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Prefrontal contribution to passive coping behaviour in chronic stress and treatment by fast-acting antidepressant

Neuropsychopharmacology (2025)Cite this article

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Abstract

Persistent passive coping (p-coping) behaviour is a hallmark feature in major depression and is reversed by fast-acting antidepressants (such as ketamine). This behaviour is regulated by a specific cortico-midbrain circuit. However, the contribution of inhibition in prefrontal cortex to p-coping modulation, and its relevance to chronic stress and/or fast-acting antidepressant effects, are poorly understood. Here, we found that rostral prelimbic cortex (rPL) bidirectionally controls p-coping behaviour where excitatory and inhibitory neurons play opposite roles. Chronic stress leads to a reduced excitation/inhibition (E/I) ratio, reflected as alterations of in vivo spiking rate, synaptic strength, and intrinsic excitability of rPL neurons. A fast-acting antidepressant, (2 R,6 R)-hydroxynorketamine (HNK), reduced p-coping, restored rPL E/I ratio, and partially reversed neuronal changes in chronically stressed mice. Notably, chronic stress and HNK significantly affected fast-spiking/parvalbumin inhibitory neurons which also bidirectionally regulate the passive coping behaviour, highlighting the critical roles of these neurons in the above processes. These findings underscore the importance of rPL E/I balance in regulating p-coping behaviour, which is disrupted by chronic stress and rapidly restored by fast-acting antidepressant.

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Fig. 1: Chronic stress induces depression-like behaviours and alters rPL activity.
Fig. 2: Chronic stress alters the properties of rPL excitatory and inhibitory neurons and E/I balance.
Fig. 3: Impact of rPL excitation or inhibition on passive coping behaviour.
Fig. 4: HNK reduces passive coping behaviour in chronically stressed mice.
Fig. 5: HNK partially reverses synaptic alterations in rPL neurons in chronically stressed mice.

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References

  1. Joëls M, Karst H, Sarabdjitsingh RA. The stressed brain of humans and rodents. Acta Physiol (Oxf). 2018;223:e13066.

    Article  PubMed  Google Scholar 

  2. de Kloet ER, Joëls M, Holsboer F. Stress and the brain: from adaptation to disease. Nat Rev Neurosci. 2005;6:463–75.

    Article  PubMed  Google Scholar 

  3. Herman JP. Neural control of chronic stress adaptation. Front Behav Neurosci. 2013;7:61.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Radley JJ, Herman JP. Preclinical models of chronic stress: adaptation or pathology? Biol Psychiatry. 2023;94:194–202.

    Article  PubMed  CAS  Google Scholar 

  5. Carroll L Passive Coping Strategies. In: Gellman MD, Turner JR, editors. Encyclopedia of behavioral medicine. New York, NY: Springer New York; 2013. p. 1442-.

  6. Molendijk ML, de Kloet ER. Coping with the forced swim stressor: current state-of-the-art. Behav Brain Res. 2019;364:1–10.

    Article  PubMed  Google Scholar 

  7. Molendijk ML, de Kloet ER. Forced swim stressor: Trends in usage and mechanistic consideration. Eur J Neurosci. 2022;55:2813–31.

    Article  PubMed  CAS  Google Scholar 

  8. Johnson SB, Emmons EB, Lingg RT, Anderson RM, Romig-Martin SA, LaLumiere RT, et al. Prefrontal-Bed Nucleus Circuit Modulation of a Passive Coping Response Set. J Neurosci. 2019;39:1405–19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Johnson SB, Lingg RT, Skog TD, Hinz DC, Romig-Martin SA, Viau V, et al. Activity in a prefrontal-periaqueductal gray circuit overcomes behavioral and endocrine features of the passive coping stress response. Proc Natl Acad Sci USA. 2022;119:e2210783119.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. McKlveen JM, Moloney RD, Scheimann JR, Myers B, Herman JP. Braking” the prefrontal cortex: the role of glucocorticoids and interneurons in stress adaptation and pathology. Biol Psychiatry. 2019;86:669–81.

    Article  PubMed  CAS  Google Scholar 

  11. Cerniauskas I, Winterer J, de Jong JW, Lukacsovich D, Yang H, Khan F, et al. Chronic stress induces activity, synaptic, and transcriptional remodeling of the lateral habenula associated with deficits in motivated behaviors. Neuron. 2019;104:899–915.e8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. McKlveen JM, Morano RL, Fitzgerald M, Zoubovsky S, Cassella SN, Scheimann JR, et al. Chronic stress increases prefrontal inhibition: a mechanism for stress-induced prefrontal dysfunction. Biol Psychiatry. 2016;80:754–64.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Nawreen N, Cotella EM, Morano R, Mahbod P, Dalal KS, Fitzgerald M, et al. Chemogenetic inhibition of infralimbic prefrontal cortex GABAergic parvalbumin interneurons attenuates the impact of chronic stress in male mice. eNeuro. 2020;7:ENEURO.0423-19.

