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Cited by 233Neurotransmitter Receptor Influence on BehaviorTreatment of Major DepressionNeuroscience and Neuropharmacology Research

The molecular and cellular mechanisms of depression: a focus on reward circuitry

Open access
Fox, Megan E., Lobo, Mary Kay·2019·Molecular Psychiatry
DOI 10.1038/s41380-019-0415-3PMC PMC6785351
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Abstract

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.

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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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Integrity signals

Registry

Crossref · 10.1038/s41380-019-0415-3

Cites

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Statistics

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Claims the paper makes

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  • Premisecitation

    The remaining approximately 30% of mice retain preference for social interaction and are termed stress-resilient.

    “The remaining ~30% of mice retain preference for social interaction and are termed “stress-resilient.””
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • Interpretationcitation

    Chronic physical or psychosocial stressors increase ventral tegmental area dopamine neuron activity to elicit depression-like behavior.

    “Chronic physical or psychosocial stressors increase VTA dopamine neuron activity to elicit depression-like behavior.”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [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 in the free run.

    • cites [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

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  • Premisecitation

    Compounds that produce acute behavioral effects in a forced-swim or tail-suspension test may not translate to meaningful therapeutics when administered chronically.

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

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  • Premisecitation

    Stressed animals tend to spend less time struggling against inescapable stressors such as forced swimming or tail suspension.

    “Stressed animals also tend to spend less time struggling against inescapable stressors such as forced swimming or tail suspension.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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

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    • cites [8] Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. Nat Neurosci. 2010;13:1161–9. source

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  • Premisecitation

    Ventral tegmental area dopaminergic neurons also respond to aversive events.

    “they also respond to aversive events [21, 22]”
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    • cites [21] Matsumoto M, Hikosaka O. Two types of dopamine neuron distinctly convey positive and negative motivational signals. Nature. 2009;459:837–41. source

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    • cites [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

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    Premisecitation

    Stress-induced behavioral phenotypes are reversed by chronic, but not acute antidepressant treatment, and are thus posited to have both face and predictive validity.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. Nat Neurosci. 2010;13:1161–9. source

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    Premisecitation

    Reward learning and connectivity between the ventral tegmental area and striatum is impaired in major depressive disorder patients.

    “Reward learning and connectivity between the VTA and striatum is impaired in MDD patients [18, 19].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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

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    • cites [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

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    Premisecitation

    Dopaminergic neurons in the ventral tegmental area fire in response to unpredicted reward and in anticipation of impending reward.

    “dopaminergic neurons in the VTA fire in response to unpredicted reward and in anticipation of impending reward [20]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Schultz W. Reward prediction error. Curr Biol. 2017;27:R369–R371. source

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    Premisecitation

    In chronic unpredictable stress, rodents are exposed to a series of stressors such as cage tilting and disrupted lights for 8-12 weeks, after which animals show reduced sucrose preference.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Willner P. The chronic mild stress (CMS) model of depression: history, evaluation and usage. Neurobiol Stress. 2017;6:78–93. source

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    Premisecitation

    Approximately 70% of mice that undergo chronic social defeat stress are stress-susceptible, displaying reduced social interaction, increased anhedonia, and significant body-weight changes.

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

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    Premisecitation

    Inhibiting ventral tegmental area dopamine neurons that project to the nucleus accumbens induces resilience, but inhibiting ventral tegmental area dopamine projections to medial prefrontal cortex promotes chronic social defeat stress susceptibility.

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

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    Premisecitation

    Increased Ih currents occur specifically in nucleus accumbens, but not medial prefrontal cortex, projecting ventral tegmental area dopamine neurons.

    “Increased Ih currents occur specifically in NAc, but not mPFC projecting VTA dopamine neurons [30]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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    Premisecitation

    Ih and intrinsic excitability are upregulated in chronic social defeat stress-susceptible mice, but Ih is upregulated to a greater extent in resilient mice.

