CoChat
Sign Up
Cited by 0Treatment of Major DepressionNeurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology Research

A nucleus accumbens-projecting prefrontal cortex circuit underlies chronic social stress-induced depression-like behaviors

Open access
Ma, Xiaokuang, Kim, Heedae, Zhang, Le, Chen, Peng, Wei, Jing, Cui, Yuehua, Chen, Lishu, Xu, Yuan +4 more·2026·Translational Psychiatry
DOI 10.1038/s41398-026-04128-wPMC PMC13454594
Open this paper in CoChat — free accountOpen PDF

Abstract

Major depressive disorder (MDD) is a prevalent and debilitating psychiatric illness with limited treatment success. While chronic social stress is a well-established risk factor, the neural circuits that determine individual susceptibility or resilience to MDD remain poorly defined. Here, we identify a distinct subpopulation of layer 5 neurons in the medial prefrontal cortex (mPFC) that project to the nucleus accumbens (NAc) that are selectively activated by chronic social defeat stress (cSDS) in male mice. Using activity-dependent genetic tagging (TRAP), retrograde tracing, and electrophysiology recordings, we demonstrate that these stress-responsive mPFC-NAc neurons exhibit circuit-specific synaptic dysfunction-characterized by reduced excitatory postsynaptic currents, impaired local excitatory connectivity, and dendritic spine loss-in mice susceptible to stress, but not in resilient individuals. Optogenetic modulation further reveals a causal role for this pathway: activation of the mPFC-NAc circuit during cSDS promotes resilience, whereas inhibition increases susceptibility to stress. Together, these findings define a functionally distinct corticolimbic circuit that regulates depression-like behaviors and highlight a potential target for circuit-based interventions in MDD.

AI snapshot

Written from the paper’s full text.

TL;DR

Chronic social defeat stress (cSDS) selectively activates layer 5 medial prefrontal cortex neurons projecting to the nucleus accumbens (mPFC→NAc) in male mice. These stress-activated neurons show synaptic and structural deficits in susceptible, but not resilient, mice, and bidirectional optogenetic manipulation of this pathway causally alters social avoidance.

Key findings

  • cSDS preferentially recruited mPFC→NAc projection neurons, whereas acute social defeat stress (aSDS) preferentially recruited dorsal striatum-projecting neurons: dSTR aSDS 35.2 ± 3.2% vs cSDS 7.1 ± 1.8% (*p < 0.001); NAc aSDS 8.3 ± 1.79% vs cSDS 44.7 ± 3.4% (*p < 0.001); VTA-projecting neurons did not differ (aSDS 11.5 ± 1.59% vs cSDS 14.5 ± 1.11%, p = 0.79).
  • In susceptible mice, cSDS-activated tdT⁺ NAc-projecting L5 mPFC neurons showed reduced mEPSC frequency (resilient 3.17 ± 0.21 Hz vs susceptible 2.08 ± 0.29 Hz; t₁₇ = 3.38, p = 0.004) and reduced mEPSC amplitude (p < 0.05, K–S test), plus lower spine density (12.3 ± 0.53 vs 10.4 ± 0.42 spines/10 μm, p = 0.018) and smaller spine head width (p = 0.002); neighboring tdT⁻ neurons and mIPSCs showed no significant differences.
  • LSPS mapping showed reduced L2/3 excitatory input onto cSDS-activated NAc-projecting neurons in susceptible mice (resilient 39.4 ± 3.89 pA vs susceptible 24.3 ± 2.26 pA; t₂₈ = 3.1, p = 0.0024), while inhibitory input was unchanged (resilient 59.9 ± 3.8 pA vs susceptible 65.8 ± 2.7 pA; t₂₅ = 1.3, p = 0.20).
  • Optogenetic activation of cSDS⁺ mPFC→NAc neurons in susceptible mice increased social interaction time (OFF 79.1 ± 10.0 s vs ON 147.8 ± 13.5 s; t₇ = 3.57, p = 0.009), whereas inhibition in resilient mice decreased social interaction time (OFF 135.3 ± 11.9 s vs ON 34.1 ± 8.6 s; t₇ = 7.59, p < 0.0001).

