Marques F, Pinto L, Palha JA, Almeida OFX, et al. Stress-induced anhedonia is associated with hypertrophy of medium spiny neurons of the nucleus accumbens. Transl Psychiatry. 2013;3:e266–e266. source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
None of the sources cited for this claim have been checked yet.
In the paper
“Reduced dendritic complexity largely agrees with changes in other brain regions [151, 152] and is associated with reduced excitatory input but increased intrinsic excitability [88, 89], which may reflect homeostatic self-tuning [153].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [88] 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;22:1512–9. source
- Not checked yetcites [89] Francis TC, Gaynor A, Chandra R, Fox ME, Lobo MK. The selective RhoA inhibitor Rhosin promotes stress resiliency through enhancing D1-MSN plasticity and reducing hyperexcitability. Biol Psychiatry. 2019. https://doi.org/10.1016/j.biopsych.2019.02.007 . source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“CSDS-susceptible mice upregulate cytokines IL-1β and CXCL1, and have more circulating leukocytes [175].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [175] Hodes GE, Pfau ML, Leboeuf M, Golden SA, Christoffel DJ, Bregman D, et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc Natl Acad Sci USA. 2014;111:16136–41. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
None of the sources cited for this claim have been checked yet.
In the paper
“Mice lacking p11 [162], p11 reductions in NAc [163], or p11 knockout in NAc ChIs [158] is sufficient to reduce sucrose preference and increase forced-swim immobility (Fig. 2, top).”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [162] Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M, et al. Alterations in 5-HT1B receptor function by p11 in depression-like states. Science. 2006;311:77–80. source
- Not checked yetcites [163] Alexander B, Warner-Schmidt J, Eriksson T, Tamminga C, Arango-Llievano M, Ghose S, et al. Reversal of depressed behaviors in mice by p11 gene therapy in the nucleus accumbens. Sci Transl Med. 2010;2:54ra76–54ra76. source
- Not checked yetcites [158] Warner-Schmidt JL, Schmidt EF, Marshall JJ, Rubin AJ, Arango-Lievano M, Kaplitt MG, et al. Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior. Proc Natl Acad Sci USA. 2012;109:11360–5. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Silencing NAc cholinergic interneurons (ChIs) results in anhedonia and increases immobility in the forced-swim and tail-suspension tests [158].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Nucleus accumbens
What the sources say
- Not checked yetcites [158] Warner-Schmidt JL, Schmidt EF, Marshall JJ, Rubin AJ, Arango-Lievano M, Kaplitt MG, et al. Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior. Proc Natl Acad Sci USA. 2012;109:11360–5. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“IL-6 drives production of inflammatory T-helper 17 (Th17) cells, which promote learned helplessness and social avoidance, and mice unable to produce Th17 are resilient to learned helplessness [178].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [178] Beurel E, Harrington LE, Jope RS. Inflammatory T helper 17 cells promote depression-like behavior in mice. Biol Psychiatry. 2013;73:622–30. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
None of the sources cited for this claim have been checked yet.
In the paper
“At least 40% of cells in the rodent [171] and human [172] brain are non-neuronal, but how non-neuronal cells interact with reward circuitry in MDD is unknown.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [171] Herculano-Houzel S, Lent R. Isotropic fractionator: a simple, rapid method for the quantification of total cell and neuron numbers in the brain. J Neurosci. 2005;25:2518–21. source
- Not checked yetcites [172] von Bartheld CS, Bahney J, Herculano-Houzel S. The search for true numbers of neurons and glial cells in the human brain: a review of 150 years of cell counting. J Comp Neurol. 2016;524:3865–95. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Microglia found in healthy reward circuitry are incredibly diverse [196] and more work is needed to profile their function in pathologic states.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [196] De Biase LM, Schuebel KE, Fusfeld ZH, Jair K, Hawes IA, Cimbro R, et al. Local cues establish and maintain region-specific phenotypes of basal ganglia microglia. Neuron. 2017;95:341–.e6. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Microglia in CUS mice have enhanced colony stimulating factor 1 receptor expression and enhanced phagocytotic activity, paralleled by CSF1 elevations in postmortem MDD tissue [185].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [185] Wohleb ES, Terwilliger R, Duman CH, Duman RS. Stress-induced neuronal colony stimulating factor 1 provokes microglia-mediated neuronal remodeling and depressive-like behavior. Biol Psychiatry. 2018;83:38–49. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Postmortem MDD brain tissue gene expression changes reflect antemortem MDD pathophysiology.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Bacteria in the gastrointestinal tract directly influence neural activity through sensory neurons, or by modulating the function of the hypothalamic–pituitary–adrenal axis (reviewed in ref. [197]).”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [197] Foster JA, McVey Neufeld K-A. Gut–brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36:305–12. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In the absence of stress, constitutively active IKK increases thin spine density, increases forced-swim immobility, and decreases sucrose preference after acute stress [156, 157].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [156] Christoffel DJ, Golden SA, Dumitriu D, Robison AJ, Janssen WG, Ahn HF, et al. IκB kinase regulates social defeat stress-induced synaptic and behavioral plasticity. J Neurosci. 2011;31:314–21. source
- Not checked yetcites [157] Christoffel DJ, Golden SA, Heshmati M, Graham A, Birnbaum S, Neve RL, et al. Effects of inhibitor of κB kinase activity in the nucleus accumbens on emotional behavior. Neuropsychopharmacology. 2012;37:2615–23. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
None of the sources cited for this claim have been checked yet.
