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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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“Gq DREADD mice exhibit an increase in the latency to approach and spend less time interacting with their pups in the maternal approach test compared to AAVGFP controls (Figure 5g,h; latency t(22) = −2.”
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Chemogenetics revealed: DREADD occupancy and activation via converted clozapine
Gomez, J. L., Bonaventura, J., Lesniak, W., Mathews, W. B., Sysa-Shah, P., Rodriguez, L. A., Ellis, R. J., Richie, C. T., Harvey, B. K., Dannals, R. F., et al. (2017) · Science · doi:10.1126/science.aan2475 · Cited by 980
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Liu, S., Wang, L., Nie, X.-K., Song, C.-Y., Chen, Y.-H., Wang, L., & Lian, C.-Y. (2026) · Applied Animal Behaviour Science · doi:10.1016/j.applanim.2026.107103
Potential of Neurosteroids for Precision Medicine in Psychiatry
Dargan, T., Walton, N. L., & Maguire, J. L. (2026) · Biological Psychiatry · doi:10.1016/j.biopsych.2026.07.009
Self-citationJoyal, K. G., & Maguire, J. L. (2026) · Epilepsy Research · doi:10.1016/j.eplepsyres.2026.107888
Self-citationVandendoren, M., Landen, J. G., Rogers, J. F., Killmer, S., Alamiri, B., Pohlman, C., Tattersall, G. J., Bedford, N. L., & Nelson, A. C. (2026) · eLife · doi:10.7554/elife.108212.3
Father knows stress: Interactions among stress, glucocorticoids, and paternal care in mammals
Wendy Saltzman, A., & Harris, B. N. (2026) · Journal of Neuroendocrinology · doi:10.1111/jne.70271
Saunders, S. E., Dow, K. E., Bostic, G. E., Boychuk, J. A., Maguire, J. L., & Boychuk, C. R. (2026) · eLife · doi:10.7554/elife.111303.2
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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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