Methods

  • Male TRAP2:Ai14 mice, 10–12 weeks old, underwent acute or chronic social defeat stress; cSDS consisted of 10 daily defeat sessions with a novel CD1 aggressor, followed by social interaction (SI) testing to classify susceptible (SI ratio ≤ 1.0) vs resilient (SI ratio > 1.0) phenotypes.
  • Activity-dependent TRAP labeling with tamoxifen was combined with retrograde bead injections into NAc, dSTR, or VTA; whole-cell patch clamp recorded mEPSCs/mIPSCs and biocytin-based morphology, and laser scanning photostimulation (LSPS) mapped local excitatory and inhibitory inputs.
  • Circuit-specific optogenetics used retrograde AAVrg-DIO-hChR2-EYFP for excitation or AAVrg-FLEX-Jaws-GFP for inhibition in NAc, with bilateral optic fibers above mPFC and interleaved ON/OFF light during SI testing; statistics used t-tests, ANOVA, Mann–Whitney, and Kolmogorov–Smirnov tests as appropriate.

Limitations

  • Stated: all experiments used male mice, limiting generalizability to females.
  • Stated: the study focused on social interaction/withdrawal behavior and did not extensively measure anhedonia, behavioral despair/passive coping, anxiety-related behavior, or motivation/effort-related behaviors.
  • Evident from the text: TRAP labeling for cSDS was performed before the final defeat session on day 10, so it captures neurons engaged during the terminal phase of repeated stress rather than early acquisition or single-episode stress; the study also relies on a single SI-based classification criterion for susceptible vs resilient phenotypes.

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

Integrity signals

Registry

Crossref · 10.1038/s41398-026-04128-w

Cites

39 of 39 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

29 of 32 cited sources checked · 13 supported · 0 flagged · accuracy not yet measured

  • Findingown data

    The proportion of tdT+ neurons retrogradely labeled with beads is comparable between resilient and susceptible mice.

    “The proportion of tdT⁺ neurons retrogradely labeled with beads is comparable between resilient and susceptible mice. P = 0.88, unpaired t test.”
    Quote in the paperSubstantial claim
  • Findingown data

    In susceptible mice, tdT+/beads+ neurons display significantly reduced mEPSC amplitude compared to resilient mice.

    “In susceptible mice, tdT⁺/beads⁺ neurons displayed significantly reduced mEPSC amplitude (p < 0.05, Kolmogorov–Smirnov test on cumulative histogram curve)”
    Quote in the paperSubstantial claim
  • Findingown data

    Resilient and susceptible mice have similar densities of TRAP-labeled (tdT+) neurons in the mPFC.

    “Quantification showing that resilient and susceptible mice have similar densities of TRAP-labeled (tdT⁺) neurons in the mPFC. P = 0.82, unpaired t test.”
    Quote in the paperSubstantial claim
  • Findingown data

    Susceptible mice demonstrate significantly increased immobility time during the tail suspension test.

    “and significantly increased immobility time during a tail suspension test (TST, Supplementary Fig. 1B)”
    Quote in the paperNot a substantial claim
  • Findingown data

    No tdT+ expression is observed in mice that do not receive TAM.

    “no tdT⁺ expression was observed in mice that did not receive TAM (Fig. 1E, F), confirming the inducibility and specificity of the TRAP system.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 10
  • May combine two claims. 14
  • The quote only partly states this claim. 1

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

    Premisecitation

    mPFC L5 neurons are heterogeneous in molecular marker, synaptic properties, projection targets, local circuit integration, and functional specialization.