  14. Grunebaum MF, Galfalvy HC, Choo TH, Keilp JG, Moitra VK, Parris MS, et al. Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial. Am J Psychiatry. 2018;175:327–35.

    Article  PubMed  Google Scholar 

  15. Phillips JL, Norris S, Talbot J, Birmingham M, Hatchard T, Ortiz A, et al. Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: a randomized controlled trial. Am J Psychiatry. 2019;176:401–9.

    Article  PubMed  Google Scholar 

  16. Fogaça MV, Wu M, Li C, Li XY, Picciotto MR, Duman RS. Inhibition of GABA interneurons in the mPFC is sufficient and necessary for rapid antidepressant responses. Mol Psychiatry. 2021;26:3277–91.

    Article  PubMed  Google Scholar 

  17. Chen JY, Wu K, Guo MM, Song W, Huang ST, Zhang YM. The PrL(Glu)→avBNST(GABA) circuit rapidly modulates depression-like behaviors in male mice. iScience. 2023;26:107878.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Johnston JN, Kadriu B, Kraus C, Henter ID, Zarate CA Jr. Ketamine in neuropsychiatric disorders: an update. Neuropsychopharmacology. 2024;49:23–40.

    Article  PubMed  Google Scholar 

  19. Hess EM, Riggs LM, Michaelides M, Gould TD. Mechanisms of ketamine and its metabolites as antidepressants. Biochem Pharm. 2022;197:114892.

    Article  PubMed  CAS  Google Scholar 

  20. Riggs LM, Gould TD. Ketamine and the future of rapid-acting antidepressants. Annu Rev Clin Psychol. 2021;17:207–31.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Highland JN, Zanos P, Riggs LM, Georgiou P, Clark SM, Morris PJ, et al. Hydroxynorketamines: pharmacology and potential therapeutic applications. Pharm Rev. 2021;73:763–91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Raja SM, Guptill JT, Mack M, Peterson M, Byard S, Twieg R, et al. A phase 1 assessment of the safety, tolerability, pharmacokinetics and pharmacodynamics of (2R,6R)-hydroxynorketamine in healthy volunteers. Clin Pharmacol Ther. 2024;116:1314–24.

  23. Srikumar BN, Paschapur M, Kalidindi N, Adepu B, Das ML, Sreedhara MV, et al. Characterization of the adrenocorticotrophic hormone - induced mouse model of resistance to antidepressant drug treatment. Pharm Biochem Behav. 2017;161:53–61.

    Article  CAS  Google Scholar 

  24. Walker AJ, Burnett SA, Hasebe K, McGillivray JA, Gray LJ, McGee SL, et al. Chronic adrenocorticotrophic hormone treatment alters tricyclic antidepressant efficacy and prefrontal monoamine tissue levels. Behav Brain Res. 2013;242:76–83.

    Article  PubMed  CAS  Google Scholar 

  25. Ma X, Yang S, Zhang Z, Liu L, Shi W, Yang S, et al. Rapid and sustained restoration of astrocytic functions by ketamine in depression model mice. Biochem Biophys Res Commun. 2022;616:89–94.

    Article  PubMed  CAS  Google Scholar 

  26. Kupferschmidt DA, Cummings KA, Joffe ME, MacAskill A, Malik R, Sánchez-Bellot C, et al. Prefrontal interneurons: populations, pathways, and plasticity supporting typical and disordered cognition in rodent models. J Neurosci. 2022;42:8468–76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Wang T, Yan R, Zhang X, Wang Z, Duan H, Wang Z, et al. Paraventricular thalamus dynamically modulates aversive memory via tuning prefrontal inhibitory circuitry. J Neurosci. 2023;43:3630–46.

    PubMed  PubMed Central  CAS  Google Scholar 

  28. Bartolini G, Ciceri G, Marín O. Integration of GABAergic interneurons into cortical cell assemblies: lessons from embryos and adults. Neuron. 2013;79:849–64.

    Article  PubMed  CAS  Google Scholar 

  29. Meyer HC, Sangha S, Radley JJ, LaLumiere RT, Baratta MV. Environmental certainty influences the neural systems regulating responses to threat and stress. Neurosci Biobehav Rev. 2021;131:1037–55.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Yoon SH, Chung G, Song WS, Oh SP, Kim SJ, Kim M-H. Shifting hippocampal excitation/inhibition balance modifies despair-like behavior in mice. bioRxiv. 2020. 2020.02.18.953786.