    “Ih and intrinsic excitability are upregulated in CSDS-susceptible mice [30], but somewhat paradoxically, Ih is upregulated to a greater extent in resilient mice.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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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    Premisecitation

    KCNQ channel Kv7.4 is more selectively expressed in ventral tegmental area (not substantia nigra) dopamine neurons and Kv7.4 currents are reduced in susceptible mice.

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

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    Premisecitation

    KCNQ overexpression or administration of KCNQ-openers rescues depressive behavior by reducing firing of nucleus accumbens projecting, but not prefrontal cortex projecting, ventral tegmental area dopamine neurons.

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

    • cites [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 in the free run.

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    Premisecitation

    Ih potentiation with repeated lamotrigine increases K+ currents and decreases neuronal excitability in previously susceptible mice to reverse social and sucrose preference deficits.

    “Ih potentiation with repeated lamotrigine increases K+ currents and decreases neuronal excitability in previously susceptible mice to reverse social and sucrose preference deficits [25].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    Sucrose preference deficits, social avoidance, and ventral tegmental area excitability are reduced by opening Kv7.4 channels with fasudil.

    “Sucrose preference deficits, social avoidance, and VTA excitability are reduced by opening Kv7.4 channels with fasudil [27]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

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    Premisecitation

    Chronic stress increases ERK2 activity in the ventral tegmental area, and inhibiting ventral tegmental area ERK2 rescues chronic social defeat stress susceptibility and reduces forced-swim and tail-suspension immobility by reducing dopamine neuron excitability.

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

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    Premisecitation

    Rats exposed to chronic mild stress have fewer spontaneously active dopamine neurons, an effect more pronounced in females.

    “Rats exposed to chronic mild stress have fewer spontaneously active dopamine neurons [52, 53], an effect more pronounced in females [53].”
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    • cites [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

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    Premisecitation

    CB2 activation reduces ventral tegmental area dopamine neuron firing and immobility in forced-swim and tail-suspension tests.

    “CB2 activation reduces VTA dopamine neuron firing [39] and immobility in forced-swim and tail-suspension tests [40].”
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    • cites [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

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    Premisecitation

    Ventral tegmental area firing is reduced in mice exposed to chronic unpredictable stress, and optogenetic stimulation in this context reverses stress-induced behavioral deficits.

    “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].”
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    • cites [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

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    Premisecitation

    Long-term activation of PPARα decreases β2-nAChR phosphorylation, increases dopamine neuron bursting, and rescues sucrose self-administration after stress.

    “long-term activation of PPARα decreases β2-nAChR phosphorylation, increases dopamine neuron bursting, and rescues sucrose self-administration after stress [59].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    PPARα signaling increases β2-nAChR phosphorylation, which subsequently decreases ventral tegmental area dopamine neuron firing.

    “Peroxisome proliferator-activated receptor α (PPARα) signaling increases β2-nAChR phosphorylation, which subsequently decreases VTA dopamine neuron firing [58].”
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    • cites [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

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    Premisecitation

    β-Cat regulates Dicer1, which modulates pro-susceptibility genes such as Arc and Npas4.

    “β-Cat regulates Dicer1, a microRNA regulator that, in turn, modulates other known pro-susceptibility genes such as Arc and Npas4 [127].”
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    • cites [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

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    Premisecitation

    FNDC5 induces thermogenesis and elevates mitochondrial gene expression.

    “FNDC5 induces thermogenesis and elevates mitochondrial gene expression [131], and resilient mice have increased NAc metabolism [132].”
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    • cites [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

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    Premisecitation

    In both male and female mice, NAc ERα overexpression increases sucrose preference and promotes CSDS-resilience in males.

    “In both male and female mice, NAc ERα overexpression increases sucrose preference and promotes CSDS-resilience in males [133].”
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    • cites [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

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    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

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    Premisecitation

    Egr3 knockdown can prevent altered synaptic activity and stress susceptibility.

    “Egr3 is upregulated specifically in D1-MSNs of susceptible mice and its knockdown can prevent altered synaptic activity and stress susceptibility [88].”
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    • cites [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

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    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

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    Premisecitation

    Social defeat increases NAc PGC1α and its downstream myokine FNDC5.