    “mPFC L5 neurons are heterogenous populations, in terms of their molecular marker, synaptic properties, projection targets, local circuit integration, and functional specialization [15–18].”
    Quote in the paperSubstantial claim4 of 4 sources checked
    • cites [15] Anastasiades PG, Carter AG. Circuit organization of the rodent medial prefrontal cortex. Trends Neurosci. 2021;44:550–63. source
    • cites [16] Le Merre P, Ahrlund-Richter S, Carlen M. The mouse prefrontal cortex: unity in diversity. Neuron. 2021;109:1925–44. source

      The Introduction describes distinct prefrontal populations with different long-range wiring, gene-expression profiles, and effects on behavior. It does not establish that these are specifically mPFC layer 5 neurons or that they differ in synaptic properties and local circuit integration. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [17] Liu WZ, Wang CY, Wang Y, Cai MT, Zhong WX, Liu T, et al. Circuit- and laminar-specific regulation of medial prefrontal neurons by chronic stress. Cell Biosci. 2023;13:90. source

      The Results (Anatomical characterization; page unavailable) identify distinct BLA- and NAc-projecting populations in mPFC layer V. The Discussion (page unavailable) describes projection-dependent synaptic responses to stress and mentions molecular profiles and differing circuit functions. The paper does not establish heterogeneity in local circuit integration or specifically demonstrate molecular-marker differences among layer V neurons. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [18] Moberg S, Takahashi N. Neocortical layer 5 subclasses: from cellular properties to roles in behavior. Front Synaptic Neurosci. 2022;14:1006773. source

  • Classified as probably not a substantial claim.

    Premisecitation

    The rodent cSDS model is one of the most robust and translationally relevant paradigms for modeling key features of human depression, such as anhedonia, social avoidance, and cognitive inflexibility.

    “In particular, the rodent model of cSDS has emerged as one of the most robust and translationally relevant paradigms for modeling key features of human depression, such as anhedonia, social avoidance, and cognitive inflexibility [7–9].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [7] Krishnan V, Han MH, 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
    • cites [8] Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008;455:894–902. source

      The passage labeled Abstract identifies chronic social defeat as a model of longer-lasting depression-related behavior and notes that chronic-stress models show an antidepressant-response pattern comparable to treatment in humans. Other passages in that section link social defeat to social avoidance and decreased sucrose intake after chronic stress to anhedonia. The copy does not establish cognitive inflexibility as a feature modeled by chronic social defeat or rank it as one of the most robust paradigms. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [9] Vialou V, Bagot RC, Cahill ME, Ferguson D, Robison AJ, Dietz DM, et al. Prefrontal cortical circuit for depression- and anxiety-related behaviors mediated by cholecystokinin: role of DeltaFosB. J Neurosci. 2014;34:3878–87. source

      The Introduction calls chronic social defeat stress an ethologically valid model of depression. The Methods and Figure 2 report social avoidance and a sucrose-preference deficit in defeated mice, supporting those examples. The copy does not establish cognitive inflexibility or the comparative claim that this is one of the most robust and translationally relevant paradigms. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    The mPFC is a key hub for emotional regulation and stress adaptation.

    “The medial prefrontal cortex (mPFC) is a key hub for emotional regulation and stress adaptation [9, 11].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [9] Vialou V, Bagot RC, Cahill ME, Ferguson D, Robison AJ, Dietz DM, et al. Prefrontal cortical circuit for depression- and anxiety-related behaviors mediated by cholecystokinin: role of DeltaFosB. J Neurosci. 2014;34:3878–87. source
    • cites [11] Murugan M, Jang HJ, Park M, Miller EM, Cox J, Taliaferro JP, et al. Combined social and spatial coding in a descending projection from the prefrontal cortex. Cell. 2017;171:1663–77. e1616. source

      The Abstract describes the medial prefrontal cortex’s prelimbic region in social behavior and social-spatial learning, not emotional regulation or stress adaptation. Searches for those terms and for anxiety-related language found no passage in the paper’s text supporting the attributed claim; an anxiety-related study appears only in the References. (LLM, conf=0.74)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Dysregulation of mPFC activity, particularly within L5 projection neurons, is implicated in the pathophysiology of depression through clinical imaging and preclinical models.

