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Adult hippocampal neurogenesis-mediated cognitive behavior participates in stress resilience to anxiety and depression-like behaviors in postpartum dams

Molecular Psychiatry volume 30, pages 4868–4880 (2025)Cite this article

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Abstract

Postpartum period being a critical phase affecting women’s health recovery, and stressful events during this period are major risk factors for postpartum depression. Pup separation (PS) serves as a natural model of postpartum maternal care. However, the effects of different PS (no separation, NPS; 15 min/day, PS15, brief PS; 180 min/day, PS180, long PS) during lactation on stress-induced behavioral deficits in dams, along with the underlying mechanisms of resilience remain unclear. In this study, we assessed cognitive and emotional behaviors in lactating C57BL/6 J dams subjected to different PS from postnatal day 1 to day 21, along with chronic restraint stress (CRS). Subsequently, hippocampal samples were collected to analyze the expression of NLRP3, IL-18, and IL-1β, along with microglial activation and adult hippocampal neurogenesis (AHN) in the hippocampal dentate gyrus. We further modulated AHN using viral and examined the effects of AHN overexpression or inhibition on behavior and hippocampal neuroinflammation. Dams subjected to brief PS exhibited reduced anxiety and depressive-like behaviors and improved cognitive function. Additionally, PS15 dams showed decreased hippocampal expression of NLRP3, IL-18, and IL-1β, reduced microglia activation, and increased AHN. Overexpression of AHN can significantly improved cognitive function, but no significant changes in emotional behaviors were observed. Besides, AHN-mediated cognitive behavior participates in resilience to anxiety and depression-like behaviors of dams after CRS. Similarly, inhibition of hippocampal NLRP3 expression enhanced AHN-related cognitive behavior and promoted stress resilience in adult female mice. Brief PS resulted in resilience to anxiety and depressive-like behaviors in dams and mitigated memory impairments induced by CRS. This study confirmed AHN-mediated cognitive behavior participates in stress resilience to anxiety and depression-like behaviors in postpartum dams after CRS.

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Fig. 1: CRS induced the cognition deficits and anxiety and depression-like behaviors of NPS dams.
Fig. 2: Brief PS reversed the cognition deficits and anxiety and depression-like behaviors of dams after CRS.
Fig. 3: LV-Wnt3 injection prevented the cognition deficits and anxiety and depression-like behaviors of dams after CRS.
Fig. 4: Arac injection promoted the cognition deficits and anxiety and depression-like behaviors of dams after CRS.
Fig. 5: NLRP3 overexpression in the hippocampus increased cognition deficits and anxiety and depression like behaviors.
Fig. 6: NLRP3 inhibition in the hippocampus reversed cognition deficits and anxiety and depression like behaviors.

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References

  1. Lex C, Bäzner E, Meyer TD. Does stress play a significant role in bipolar disorder? A meta-analysis. J Affect Disord. 2017;208:298–308.

    PubMed  Google Scholar 

  2. Lee S, Jeong J, Kwak Y, Park SK. Depression research: where are we now? Mol Brain. 2010;3:8.

    PubMed  PubMed Central  Google Scholar 

  3. Bhatnagar S. Rethinking stress resilience. Trends Neurosci. 2021;44:936–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Russo SJ, Murrough JW, Han MH, Charney DS, Nestler EJ. Neurobiology of resilience. Nat Neurosci. 2012;15:1475–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Kjelstrup KB, Solstad T, Brun VH, Hafting T, Leutgeb S, Witter MP, et al. Finite scale of spatial representation in the hippocampus. Science. 2008;321:140–3.

    CAS  PubMed  Google Scholar 

  6. Strange BA, Witter MP, Lein ES, Moser EI. Functional organization of the hippocampal longitudinal axis. Nat Rev Neurosci. 2014;15:655–69.