In the paper
“CSDS increases IKK and NF-κB, along with the number of immature dendritic spines in the NAc of susceptible mice [156, 157].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [156] Christoffel DJ, Golden SA, Dumitriu D, Robison AJ, Janssen WG, Ahn HF, et al. IκB kinase regulates social defeat stress-induced synaptic and behavioral plasticity. J Neurosci. 2011;31:314–21. source
- Not checked yetcites [157] Christoffel DJ, Golden SA, Heshmati M, Graham A, Birnbaum S, Neve RL, et al. Effects of inhibitor of κB kinase activity in the nucleus accumbens on emotional behavior. Neuropsychopharmacology. 2012;37:2615–23. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“When lymphocytes from socially defeated mice are transplanted into Rag2−/− lymphopoenic mice, recipient mice exhibit more social interaction and less tail-suspension immobility [193].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [193] Brachman RA, Lehmann ML, Maric D, Herkenham M. Lymphocytes from chronically stressed mice confer antidepressant-like effects to naive mice. J Neurosci. 2015;35:1530–8. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Mice that lack microglial autophagy-related protein 7 exhibit impaired social interaction and increased immature synapses [194].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [194] Kim H-J, Cho M-H, Shim WH, Kim JK, Jeon E-Y, Kim D-H, et al. Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects. Mol Psychiatry. 2017;22:1576–84. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Microglia from socially defeated mice have an increased inflammatory profile and produce more IL-6 after lipopolysaccharide (LPS) stimulation [191], similar to enhanced IL-6 release from the peripheral leukocytes of stressed mice [175].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [191] Wohleb ES, Hanke ML, Corona AW, Powell ND, Stiner LM, Bailey MT, et al. β-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat. J Neurosci. 2011;31:6277–88. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Ccl2 reduction with short hairpin RNA restores sucrose preference and increases swimming in the forced-swim test [192].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [192] Wu X-B, Jing P-B, Zhang Z-J, Cao D-L, Gao M-H, Jiang B-C, et al. Chemokine receptor CCR2 contributes to neuropathic pain and the associated depression via increasing NR2B-mediated currents in both D1 and D2 dopamine receptor-containing medium spiny neurons in the nucleus accumbens shell. Neuropsychopharmacology. 2018;43:2320–30. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Viral knockdown of neuronal Csf1 attenuates dendritic spine pruning on mPFC neurons and prevents stress-induced anhedonia and forced-swim immobility [185].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [185] Wohleb ES, Terwilliger R, Duman CH, Duman RS. Stress-induced neuronal colony stimulating factor 1 provokes microglia-mediated neuronal remodeling and depressive-like behavior. Biol Psychiatry. 2018;83:38–49. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Similarly, although we know changes to NAc D1-and D2-MSN function are bidirectional, most of this work was done solely in male rodents.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Concluding remarks
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Mice with reduced glutamate transporter GLT-1 expression in habenular astrocytes are more stress-susceptible and exhibit increased tail-suspension immobility at baseline [200], in agreement with reduced glutamate transporter expression in learned helpless rats [201].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [200] Cui W, Mizukami H, Yanagisawa M, Aida T, Nomura M, Isomura Y, et al. Glial dysfunction in the mouse habenula causes depressive-like behaviors and sleep disturbance. J Neurosci. 2014;34:16273–85. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“The gut microbiome controls gut permeability and inflammation, and may thus participate in the neuroimmune mechanisms of depression [197].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [197] Foster JA, McVey Neufeld K-A. Gut–brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36:305–12. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These studies have revealed important adaptations in both dopaminergic and glutamatergic function within the VTA and NAc, and notably these adaptations can differ in directionality based on cell type or stress paradigm.”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Concluding remarks
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
In the paper
“Recent work indicates gut microbiota can also influence neural metabolism [198].”
§ The molecular and cellular mechanisms of depression: a focus on reward circuitry > Introduction > Non-neuronal cell types in reward circuitry
What the sources say
- Not checked yetcites [198] Zheng P, Zeng B, Zhou C, Liu M, Fang Z, Xu X, et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol Psychiatry. 2016;21:786–96. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Altered reward circuit function underlies the loss of pleasure and amotivational syndrome experienced by most major depressive disorder patients.
“Altered reward circuit function is theorized to underlie the loss of pleasure and amotivational syndrome experienced by most MDD patients”
The paper relies on this without support.
Preclinical rodent models are useful for identifying cell-type-specific mechanisms that are otherwise inaccessible in human studies.
“Preclinical rodent models for studying depression have been useful for identifying the cell-type-specific mechanisms that are otherwise inaccessible in human studies.”
The paper relies on this without support.
Rats and mice do not likely experience the complex cognitive aspects of clinical depression.
