Amygdala AVPR1A mediates susceptibility to chronic social isolation in female mice.

Nov 4, 2025Nature communications

How a Brain Receptor Affects Women's Response to Loneliness

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Abstract

Arginine vasopressin receptor 1a (AVPR1A) may mediate enhanced anxiety in female mice exposed to chronic social isolation stress.

Females show greater sensitivity to social isolation stress compared to males.
Chemogenetic activation of AVPR1A circuits induces anxiety-related behaviors in both sexes.
Endogenous activation of AVPR1A in the central amygdala is specifically engaged in females during social isolation stress.
A major source of the AVP ligand is identified in the medial amygdala, affecting anxiety responses.
Three circuit nodes contribute to sex-specific anxiety responses: ERα signaling in AVP neurons, AVPR1A pathway engagement in the central amygdala, and AVPR1A projections to the dorsolateral striatum.

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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 AVPR1Acircuits 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 AVPR1Aneurons, 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 AVPneurons; 2) engagement of the AVPR1A pathway in the CeA; and 3) number of AVPR1Aprojections to the DLS. These data support new therapeutic applications for AVPR1A antagonists in women experiencing social isolation or loneliness. CeA CeA MePD CeA

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