    “Dysregulation of mPFC activity—particularly within layer 5 (L5) projection neurons—has been implicated in the pathophysiology of depression through both clinical imaging studies and preclinical models [12–14].”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [12] Bittar TP, Labonte B. Functional contribution of the medial prefrontal circuitry in major depressive disorder and stress-induced depressive-like behaviors. Front Behav Neurosci. 2021;15:699592. source

      The Introduction reports altered mPFC activity in patients with major depressive disorder, and the E/I Balance Integrity section links mPFC pyramidal-neuron activity to depressive-like behaviors in animal models. The Laminar Organization section places some projection neurons in layer V, but the paper does not establish that layer V projection neurons in particular are implicated by both the clinical imaging and preclinical evidence. Page numbers are unavailable in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [13] Duman RS, Sanacora G, Krystal JH. Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments. Neuron. 2019;102:75–90. source

      The paper’s ‘Structural and functional connectivity alterations in depression’ section reports abnormal PFC connectivity in clinical imaging studies. Its ‘Glutamate alterations in MDD and stress’ section reports that chronic stress reduces dendritic branching in mPFC layer V pyramidal neurons. These passages support the broad link, but the imaging findings do not establish activity changes specifically in L5 projection neurons, and the layer V preclinical finding concerns neuronal structure rather than measured activity. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [14] Solakoglu ST, Erdener SE, Gliko O, Can A, Sumbul U, Eren-Kocak E. Layer-specific input to medial prefrontal cortex is linked to stress susceptibility. Transl Psychiatry. 2025;15:134. source

      The Introduction (page not available) links mPFC activity and layer V neuronal changes to stress and depression-like behavior in preclinical models. The Discussion (page not available) reports disrupted inputs to deep mPFC layers in stress-susceptible mice. The paper does not provide clinical imaging evidence or establish that the disruption is specifically within layer V projection neurons. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Not all animals exposed to cSDS develop maladaptive behaviors; a subset exhibit depression-like behaviors (susceptible), while others maintain normal behavior (resilient).

    “Importantly, not all animals exposed to cSDS develop maladaptive behaviors. Similar to variability observed in human populations, a subset of mice subjected to cSDS exhibit depression-like behaviors (‘susceptible’), while others maintain normal behavior and are considered ‘resilient’ [8, 10].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [8] Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008;455:894–902. source
    • cites [10] 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

  • Classified as probably not a substantial claim.

    Premisecitation

    Chronic social stress, particularly cSDS, is one of the most potent environmental risk factors precipitating depressive symptoms, as shown in human epidemiological data and animal models.

    “Chronic social stress, particularly paradigms like chronic social defeat stress (cSDS), stands out as one of the most potent environmental risk factors precipitating depressive symptoms, as demonstrated in both human epidemiological data and well - established animal models of depression [4–6].”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [4] Iniguez SD, Riggs LM, Nieto SJ, Dayrit G, Zamora NN, Shawhan KL, et al. Social defeat stress induces a depression-like phenotype in adolescent male c57BL/6 mice. Stress. 2014;17:247–55. source

      The Introduction describes social defeat as a robust animal model of stress-induced mood disorders, and the Conclusions report that 10 days of defeat induced depression- and anxiety-like symptoms in adolescent male mice. The paper does not present human epidemiological evidence that chronic social stress is among the most potent environmental risk factors for depression; its epidemiological discussion concerns the age at which depression first occurs. The supplied passages have section labels but no page numbers. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [5] Slavich GM, Irwin MR. From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol Bull. 2014;140:774–815. source