“Although rats and mice do not likely experience the complex cognitive aspects of clinical depression”
The paper relies on this without support.
Rodents, similar to humans, want to work for rewards such as food, sex, and social interaction.
“rodents, similar to humans, want to work for rewards such as food, sex, and social interaction.”
The paper relies on this without support.
The stressful experiences that precipitate major depressive disorder likely represent a combination of physical and psychosocial stressors.
“the stressful experiences that precipitate MDD likely represent a combination thereof.”
The paper relies on this without support.
Postmortem MDD brain tissue gene expression changes reflect antemortem MDD pathophysiology.
“Much of the validation of the molecular changes found in rodents relies on tissue collected from postmortem MDD brains.”
The paper relies on this without support.
Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.
“Together, these studies provide insight into how stress exposure alters NAc MSN physiology to elicit depressive behavior.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“A number of studies have found that chronic stressors cause maladaptive adaptations in the mesolimbic DA system [148], the details of which seem to be influenced by the nature and the degree of the stressor.”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [148]
Citations
Cites
1 retracted
Yang, C., Shirayama, Y., Zhang, J.-C., Ren, Q., & Hashimoto, K. (2015) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyu121 · Cited by 103
RetractedA PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis
Boström, P., Wu, J., Jedrychowski, M. P., Korde, A., Ye, L., Lo, J. C., Rasbach, K. A., Boström, E. A., Choi, J. H., Long, J. Z., et al. (2012) · Nature · doi:10.1038/nature10777 · Cited by 4,810
Nestler, E. J., Barrot, M., DiLeone, R. J., Eisch, A. J., Gold, S. J., & Monteggia, L. M. (2002) · Neuron · doi:10.1016/s0896-6273(02)00653-0 · Cited by 3,217
Structural basis of long-term potentiation in single dendritic spines
Matsuzaki, M., Honkura, N., Ellis-Davies, G. C. R., & Kasai, H. (2004) · Nature · doi:10.1038/nature02617 · Cited by 2,483
Gut–brain axis: How the microbiome influences anxiety and depression
Foster, J. A., & McVey Neufeld, K.-A. (2013) · Trends in Neurosciences · doi:10.1016/j.tins.2013.01.005 · Cited by 2,460
Krishnan, V., Han, M.-H., Graham, D. L., Berton, O., Renthal, W., Russo, S. J., LaPlant, Q., Graham, A., Lutter, M., Lagace, D. C., et al. (2007) · Cell · doi:10.1016/j.cell.2007.09.018 · Cited by 2,307
Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases
Tang, Y., & Le, W. (2016) · Molecular Neurobiology · doi:10.1007/s12035-014-9070-5 · Cited by 2,190
Resting-state connectivity biomarkers define neurophysiological subtypes of depression
Drysdale, A. T., Grosenick, L., Downar, J., Dunlop, K., Mansouri, F., Meng, Y., Fetcho, R. N., Zebley, B., Oathes, D. J., Etkin, A., et al. (2017) · Nature Medicine · doi:10.1038/nm.4246 · Cited by 2,170
Self-citationSTRESS AND HIPPOCAMPAL PLASTICITY
McEwen, B. S. (1999) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.22.1.105 · Cited by 2,087
Animal models of neuropsychiatric disorders
Nestler, E. J., & Hyman, S. E. (2010) · Nature Neuroscience · doi:10.1038/nn.2647 · Cited by 2,023
Cited by
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Major Depression: One Brain, One Disease, One Set of Intertwined Processes
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Li, Z., Liu, Y., Wei, R., Yong, V. W., & Xue, M. (2022) · Biomolecules · doi:10.3390/biom13010028 · Cited by 170
Gebara, E., Zanoletti, O., Ghosal, S., Grosse, J., Schneider, B. L., Knott, G. W., Astori, S., & Sandi, C. (2020) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.12.003 · Cited by 152
Tan, T., Wang, W., Liu, T., Zhong, P., Conrow‐Graham, M., Tian, X., & Yan, Z. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.108874 · Cited by 104
Metadata
- Authors
- Fox, M. E., & Lobo, M. K.
- Affiliations
- University of Maryland, Baltimore (US)
- Corresponding author
- Lobo, Mary Kay
- Venue
- Molecular Psychiatry
- Published
- 2019-04-09
- Volume
- 24
- Issue
- 12
- Pages
- 1798-1815
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC6785351
- OpenAlex
- W2937907669
- Cited by
- 232
- References
- 209
- Citations by year
- 2026: 19 · 2025: 41 · 2024: 37 · 2023: 41 · 2022: 40 · 2021: 38 · 2020: 13 · 2019: 2
- FWCI
- 3.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R01MH106500, F32 MH116574)
- U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (R01DA038613, R01DA047843)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- depression, reward systems, anhedonia, social withdrawal, neurovegetative symptoms, weight loss, neurophysiological mechanisms, rodent models of depression
- MeSH terms
- Animals, Depression, Major Depressive Disorder, Disease Models, Animal, Humans, Motivation, Reward, Social Behavior, Weight Loss, Anhedonia
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
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