  31. Luykx JJ, Laban KG, van den Heuvel MP, Boks MP, Mandl RC, Kahn RS, et al. Region and state specific glutamate downregulation in major depressive disorder: a meta-analysis of (1)H-MRS findings. Neurosci Biobehav Rev. 2012;36:198–205.

    Article  PubMed  CAS  Google Scholar 

  32. Yildiz-Yesiloglu A, Ankerst DP. Review of 1H magnetic resonance spectroscopy findings in major depressive disorder: a meta-analysis. Psychiatry Res. 2006;147:1–25.

    Article  PubMed  CAS  Google Scholar 

  33. Arnone D, Mumuni AN, Jauhar S, Condon B, Cavanagh J. Indirect evidence of selective glial involvement in glutamate-based mechanisms of mood regulation in depression: meta-analysis of absolute prefrontal neuro-metabolic concentrations. Eur Neuropsychopharmacol. 2015;25:1109–17.

    Article  PubMed  CAS  Google Scholar 

  34. Moriguchi S, Takamiya A, Noda Y, Horita N, Wada M, Tsugawa S, et al. Glutamatergic neurometabolite levels in major depressive disorder: a systematic review and meta-analysis of proton magnetic resonance spectroscopy studies. Mol Psychiatry. 2019;24:952–64.

    Article  PubMed  CAS  Google Scholar 

  35. Ali F, Gerhard DM, Sweasy K, Pothula S, Pittenger C, Duman RS, et al. Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines. Nat Commun. 2020;11:72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Fogaça MV, Daher F, Picciotto MR. Effects of ketamine on GABAergic and glutamatergic activity in the mPFC: biphasic recruitment of GABA function in antidepressant-like responses. Neuropsychopharmacology. 2025;50:673–84.

    Article  PubMed  Google Scholar 

  37. Lumsden EW, Troppoli TA, Myers SJ, Zanos P, Aracava Y, Kehr J, et al. Antidepressant-relevant concentrations of the ketamine metabolite (2R,6R)-hydroxynorketamine do not block NMDA receptor function. Proc Natl Acad Sci USA. 2019;116:5160–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Duman RS, Shinohara R, Fogaça MV, Hare B. Neurobiology of rapid-acting antidepressants: convergent effects on GluA1-synaptic function. Mol Psychiatry. 2019;24:1816–32.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Gerhard DM, Pothula S, Liu RJ, Wu M, Li XY, Girgenti MJ, et al. GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions. J Clin Invest. 2020;130:1336–49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Ghosal S, Duman CH, Liu RJ, Wu M, Terwilliger R, Girgenti MJ, et al. Ketamine rapidly reverses stress-induced impairments in GABAergic transmission in the prefrontal cortex in male rodents. Neurobiol Dis. 2020;134:104669.

    Article  PubMed  CAS  Google Scholar 

  41. Li Y, Du Y, Wang C, Lu G, Sun H, Kong Y, et al. (2R,6R)-hydroxynorketamine acts through GluA1-induced synaptic plasticity to alleviate PTSD-like effects in rat models. Neurobiol Stress. 2022;21:100503.

  42. Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533:481–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Wamsley B, Fishell G. Genetic and activity-dependent mechanisms underlying interneuron diversity. Nat Rev Neurosci. 2017;18:299–309.

    Article  PubMed  CAS  Google Scholar 

  44. Page CE, Coutellier L. Prefrontal excitatory/inhibitory balance in stress and emotional disorders: Evidence for over-inhibition. Neurosci Biobehav Rev. 2019;105:39–51.

    Article  PubMed  CAS  Google Scholar 

  45. Wohleb ES, Wu M, Gerhard DM, Taylor SR, Picciotto MR, Alreja M, et al. GABA interneurons mediate the rapid antidepressant-like effects of scopolamine. J Clin Invest. 2016;126:2482–94.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Malik R, Li Y, Schamiloglu S, Sohal VS. Top-down control of hippocampal signal-to-noise by prefrontal long-range inhibition. Cell. 2022;185:1602–17.e17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Wang Q, Jie W, Liu JH, Yang JM, Gao TM. An astroglial basis of major depressive disorder? An overview. Glia. 2017;65:1227–50.

    Article  PubMed  Google Scholar 

  48. Lu CL, Ren J, Cao X. An astroglial basis of major depressive disorder: molecular, cellular, and circuit features. Biol Psychiatry. 2024;97:217–26.