    “Social defeat increases NAc PGC1α and its downstream myokine FNDC5, and FNDC5 is upregulated more in resilient mice [130].”
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    • cites [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

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    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

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    Premisecitation

    In stress-naive mice, increased RhoA in D1-MSNs decreases sucrose preference in males, grooming behavior in females, and forced-swim immobility.

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

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    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

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    Premisecitation

    Intra-NAc HDAC inhibition reverses social avoidance induced by CSDS, likely caused by increased Rac1 expression.

    “Intra-NAc HDAC inhibition reverses social avoidance induced by CSDS, likely caused by increased Rac1 expression [141].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

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    Premisecitation

    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.

    “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.”
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    • cites [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

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    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

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    Premisecitation

    Subchronic stress upregulates NAc Dnmt3a, but to a greater extent in stressed females.

    “Subchronic stress also upregulates NAc Dnmt3a, but to a greater extent in stressed females.”
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    • cites [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

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    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

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    Premisecitation

    G9a overexpression promotes resilience, thought to occur by normalization of TrkB-CREB signaling.

    “G9a overexpression promotes resilience, thought to occur by normalization of TrkB-CREB signaling [140].”
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    • cites [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

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    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

  • May combine two claims.

    Premisecitation

    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.

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

      Not checked in the free run.

    • 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.

  • May combine two claims.

    Premisecitation

    Pro-susceptibility Dnmt3a overexpression or constitutively active IKK both increase MSN spine density.

    “Pro-susceptibility Dnmt3a overexpression [143] or constitutively active IκB kinase (IKK) [156, 157] both increase MSN spine density.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

  • May combine two claims.

    Premisecitation

    Histone acetylation on the Fosb promotor drives resilience in D1-MSNs, but susceptibility in D2-MSNs.

    “Histone acetylation on the Fosb promotor drives resilience in D1-MSNs, but susceptibility in D2-MSNs [124].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

  • May combine two claims.

    Premisecitation

    CUS increases dendritic length of NAc core MSNs, which is reversed by imipramine or fluoxetine treatment.

    “In contrast, CUS increases dendritic length of NAc core MSNs, which is reversed by imipramine or fluoxetine treatment [154].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

  • May combine two claims.

    Premisecitation

    Reduced dendritic complexity is associated with reduced excitatory input but increased intrinsic excitability.

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

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    CSDS-susceptible mice upregulate cytokines IL-1β and CXCL1, and have more circulating leukocytes.

    “CSDS-susceptible mice upregulate cytokines IL-1β and CXCL1, and have more circulating leukocytes [175].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

  • May combine two claims.

    Premisecitation

    p11 deficiency, p11 reductions in NAc, or p11 knockout in NAc ChIs is sufficient to reduce sucrose preference and increase forced-swim immobility.

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

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

  • May combine two claims.

    Premisecitation

    Silencing NAc cholinergic interneurons results in anhedonia and increases immobility in the forced-swim and tail-suspension tests.

    “Silencing NAc cholinergic interneurons (ChIs) results in anhedonia and increases immobility in the forced-swim and tail-suspension tests [158].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

  • May combine two claims.

    Premisecitation

    Th17 cells promote learned helplessness and social avoidance.

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

      Not checked in the free run.

    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

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

    Premisecitation

    At least 40% of cells in the rodent and human brain are non-neuronal.

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

    • cites [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

      Not checked in the free run.

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

    Premisecitation

    Microglia found in healthy reward circuitry are incredibly diverse.

    “Microglia found in healthy reward circuitry are incredibly diverse [196] and more work is needed to profile their function in pathologic states.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglia in CUS mice have enhanced colony stimulating factor 1 receptor expression and enhanced phagocytotic activity, paralleled by CSF1 elevations in postmortem MDD tissue.

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

      Not checked in the free run.

    • 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.

  • May combine two claims.