      The section “Stress Is Associated With Major Depression” reports epidemiologic evidence that interpersonal loss and social rejection are particularly strong predictors of depression. However, the passages found do not establish chronic social defeat stress (cSDS) as a particularly potent risk factor or demonstrate that claim in animal models; the animal studies discussed in “Inflammatory Cytokines and Effects on Behavior: Evidence From Basic Studies” instead use inflammatory challenges. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [6] Yoshida K, Drew MR, Kono A, Mimura M, Takata N, Tanaka KF. Chronic social defeat stress impairs goal-directed behavior through dysregulation of ventral hippocampal activity in male mice. Neuropsychopharmacology. 2021;46:1606–16. source

      The Introduction calls stress a major risk factor for mood disorders and describes chronic social defeat stress as an animal model; the Results report stress-related behavioral changes in mice. The paper does not establish that chronic social stress is one of the most potent environmental risk factors, or present human epidemiological data demonstrating that specific claim. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Prior studies demonstrate layer-specific or region-specific excitation-inhibition imbalance in stress-related circuits.

    “These studies demonstrate layer-specific or region-specific excitation–inhibition imbalance in stress-related circuits”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [14] Solakoglu ST, Erdener SE, Gliko O, Can A, Sumbul U, Eren-Kocak E. Layer-specific input to medial prefrontal cortex is linked to stress susceptibility. Transl Psychiatry. 2025;15:134. source

      The Results (page not provided) report layer- and brain-region-specific changes in synaptic inputs in stress-susceptible mice. However, the Methods specify that the mapped projections were excitatory; the cited findings do not establish an excitation–inhibition imbalance. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [28] Tao C, Zhang GW, Sun WJ, Huang JJ, Zhang LI, Tao HW. Excitation-inhibition imbalance in medial preoptic area circuits underlies chronic stress-induced depression-like states. Nat Commun. 2024;15:8575. source

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

    Premisecitation

    Altered connectivity and disruptions in E/I balance contribute to the core pathophysiology of major depressive disorder.

    “These findings align with previous reports indicating altered connectivity [13] and disruptions in E/I balance contribute to the core pathophysiology of major depressive disorder [28, 31, 32].”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [13] Duman RS, Sanacora G, Krystal JH. Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments. Neuron. 2019;102:75–90. source
    • cites [28] Tao C, Zhang GW, Sun WJ, Huang JJ, Zhang LI, Tao HW. Excitation-inhibition imbalance in medial preoptic area circuits underlies chronic stress-induced depression-like states. Nat Commun. 2024;15:8575. source
    • cites [31] Ferguson BR, Gao WJ. PV interneurons: critical regulators of E/I balance for prefrontal cortex-dependent behavior and psychiatric disorders. Front Neural Circuits. 2018;12:37. source

      In “E/I Balance in Psychiatric Disease” (page unavailable), the review says a pattern of GABAergic dysfunction seen in schizophrenia also occurs in depression. It does not specifically establish that disrupted E/I balance contributes to the core pathophysiology of major depressive disorder. The altered-connectivity clause is cited to a different source [13], so it is not assessed here. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Non-selective activation of the mPFC can reverse behavioral deficits in depression models.

    “Our findings build upon prior studies showing that non-selective activation of the mPFC can reverse behavioral deficits in depression models [36–39]”
    Quote in the paperNot a substantial claim4 of 4 sources checked
    • cites [36] Covington HE 3rd, Lobo MK, Maze I, Vialou V, Hyman JM, Zaman S, et al. Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J Neurosci. 2010;30:16082–90. source
    • cites [37] Fuchikami M, Thomas A, Liu R, Wohleb ES, Land BB, DiLeone RJ, et al. Optogenetic stimulation of infralimbic PFC reproduces ketamine’s rapid and sustained antidepressant actions. Proc Natl Acad Sci USA. 2015;112:8106–11. source

