Amygdala AVPR1A mediates susceptibility to chronic social isolation in female mice
Sex differences in responsiveness to social stress in adulthood are highly conserved across species, with females more sensitive to isolation. Here, we show that Arginine vasopressin receptor 1a (AVPR1A) in the central nucleus of the amygdala (CeA) mediates the enhanced susceptibility of females to post-pubertal chronic social isolation stress (CSIS) in mice. Chemogenetic activation of AVPR1A<sup>CeA</sup> circuits induces anxiety-related behaviors in both sexes. However, genetic, pharmacological, chemogenetic and optogenetic loss of function approaches support the idea that it is only endogenously engaged in females in the context of CSIS. Using a combination of virus-based tools, we identified a major source of AVP ligand in the posterodorsal part of the medial amygdala (MePD) as well as an important downstream target of AVPR1A<sup>CeA</sup> neurons, the dorsolateral striatum (DLS). Loss of function approaches identified three nodes in the circuit that provide sex-specificity in the effects of CSIS on anxiety-related behaviors: 1) ERα signaling in AVP<sup>MePD</sup> neurons; 2) engagement of the AVPR1A pathway in the CeA; and 3) number of AVPR1A<sup>CeA</sup> projections to the DLS. These data support new therapeutic applications for AVPR1A antagonists in women experiencing social isolation or loneliness.
Authors
- Brenna L. Williams (ORCID: https://orcid.org/0000-0003-4956-2795)
- Lucas A. C. Souza (ORCID: https://orcid.org/0000-0003-1512-3030)
- Kelly A. Vranich (ORCID: https://orcid.org/0009-0001-1565-7510)
- Christopher D. Makinson (ORCID: https://orcid.org/0000-0002-1427-8148)
- Daniele Neri (ORCID: https://orcid.org/0000-0003-4376-6324)
- Rim Hassouna (ORCID: https://orcid.org/0000-0002-8237-8431)
- Alexandre Lafond
- Isabella Canal Delgado (ORCID: https://orcid.org/0000-0001-8765-5082)
- Sebastian E. Ho
- Kevin G. Bath (ORCID: https://orcid.org/0000-0003-2229-177X)
- Lori M. Zeltser (ORCID: https://orcid.org/0000-0002-4330-6240)
- Eastman M. Lewis (ORCID: https://orcid.org/0000-0003-0647-0719)
- Gül Dölen (ORCID: https://orcid.org/0000-0003-1780-995X)
- Marie François (ORCID: https://orcid.org/0000-0002-0418-6282)
- Mia Kuromaru
- Natalie R. Lopatinsky
- Youjin Oh (ORCID: https://orcid.org/0000-0003-0906-6359)
- Thomas L. Davis
Institutions
- Johns Hopkins University (US)
- Columbia University Irving Medical Center (US)
- Johns Hopkins Medicine (US)
- New York Psychoanalytic Society and Institute (US)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (US)
- University of California, Berkeley (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-04
- DOI
- https://doi.org/10.1038/s41467-025-64742-y
- Citations
- 1
- Primary Topic
- Neuroendocrine regulation and behavior
- Type
- article
- Field-Weighted Citation Impact
- 2.44
Funders
- University of Michigan
- National Institutes of Health
- Michigan Diabetes Research Center, University of Michigan
- National Cancer Institute
- National Institute of Diabetes and Digestive and Kidney Diseases