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Inability to suppress the stress-induced activation of the HPA axis during the peripartum period engenders deficits in postpartum behaviors in mice.
Open accessAbstract
The stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis is normally suppressed during pregnancy. Dysregulation of the HPA axis has been proposed to play a role in postpartum depression. However, direct investigation into the relationship between the HPA axis and postpartum depression has been hindered by the lack of useful animal models. Building on our discovery of a role for the K+/Cl-co-transporter, KCC2, in the GABAergic regulation of CRH neurons in the paraventricular nucleus of the hypothalamus (PVN), critical for mounting the body's physiological response to stress, we assessed the role of KCC2 in the regulation of the HPA axis during pregnancy and the postpartum period. Here we demonstrate that the normal suppression of the stress-induced activation of the HPA axis during the peripartum period involves maintenance of KCC2 in the PVN. Mice lacking KCC2 specifically in corticosterone-releasing hormone (CRH) neurons, which govern the activity of the HPA axis (KCC2/Crh mice), exhibit dysregulation of the HPA axis and abnormal postpartum behaviors. Loss of KCC2 specifically in CRH neurons in the PVN is sufficient to reproduce the depression-like phenotype and deficits in maternal behaviors during the postpartum period. Similarly, chemogenetic activation of CRH neurons in the PVN is sufficient to induce abnormal postpartum behaviors and chemogenetic silencing of CRH neurons in the PVN can ameliorate abnormal postpartum behaviors observed in KCC2/Crh mice. This study demonstrates that dysregulation of the HPA axis is sufficient to induce abnormal postpartum behaviors and deficits in maternal behaviors in mice, providing empirical support for a role of HPA axis dysfunction in the pathophysiology of postpartum depression.
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“The role of GABAergic signaling is further supported by animal model studies demonstrating PPD-like behaviors in mice lacking the extrasynaptic GABAAR δ subunit or potassium/chloride cotransporter KCC2, and these PPD models also functionally link GABA with the hypothalamic-pituitary axis, a stress pathway implicated in PPD.34,35”
From Effect of Zuranolone vs Placebo in Postpartum Depression (2021) · cites this paper as [35]
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Numan, M. (2020) · Oxford University Press eBooks · doi:10.1093/oso/9780190848675.002.0003
Abbreviations Used for Major Brain Regions
Numan, M. (2020) · Oxford University Press eBooks · doi:10.1093/oso/9780190848675.002.0007
Numan, M. (2020) · Oxford University Press eBooks · doi:10.1093/oso/9780190848675.002.0004
Chapter 24. Brexanolone and Other Neurosteroids
Patterson, R., Krohn, H., & Meltzer-Brody, S. E. (2024) · American Psychiatric Association Publishing eBooks · doi:10.1176/appi.books.9781615375523.as24
SHUKLA, A. K., & MISRA, S. (2025) · International Journal of Current Pharmaceutical Research · doi:10.22159/ijcpr.2025v17i4.7035
Büyükdemirtaş, B., Benn, M., Kwon, H. B., Rosen, E., & Melón, L. C. (2025) · Psychopharmacology · doi:10.1007/s00213-025-06969-7
Self-citationHu, Y., Pardo, N., Yang, X., Yang, T., Yan, X., Khalili, R., Wolf-Jacobs, A., Chen, X., Niu, Z., Toledo‐Corral, C. M., et al. (2025) · Environmental Research · doi:10.1016/j.envres.2025.123527
Self-citationImpact of impaired endogenous neurosteroidogenesis on outcomes following chronic alcohol exposure
Blandino, K. L., He, Y., Htet, L., Okoudjou, F., Lee, J., Chinatti, M., Ahn, K., Lewis, M., Gray, S., Miczek, K. A., et al. (2026) · Alcohol · doi:10.1016/j.alcohol.2026.04.008
Self-citationStewart, A., Towers, E. B., Wenzel, E., & Payne, J. L. (2026) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2026.2675004
Metadata
- Authors
- Melón, L. C., Hooper, A., Yang, X., Moss, S. J., & Maguire, J.
- Affiliations
- Tufts University (US)
- Corresponding author
- Maguire, Jamie
- Venue
- Psychoneuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2018-04
- Volume
- 90
- Pages
- 182-193
- ISSN
- 0306-4530 (ISSN-L)
- PMC
- PMC6613202
- OpenAlex
- W2777121311
- Cited by
- 106
- References
- 60
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 11 · 2023: 8 · 2022: 8 · 2021: 9 · 2020: 30 · 2019: 11 · 2018: 9
- FWCI
- 12.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Psychoneuroendocrinology (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH-NINDS (NS073574, NS102937, NS087662, MH106954)
- NIH-NIGMS (K12GM074869)
- IRACDA postdoctoral training grant to Tufts University, Training in Education and Critical Research Skills (TEACRS)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
- Keywords
- hypothalamic-pituitary-adrenal axis, postpartum depression, KCC2, CRH neurons, paraventricular nucleus, maternal behavior, transition period, pregnancy, stress response, GABAergic regulation, chemogenetic manipulation
- MeSH terms
- K Cl- Cotransporters, Animals, Behavior, Animal, Corticosterone, Corticotropin-Releasing Hormone, Depression, Female, Hypothalamo-Hypophyseal System, Hypothalamus, Neurons, Paraventricular Hypothalamic Nucleus, Pituitary-Adrenal System, Depression, Postpartum, Symporters, Postpartum Period, Mice, Peripartum Period
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