      The section “Optogenetic Stimulation of IL-PFC Produces Antidepressant Behavioral” reports antidepressant-like effects after activating the infralimbic PFC, but not after activating the prelimbic PFC; it does not establish the effect for non-selective activation of the mPFC as a whole. The Discussion states that the animals were unstressed and that chronic-stress or social-defeat models remain to be tested, so reversal of deficits in depression models was not demonstrated. Page numbers are unavailable in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [38] Hare BD, Shinohara R, Liu RJ, Pothula S, DiLeone RJ, Duman RS. Optogenetic stimulation of medial prefrontal cortex Drd1 neurons produces rapid and long-lasting antidepressant effects. Nat Commun. 2019;10:223. source

      The Results section (‘Drd1 stimulation drives antidepressant responses’; page unavailable) reports that previous studies found antidepressant effects from non-selective mPFC photostimulation in sucrose-preference and novelty-suppressed-feeding tests. It does not establish that this stimulation reversed pre-existing behavioral deficits in depression models; the Discussion also distinguishes the present experiments from typical preclinical depression models. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [39] Riga D, Matos MR, Glas A, Smit AB, Spijker S, Van den Oever MC. Optogenetic dissection of medial prefrontal cortex circuitry. Front Syst Neurosci. 2014;8:230. source

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

    Premisecitation

    Previous work implicates mPFC dysfunction in depression.

    “Our results also expand on other previous work implicating mPFC dysfunction in depression [7, 9, 29, 30]”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [7] Krishnan V, Han MH, 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
    • cites [9] Vialou V, Bagot RC, Cahill ME, Ferguson D, Robison AJ, Dietz DM, et al. Prefrontal cortical circuit for depression- and anxiety-related behaviors mediated by cholecystokinin: role of DeltaFosB. J Neurosci. 2014;34:3878–87. source
    • cites [29] Nestler EJ. Role of the Brain’s reward circuitry in depression: transcriptional mechanisms. Int Rev Neurobiol. 2015;124:151–70. source

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

    Premisecitation

    In rodent models of depression and depressive-like behaviors, multiple behavioral assays in addition to social interaction test, including sucrose preference, tail suspension, and forced swim tests are often used.

    “In rodent models of depression and depressive-like behaviors, multiple behavioral assays in addition to social interaction test, including sucrose preference, tail suspension, and forced swim tests are often used [7, 20, 29].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [7] Krishnan V, Han MH, 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
    • cites [20] Golden SA, Covington HE 3rd, Berton O, Russo SJ. A standardized protocol for repeated social defeat stress in mice. Nat Protoc. 2011;6:1183–91. source
    • cites [29] Nestler EJ. Role of the Brain’s reward circuitry in depression: transcriptional mechanisms. Int Rev Neurobiol. 2015;124:151–70. source

      Section 3.1 describes several rodent stress assays and changes in responses to sucrose; the References include a study using the forced swim test. These support the general point that multiple behavioral measures are used, but the copy does not identify a sucrose-preference test, tail-suspension test, or social-interaction test as such. Page numbers were not supplied. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • The quote only partly states this claim.

    Findingown data

    cSDS-activated mPFC→NAc neurons in susceptible mice exhibit reduced mEPSC frequency.

    “these stress-responsive mPFC–NAc neurons exhibit circuit-specific synaptic dysfunction—characterized by reduced excitatory postsynaptic currents, impaired local excitatory connectivity, and dendritic spine loss—in mice susceptible to stress, but not in resilient individuals.”
    • Also stated in: § Introduction · plain
      “These include reductions in miniature excitatory postsynaptic current (mEPSC) amplitude and frequency”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TRAP-labeled neurons in aSDS mice are predominantly excitatory, as tdT+ neurons do not co-localize with GABA immunostaining.

    “we confirmed that TRAP-labeled neurons in aSDS mice were likely predominantly excitatory, as tdT⁺ neurons did not co-localize with GABA immunostaining”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    50 mg/kg TAM reliably induces robust tdT+ labeling in aSDS-exposed mice, particularly in cortical regions, with most prominent activation in the mPFC.

