Amygdala AVPR1A mediates susceptibility to chronic social isolation in female mice

Marie François, Kelly L. Vranich, Isabella Canal Delgado, Alexandre Lafond, Natalie R. Lopatinsky, Tronjay Davis, Eastman M. Lewis, Mia Kuromaru, Rim Hassouna, Brenna Williams, Sebastian E. Ho, Lucas A. C. Souza, Daniele Neri, Youjin Oh, Christopher D. Makinson, Kevin G. Bath, Gül Dölen and Lori M. Zeltser ()
Additional contact information
Marie François: Columbia University Irving Medical Center
Kelly L. Vranich: Columbia University Irving Medical Center
Isabella Canal Delgado: Columbia University Irving Medical Center
Alexandre Lafond: Columbia University Irving Medical Center
Natalie R. Lopatinsky: Columbia University Irving Medical Center
Tronjay Davis: Columbia University Irving Medical Center
Eastman M. Lewis: The National Institutes of Health
Mia Kuromaru: Columbia University Irving Medical Center
Rim Hassouna: Columbia University Irving Medical Center
Brenna Williams: Columbia University Irving Medical Center
Sebastian E. Ho: Columbia University Irving Medical Center
Lucas A. C. Souza: Columbia University Irving Medical Center
Daniele Neri: Columbia University Irving Medical Center
Youjin Oh: Columbia University Irving Medical Center
Christopher D. Makinson: Columbia University Irving Medical Center
Kevin G. Bath: Columbia University Irving Medical Center
Gül Dölen: University of California Berkeley
Lori M. Zeltser: Columbia University Irving Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract 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 AVPR1ACeA 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 AVPR1ACeA 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 AVPMePD neurons; 2) engagement of the AVPR1A pathway in the CeA; and 3) number of AVPR1ACeA projections to the DLS. These data support new therapeutic applications for AVPR1A antagonists in women experiencing social isolation or loneliness.

Date: 2025
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DOI: 10.1038/s41467-025-64742-y

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