    Premisecitation

    Bacteria in the gastrointestinal tract directly influence neural activity through sensory neurons, or by modulating the function of the hypothalamic-pituitary-adrenal axis.

    “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]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [197] Foster JA, McVey Neufeld K-A. Gut–brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36:305–12. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the absence of stress, constitutively active IKK increases thin spine density, increases forced-swim immobility, and decreases sucrose preference after acute stress.

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

    • cites [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

      Not checked in the free run.

    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

  • May combine two claims.

    Premisecitation

    CSDS increases IKK and NF-κB, along with the number of immature dendritic spines in the NAc of susceptible mice.

    “CSDS increases IKK and NF-κB, along with the number of immature dendritic spines in the NAc of susceptible mice [156, 157].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

  • May combine two claims.

    Premisecitation

    When lymphocytes from socially defeated mice are transplanted into Rag2−/− lymphopoenic mice, recipient mice exhibit more social interaction and less tail-suspension immobility.

    “When lymphocytes from socially defeated mice are transplanted into Rag2−/− lymphopoenic mice, recipient mice exhibit more social interaction and less tail-suspension immobility [193].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

  • May combine two claims.

    Premisecitation

    Mice that lack microglial autophagy-related protein 7 exhibit impaired social interaction and increased immature synapses.

    “Mice that lack microglial autophagy-related protein 7 exhibit impaired social interaction and increased immature synapses [194].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

  • May combine two claims.

    Premisecitation

    Microglia from socially defeated mice have an increased inflammatory profile and produce more IL-6 after lipopolysaccharide stimulation.

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

      Not checked in the free run.

    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

  • May combine two claims.

    Premisecitation

    Ccl2 reduction with short hairpin RNA restores sucrose preference and increases swimming in the forced-swim test.

    “Ccl2 reduction with short hairpin RNA restores sucrose preference and increases swimming in the forced-swim test [192].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

  • May combine two claims.

    Premisecitation

    Viral knockdown of neuronal Csf1 attenuates dendritic spine pruning on mPFC neurons and prevents stress-induced anhedonia and forced-swim immobility.

    “Viral knockdown of neuronal Csf1 attenuates dendritic spine pruning on mPFC neurons and prevents stress-induced anhedonia and forced-swim immobility [185].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

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

    Interpretationnone given

    Changes to NAc D1- and D2-MSN function are bidirectional.

    “Similarly, although we know changes to NAc D1-and D2-MSN function are bidirectional, most of this work was done solely in male rodents.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

  • May combine two claims.

    Premisecitation

    Mice with reduced glutamate transporter GLT-1 expression in habenular astrocytes are more stress-susceptible and exhibit increased tail-suspension immobility at baseline.

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

      Not checked in the free run.

    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

  • May combine two claims.

    Premisecitation

    The gut microbiome controls gut permeability and inflammation.

    “The gut microbiome controls gut permeability and inflammation, and may thus participate in the neuroimmune mechanisms of depression [197].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [197] Foster JA, McVey Neufeld K-A. Gut–brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36:305–12. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    These studies have revealed important adaptations in both dopaminergic and glutamatergic function within the VTA and NAc, and these adaptations can differ in directionality based on cell type or stress paradigm.

    “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.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Rodent chronic stress models such as CSDS and CUS produce depressive-like states relevant to human MDD.

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

    Premisecitation

    Gut microbiota can also influence neural metabolism.

    “Recent work indicates gut microbiota can also influence neural metabolism [198].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

53 of 53

  • 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.”
7 of 7

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?

  • Chronic stressors cause maladaptive adaptations in the mesolimbic DA system, the details of which seem to be influenced by the nature and degree of the stressor.

    “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]

Cites

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Authors
Fox, M. E., & Lobo, M. K.
Affiliations
University of Maryland, Baltimore (US)
Corresponding author
Lobo, Mary Kay
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2019-04-09
Volume
24
Issue
12
Pages
1798-1815
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-019-0415-3
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 · 2018: 1
FWCI
3.13
Type
journal article
Language
en
Open access
Licence
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 › 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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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