    “Through dose titration studies (10–150 mg/kg TAM; data not shown), we found that 50 mg/kg TAM reliably induced robust tdT⁺ labeling in aSDS-exposed mice, particularly within cortical regions, with the most prominent activation observed in the mPFC”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The synaptic deficits in cSDS+ mPFC→NAc neurons are circuit-specific and phenotype-dependent.

    “indicating that the synaptic deficits are both circuit-specific and phenotype-dependent.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The mPFC-NAc circuit is a functionally distinct corticolimbic circuit that regulates depression-like behaviors.

    “Together, these findings define a functionally distinct corticolimbic circuit that regulates depression-like behaviors”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Circuit engagement differs not only between acute and chronic stress, but also between susceptible and resilient individuals exposed to the same chronic stress paradigm.

    “Another key insight from this study is the discovery that circuit engagement differs not only between acute and chronic stress, but also between susceptible and resilient individuals exposed to the same chronic stress paradigm.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The activity of cSDS-activated mPFC→NAc L5 neurons is both necessary and sufficient to determine resilience versus susceptibility following chronic social stress.

    “These results demonstrate that the activity of cSDS-activated mPFC→NAc L5 neurons is both necessary and sufficient to determine resilience versus susceptibility following chronic social stress.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Repetitive activation of cSDS-responsive mPFC→NAc neurons in susceptible mice leads to synaptic dysregulation characterized by decreased excitatory synaptic drive and reduced spine integrity, without altering inhibitory synaptic connectivity.

    “Together, these results suggest that repetitive activation of cSDS-responsive mPFC→NAc neurons in susceptible mice leads to synaptic dysregulation characterized by decreased excitatory synaptic drive and reduced spine integrity, without altering inhibitory synaptic connectivity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Manipulation of this circuit via optogenetics can bidirectionally influence stress-induced behavioral outcomes, establishing a causal link between cSDS-induced neural activity in this pathway and the expression of depression-like behaviors.

    “Furthermore, we show that manipulation of this circuit via optogenetics can bidirectionally influence stress-induced behavioral outcomes, establishing a causal link between cSDS-induced neural activity in this pathway and the expression of depression-like behaviors.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Social avoidance is a valid measure of depression-like behaviors in this context.

  • May combine two claims.

    Interpretationown data

    Specific ensembles within the mPFC may encode negative valence and promote maladaptive outcomes when persistently activated, which are causatively linked to their altered activity and synaptic connectivity.

    “by demonstrating that specific ensembles within the mPFC may encode negative valence and promote maladaptive outcomes when persistently activated, which are causatively linked to their altered activity and synaptic connectivity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Repeated activation of this circuit may represent a key driver of vulnerability, potentially through activity-dependent synaptic weakening and loss of functional integration with local microcircuits.

    “These findings suggest that repeated activation of this circuit may represent a key driver of vulnerability, potentially through activity-dependent synaptic weakening and loss of functional integration with local microcircuits.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The reduction in layer 2/3 excitatory input observed in susceptible mice aligns with prior findings of diminished spontaneous mEPSCs, supporting a model in which stress-induced disruption of excitatory intracortical signaling contributes to circuit dysfunction and depressive-like behavior.

    “The reduction in layer 2/3 excitatory input observed in susceptible mice aligns with prior findings of diminished spontaneous mEPSCs, further supporting a model in which stress-induced disruption of excitatory intracortical signaling contributes to circuit dysfunction and depressive-like behavior.”
    Quote in the paperSubstantial claim
23 of 23

  • The paper relies on this without support.

    The neural circuits that determine individual susceptibility or resilience to MDD remain poorly defined.

    “While chronic social stress is a well-established risk factor, the neural circuits that determine individual susceptibility or resilience to MDD remain poorly defined.”

  • The paper relies on this without support.

    Little is known about how specific populations within the mPFC adapt to stress exposure, and how these adaptations may differ across behavioral phenotypes.