    CAS  PubMed  Google Scholar 

  7. Kheirbek MA, Drew LJ, Burghardt NS, Costantini DO, Tannenholz L, Ahmari SE, et al. Differential control of learning and anxiety along the dorsoventral axis of the dentate gyrus. Neuron. 2013;77:955–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Felix-Ortiz AC, Tye KM. Amygdala inputs to the ventral hippocampus bidirectionally modulate social behavior. J Neurosci. 2014;34:586–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Komorowski RW, Garcia CG, Wilson A, Hattori S, Howard MW, Eichenbaum H. Ventral hippocampal neurons are shaped by experience to represent behaviorally relevant contexts. J Neurosci. 2013;33:8079–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Huckleberry KA, Shue F, Copeland T, Chitwood RA, Yin W, Drew MR. Dorsal and ventral hippocampal adult-born neurons contribute to context fear memory. Neuropsychopharmacology. 2018;43:2487–96.

    PubMed  PubMed Central  Google Scholar 

  11. Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, et al. Dynamics of hippocampal neurogenesis in adult humans. Cell. 2013;153:1219–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Anacker C, Hen R. Adult hippocampal neurogenesis and cognitive flexibility - linking memory and mood. Nat Rev Neurosci. 2017;18:335–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Sahay A, Scobie KN, Hill AS, O’Carroll CM, Kheirbek MA, Burghardt NS, et al. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature. 2011;472:466–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. McAvoy KM, Scobie KN, Berger S, Russo C, Guo N, Decharatanachart P, et al. Modulating Neuronal Competition Dynamics in the Dentate Gyrus to Rejuvenate Aging Memory Circuits. Neuron. 2016;91:1356–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Stein DJ, Vasconcelos MF, Albrechet-Souza L, Ceresér KMM, de Almeida RMM. Microglial Over-Activation by Social Defeat Stress Contributes to Anxiety- and Depressive-Like Behaviors. Front Behav Neurosci. 2017;11:207.

    PubMed  PubMed Central  Google Scholar 

  16. Heneka MT, Kummer MP, Latz E. Innate immune activation in neurodegenerative disease. Nat Rev Immunol. 2014;14:463–77.

    CAS  PubMed  Google Scholar 

  17. Réus GZ, Fries GR, Stertz L, Badawy M, Passos IC, Barichello T, et al. The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders. Neuroscience. 2015;300:141–54.

    PubMed  Google Scholar 

  18. Gust K, Caccese C, Larosa A, Nguyen TV. Neuroendocrine Effects of Lactation and Hormone-Gene-Environment Interactions. Mol Neurobiol. 2020;57:2074–84.

    CAS  PubMed  Google Scholar 

  19. Medina J, Workman JL. Maternal experience and adult neurogenesis in mammals: Implications for maternal care, cognition, and mental health. J Neurosci Res. 2020;98:1293–308.

    CAS  PubMed  Google Scholar 

  20. Zhou L, Wu Z, Zhao D, Wang G, Xiao L, Wang H, et al. Brief pup separation during lactation confers resilience in behavioural deficits induced by chronic restraint stress in postpartum C57BL/6J dams. J Psychiatry Neurosci. 2023;48:E154–e170.

    PubMed  PubMed Central  Google Scholar 

  21. Leng L, Zhuang K, Liu Z, Huang C, Gao Y, Chen G, et al. Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation. Neuron. 2018;100:551–563.e7.

    CAS  PubMed  Google Scholar 

  22. Chiba S, Numakawa T, Ninomiya M, Richards MC, Wakabayashi C, Kunugi H. Chronic restraint stress causes anxiety- and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex. Prog Neuropsychopharmacol Biol Psychiatry. 2012;39:112–9.

    CAS  PubMed  Google Scholar 

  23. Hill MN, Kumar SA, Filipski SB, Iverson M, Stuhr KL, Keith JM. Disruption of fatty acid amide hydrolase activity prevents the effects of chronic stress on anxiety and amygdalar microstructure. Mol Psychiatry. 2013;18:1125–35.