  49. Murphy-Royal C, Gordon GR, Bains JS. Stress-induced structural and functional modifications of astrocytes-Further implicating glia in the central response to stress. Glia. 2019;67:1806–20.

    Article  PubMed  Google Scholar 

  50. Rajkowska G, Stockmeier CA. Astrocyte pathology in major depressive disorder: insights from human postmortem brain tissue. Curr Drug Targets. 2013;14:1225–36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Sanacora G, Banasr M. From pathophysiology to novel antidepressant drugs: glial contributions to the pathology and treatment of mood disorders. Biol Psychiatry. 2013;73:1172–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Rouach N, Koulakoff A, Abudara V, Willecke K, Giaume C. Astroglial metabolic networks sustain hippocampal synaptic transmission. Science. 2008;322:1551–5.

    Article  PubMed  CAS  Google Scholar 

  53. Østergaard L, Jørgensen MB, Knudsen GM. Low on energy? An energy supply-demand perspective on stress and depression. Neurosci Biobehav Rev. 2018;94:248–70.

    Article  PubMed  Google Scholar 

  54. Jiang T, Feng M, Hutsell A, Lüscher B. Sex-specific GABAergic microcircuits that switch vulnerability into resilience to stress and reverse the effects of chronic stress exposure. Mol Psychiatry. 2025;30:2297–308.

    Article  PubMed  CAS  Google Scholar 

  55. Shepard R, Page CE, Coutellier L. Sensitivity of the prefrontal GABAergic system to chronic stress in male and female mice: Relevance for sex differences in stress-related disorders. Neuroscience. 2016;332:1–12.

    Article  PubMed  CAS  Google Scholar 

  56. Li S, Zhang X, Cai Y, Zheng L, Pang H, Lou L. Sex difference in incidence of major depressive disorder: an analysis from the Global Burden of Disease Study 2019. Ann Gen Psychiatry. 2023;22:53.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Hu Y, Zhang X, Fong TH, Wang T, Zhang J, Zhang Y, et al. Distinct subpopulations of parvalbumin neurons participating in divergent prefrontal functions. Neuropsychopharmacology. 2025;50:1502–14.

  58. Fukumoto K, Fogaça MV, Liu RJ, Duman C, Kato T, Li XY, et al. Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2R,6R)-hydroxynorketamine. Proc Natl Acad Sci USA. 2019;116:297–302.

    Article  PubMed  CAS  Google Scholar 

  59. Riggs LM, Aracava Y, Zanos P, Fischell J, Albuquerque EX, Pereira EFR, et al. (2R,6R)-hydroxynorketamine rapidly potentiates hippocampal glutamatergic transmission through a synapse-specific presynaptic mechanism. Neuropsychopharmacology. 2020;45:426–36.

    Article  PubMed  CAS  Google Scholar 

  60. Yao N, Skiteva O, Zhang X, Svenningsson P, Chergui K. Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit. Mol Psychiatry. 2018;23:2066–77.

    Article  PubMed  CAS  Google Scholar 

  61. Chen Y, Yan P, Wei S, Zhu Y, Lai J, Zhou Q. Ketamine metabolite alleviates morphine withdrawal-induced anxiety via modulating nucleus accumbens parvalbumin neurons in male mice. Neurobiol Dis. 2023;186:106279.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank the members of Zhou’s lab for the technical supports and helpful discussion. This work is supported by grant from Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions (2023SHIBS0004), National Natural Science Foundation of China (82471548), and Wenzhou Basic Scientific Research Project (Y2023064).

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Authors and Affiliations

  1. School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China

    Tsz Hei Fong, Tianxiang Li, Xiaoyan Ma & Qiang Zhou

  2. Department of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen Clinical Research Center for Mental Disorders, Shenzhen Institute of Mental Health, Shenzhen, 518020, Guangdong, China

    Tsz Hei Fong

  3. Oujiang Laboratory, Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, School of Mental Health, Zhejiang Provincial Clinical Research Center for Mental Disorders, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

    Xiang Cai

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Contributions

Conceptualization: QZ, THF, and XM. Methodology: QZ, THF, TL, XM, and XC. Experiment and data analysis: THF, TL, and QZ. Writing—original draft: QZ and THF. Writing—review and editing: QZ, THF, and XC. Funding acquisition: QZ and XC. Project administration: QZ. Supervision, QZ.

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Correspondence to Qiang Zhou.

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Fong, T.H., Li, T., Ma, X. et al. Prefrontal contribution to passive coping behaviour in chronic stress and treatment by fast-acting antidepressant. Neuropsychopharmacol. (2025). https://doi.org/10.1038/s41386-025-02200-5

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