    “Despite these insights, little is known about how specific populations within the mPFC adapt to stress exposure, and how these adaptations may differ across behavioral phenotypes.”

  • The paper relies on this without support.

    The circuit-level substrates that mediate behavioral heterogeneity in stress susceptibility remain incompletely understood.

    “However, the circuit-level substrates that mediate this behavioral heterogeneity remain incompletely understood.”

  • The paper relies on this without support.

    The susceptible vs resilient population selected using social interaction score is consistent with other depressive-like behavior measures.

    “The susceptible vs resilient population selected using social interaction score are consistent with these depressive-like behavior measures.”

  • The paper relies on this without support.

    The behavioral assays (sucrose preference, tail suspension, forced swim) probe different behavioral domains relevant to depression, such as anhedonia, behavioral despair, social withdrawal, and anxiety-related behavior.

    “These tests probe different behavioral domains relevant to depression, such as anhedonia, behavioral despair, social withdrawal, and anxiety-related behavior.”

  • The paper relies on this without support.

    Social avoidance is a valid measure of depression-like behaviors in this context.

    “Optogenetic activation of cSDS+ mPFCNAc neurons during social exposure reduced the likelihood of developing depression-like behaviors, measured here as social avoidance”
6 of 6

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Optic fiber placement differs between Methods and Results

    Major

    The Methods place the optic fibers above the NAc injection site, whereas the Results place them above the mPFC. These are different stimulation sites for the experiment supporting the causal conclusion.

  • Abstract says optogenetic manipulation occurred during cSDS

    Major

    The abstract says activation and inhibition were performed during chronic social defeat stress, but the results describe testing them after cSDS and behavioral classification. This changes whether the experiment tested the development of susceptibility or social interaction in already-classified mice.

  • Different tests are named for the spine-head comparison

    Minor

    The Figure 4 caption identifies a Wilcoxon signed-rank test for the tdT+ spine-head comparison, while the Results identify a Mann-Whitney test. These are different statistical tests.

  • Figure 6 reports incompatible significance thresholds for activation

    Minor

    The Figure 6 caption gives p < 0.001 for the activation effect, while the Results report p = 0.009 for that effect. A p value of 0.009 does not meet the caption's threshold.

  • Figure 2 names an amygdala injection instead of dorsal striatum

    Minor

    The Figure 2 caption lists the amygdala among the injection targets, but the Methods and accompanying Results list the dorsal striatum instead.

  • Figure 4 and Results give different p values for tdT− spine density

    Minor

    The caption reports p = 0.071 for the tdT− spine-density comparison, while the Results report p = 0.71 for the same comparison.

6 of 6

Cites

Flagged first, then by citations

Authors
Ma, X., Kim, H., Zhang, L., Chen, P., Wei, J., Cui, Y., Chen, L., Xu, Y., Zhang, J., Dai, Z., Ferguson, D., & Qiu, S.
Affiliations
University of Arizona College of Medicine- Phoenix (US)
Corresponding author
  • Ferguson, Deveroux
  • Qiu, Shenfeng
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2026-06-04
Volume
16
Issue
1
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-026-04128-w
PMC
PMC13454594
OpenAlex
W7163580670
Semantic Scholar
cf2340e3ccc5c709a3e28b21be74c243aa5436a9
Cited by
0
References
39
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (MH128192)
  • ADHS | Arizona Biomedical Research Commission
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
major depressive disorder, chronic social defeat stress, nucleus accumbens, medial prefrontal cortex, corticolimbic circuits, layer 5 neurons, synaptic dysfunction, dendritic spine loss, excitatory postsynaptic currents, optogenetic manipulation
MeSH terms
Social Defeat, Animals, Behavior, Animal, Major Depressive Disorder, Male, Mice, Inbred C57BL, Neural Pathways, Neurons, Nucleus Accumbens, Stress, Psychological, Prefrontal Cortex, Excitatory Postsynaptic Potentials, Mice, Optogenetics

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 2026-10-20.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-20.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review