    CAS  PubMed  Google Scholar 

  24. Zhou Y, Yan M, Pan R, Wang Z, Tao X, Li C, et al. Radix Polygalae extract exerts antidepressant effects in behavioral despair mice and chronic restraint stress-induced rats probably by promoting autophagy and inhibiting neuroinflammation. J Ethnopharmacol. 2021;265:113317.

    CAS  PubMed  Google Scholar 

  25. Tripathi A, Whitehead C, Surrao K, Pillai A, Madeshiya A, Li Y, et al. Type 1 interferon mediates chronic stress-induced neuroinflammation and behavioral deficits via complement component 3-dependent pathway. Mol Psychiatry. 2021;26:3043–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Torres-Platas SG, Cruceanu C, Chen GG, Turecki G, Mechawar N, et al. Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav Immun. 2014;42:50–9.

    CAS  PubMed  Google Scholar 

  27. Frick LR, Williams K, Pittenger C. Microglial dysregulation in psychiatric disease. Clin Dev Immunol. 2013;2013:608654.

    PubMed  PubMed Central  Google Scholar 

  28. Levone BR, Cryan JF, O’Leary OF. Role of adult hippocampal neurogenesis in stress resilience. Neurobiol Stress. 2015;1:147–55.

    PubMed  Google Scholar 

  29. Schoenfeld TJ, McCausland HC, Morris HD, Padmanaban V, Cameron HA. Stress and Loss of Adult Neurogenesis Differentially Reduce Hippocampal Volume. Biol Psychiatry. 2017;82:914–23.

    PubMed  PubMed Central  Google Scholar 

  30. Willner P. The chronic mild stress (CMS) model of depression: History, evaluation and usage. Neurobiol Stress. 2017;6:78–93.

    PubMed  Google Scholar 

  31. Patel D, Kas MJ, Chattarji S, Buwalda B. Rodent models of social stress and neuronal plasticity: Relevance to depressive-like disorders. Behav Brain Res. 2019;369:111900.

    PubMed  Google Scholar 

  32. Wu Z, Zhou L, Sun L, Xie Y, Xiao L, Wang H. Brief postpartum separation from offspring promotes resilience to lipopolysaccharide challenge-induced anxiety and depressive-like behaviors and inhibits neuroinflammation in C57BL/6J dams. Brain Behav Immun. 2021;95:190–202.

    CAS  PubMed  Google Scholar 

  33. Surget A, Saxe M, Leman S, Ibarguen-Vargas Y, Chalon S, Griebel G, et al. Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal. Biol Psychiatry. 2008;64:293–301.

    CAS  PubMed  Google Scholar 

  34. Surget A, Tanti A, Leonardo ED, Laugeray A, Rainer Q, Touma C. Antidepressants recruit new neurons to improve stress response regulation. Mol Psychiatry. 2011;16:1177–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA, et al. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol Psychiatry. 2009;14:764–73.

    CAS  PubMed  Google Scholar 

  36. David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I, et al. Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron. 2009;62:479–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Mohammad H, Marchisella F, Ortega-Martinez S, Hollos P, Eerola K, Komulainen E, et al. JNK1 controls adult hippocampal neurogenesis and imposes cell-autonomous control of anxiety behaviour from the neurogenic niche. Mol Psychiatry. 2018;23:362–74.

    CAS  PubMed  Google Scholar 

  38. Choi SH, Bylykbashi E, Chatila ZK, Lee SW, Pulli B, Clemenson GD, et al., Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model. Science, 2018. 361.

  39. Ramirez S, Liu X, MacDonald CJ, Moffa A, Zhou J, Redondo RL, et al. Activating positive memory engrams suppresses depression-like behaviour. Nature. 2015;522:335–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Noorjahan N, Cattini PA. Neurogenesis in the Maternal Rodent Brain: Impacts of Gestation-Related Hormonal Regulation, Stress, and Obesity. Neuroendocrinology. 2022;112:702–22.

    CAS  PubMed  Google Scholar 

  41. Clelland CD, Choi M, Romberg C, Clemenson GD Jr, Fragniere A, et al. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science. 2009;325:210–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Nakashiba T, Cushman JD, Pelkey KA, Renaudineau S, Buhl DL, McHugh TJ, et al. Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion. Cell. 2012;149:188–201.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Eliwa H, Brizard B, Le Guisquet AM, Hen R, Belzung C, Surget A. Adult neurogenesis augmentation attenuates anhedonia and HPA axis dysregulation in a mouse model of chronic stress and depression. Psychoneuroendocrinology. 2021;124:105097.

    CAS  PubMed  Google Scholar 

  44. Park SC. Neurogenesis and antidepressant action. Cell Tissue Res. 2019;377:95–106.

    PubMed  Google Scholar 

  45. Lagace DC, Donovan MH, DeCarolis NA, Farnbauch LA, Malhotra S, Berton O, et al. Adult hippocampal neurogenesis is functionally important for stress-induced social avoidance. Proc Natl Acad Sci USA. 2010;107:4436–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Anacker C, Pariante CM. Can adult neurogenesis buffer stress responses and depressive behaviour? Mol Psychiatry. 2012;17:9–10.

    CAS  PubMed  Google Scholar 

  47. Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003;302:1760–5.

    CAS  PubMed  Google Scholar 

  48. Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci USA. 2003;100:13632–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Belarbi K, Arellano C, Ferguson R, Jopson T, Rosi S. Chronic neuroinflammation impacts the recruitment of adult-born neurons into behaviorally relevant hippocampal networks. Brain Behav Immun. 2012;26:18–23.

    CAS  PubMed  Google Scholar 

  50. Green HF, Nolan YM. Inflammation and the developing brain: consequences for hippocampal neurogenesis and behavior. Neurosci Biobehav Rev. 2014;40:20–34.

    PubMed  Google Scholar 

  51. Kohman RA, Rhodes JS. Neurogenesis, inflammation and behavior. Brain Behav Immun. 2013;27:22–32.

    CAS  PubMed  Google Scholar 

  52. Oh J, McCloskey MA, Blong CC, Bendickson L, Nilsen-Hamilton M, Sakaguchi DS. Astrocyte-derived interleukin-6 promotes specific neuronal differentiation of neural progenitor cells from adult hippocampus. J Neurosci Res. 2010;88:2798–809.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Chen Z, Palmer TD. Differential roles of TNFR1 and TNFR2 signaling in adult hippocampal neurogenesis. Brain Behav Immun. 2013;30:45–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Qin Z, Shi DD, Li W, Cheng D, Zhang YD, Zhang S, et al. Berberine ameliorates depression-like behaviors in mice via inhibiting NLRP3 inflammasome-mediated neuroinflammation and preventing neuroplasticity disruption. J Neuroinflammation. 2023;20:54.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. He H, Xie X, Zhang J, Mo L, Kang X, Zhang Y, et al. Patchouli alcohol ameliorates depression-like behaviors through inhibiting NLRP3-mediated neuroinflammation in male stress-exposed mice. J Affect Disord. 2023;326:120–31.

    CAS  PubMed  Google Scholar 

  56. Wu MD, Montgomery SL, Rivera-Escalera F, Olschowka JA, O’Banion MK. Sustained IL-1β expression impairs adult hippocampal neurogenesis independent of IL-1 signaling in nestin+ neural precursor cells. Brain Behav Immun. 2013;32:9–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Ryan SM, O’Keeffe GW, O’Connor C, Keeshan K, Nolan YM. Negative regulation of TLX by IL-1β correlates with an inhibition of adult hippocampal neural precursor cell proliferation. Brain Behav Immun. 2013;33:7–13.

    CAS  PubMed  Google Scholar 

  58. Yang Y, Xing MJ, Li Y, Zhang HF, Yuan TF, Peng DH. Reduced NLRP3 inflammasome expression in the brain is associated with stress resilience. Psychoneuroendocrinology. 2021;128:105211.

    CAS  PubMed  Google Scholar 

  59. Dang R, Guo YY, Zhang K, Jiang P, Zhao MG. Predictable chronic mild stress promotes recovery from LPS-induced depression. Mol Brain. 2019;12:42.

    PubMed  PubMed Central  Google Scholar 

  60. Camargo A, Dalmagro AP, Wolin IAV, Kaster MP, Rodrigues ALS. The resilient phenotype elicited by ketamine against inflammatory stressors-induced depressive-like behavior is associated with NLRP3-driven signaling pathway. J Psychiatr Res. 2021;144:118–28.

    PubMed  Google Scholar 

  61. Rutter M. Annual Research Review: Resilience-clinical implications. J Child Psychol Psychiatry. 2013;54:474–87.

    PubMed  Google Scholar 

  62. Rakesh G, Morey RA, Zannas AS, Malik Z, Marx CE, Clausen AN, et al. Resilience as a translational endpoint in the treatment of PTSD. Mol Psychiatry. 2019;24:1268–83.

    PubMed  PubMed Central  Google Scholar 

  63. Dumitrescu L, Mahoney ER, Mukherjee S, Lee ML, Bush WS, Engelman CD, et al. Genetic variants and functional pathways associated with resilience to Alzheimer’s disease. Brain. 2020;143:2561–75.

    PubMed  PubMed Central  Google Scholar 

  64. Ryff CD. Psychological well-being revisited: advances in the science and practice of eudaimonia. Psychother Psychosom. 2014;83:10–28.

    PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81571325, 81871072 and 82071523), the Medical Science Advancement Program of Wuhan University (NO. TFLC2018001) and the key research and development program of Hubei Province (2020BCA064).

Funding

This study was supported by the National Natural Science Foundation of China (Nos. 81571325, 81871072, and 82071523) and the Medical Science Advancement Program of Wuhan University (No. TFLC2018001). The key research and development program of Hubei Province (2020BCA064) also supported the design of this study.

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  1. These authors contributed equally: Lin Zhou, Zuotian Wu.

Authors and Affiliations

  1. Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, China

    Lin Zhou, Yixin Li, Yumeng Xie, Limin Sun, Shanshan Lin, Ling Xiao, Huiling Wang & Gaohua Wang

  2. Hubei Provincial Clinical Research Center for Psychiatry, Wuhan, China

    Lin Zhou, Huiling Wang & Gaohua Wang

  3. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Zuotian Wu

  4. Institute of Neuropsychiatry, Renmin Hospital of Wuhan University, Wuhan, China

    Gaohua Wang

  5. Taikang center for life and medical sciences, Wuhan University, China Donghu Road 115#, 430071, Wuhan, China

    Gaohua Wang

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Contributions

WGH participated in the design of the experiments. ZL and WZT both carried out the experiment and drafted the manuscript. LSS and LYX carried out the analysis. SLM and XYM carried out the behavioral tests. XL and WHL advised on the experimental design and helped to draft the manuscript. All authors read, edited, and approved the final manuscript.

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Correspondence to Gaohua Wang.

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This work was carried out based on the Regulations of Experimental Animal Administmiceion issued by the State Committee of Science and Technology of the People’s Republic of China, with the approval of the Ethics Committee in Renmin Hospital of Wuhan University. All methods were performed in accordance with the relevant guidelines and regulations.

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Zhou, L., Wu, Z., Li, Y. et al. Adult hippocampal neurogenesis-mediated cognitive behavior participates in stress resilience to anxiety and depression-like behaviors in postpartum dams. Mol Psychiatry 30, 4868–4880 (2025). https://doi.org/10.1038/s41380-025-03082-1

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