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Background <p>Comprehending sex differences in stress vulnerability and the associated neurocircuitry has been elusive until the development of a method for investigating social defeat in female mice.</p> Methods <p>The Stress Alternatives Model (SAM) uses conditioning-induced agonistic behavior from novel male aggressors to separate distinct phenotypes characterized by stress-resilient active avoidance (Escape) or vulnerability (no Escape = Stay).</p> Results <p>Unlike males, females predominantly display Escape behavior, which is reversible (to Stay) by adding more social stress to behavioral environments. Despite this, females exhibit both stress-resilient and vulnerable phenotypic segregation. Stress-vulnerable females exhibit double conditioning-induced corticosterone secretion, more contextual fear conditioning, and reduced social preference. Systemic and intra-BLA injections of Orx<sub>2</sub>R or α<sub>2</sub> antagonists resulted in slower escape (Escape<sup>S</sup>), increased social avoidance, as well as increased cued and contextual freezing in stress-vulnerable females. Neurons in BLA express Orx<sub>2</sub>R mRNA (<i>Hcrtr2)</i> predominantly in cholecystokinin-positive GABA neurons. In slower escape (Escape<sup>S</sup>) females expression of <i>Hcrtr2</i> and <i>Adra2a</i> in BLA is elevated.</p> Conclusions <p>Female and male mice exposed to social stress exhibit distinct behavioral adaptations, but similarly, separate into resilient and susceptible subpopulations. Inhibiting Orx<sub>2</sub>R promotes stress-vulnerable behavior in females, and modifies transcription in BLA microcircuits, suggesting a role for Orx<sub>2</sub>R defining stress behavior.</p>

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Social defeat stress responses in the stress alternative model are dependent on sex and anterior basolateral amygdala orexin 2 receptors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月15日

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  • Jazmine D.W. Yaeger,
  • Megan M. John,
  • Leighton J. Ledesma,
  • Trent L. Greschke,
  • J. J. Gale,
  • Lauren S. Meyer,
  • Renée A. Brummels,
  • Wayne J. Korzan,
  • R. Parrish Waters,
  • Cliff H. Summers

摘要

Background

Comprehending sex differences in stress vulnerability and the associated neurocircuitry has been elusive until the development of a method for investigating social defeat in female mice.

Methods

The Stress Alternatives Model (SAM) uses conditioning-induced agonistic behavior from novel male aggressors to separate distinct phenotypes characterized by stress-resilient active avoidance (Escape) or vulnerability (no Escape = Stay).

Results

Unlike males, females predominantly display Escape behavior, which is reversible (to Stay) by adding more social stress to behavioral environments. Despite this, females exhibit both stress-resilient and vulnerable phenotypic segregation. Stress-vulnerable females exhibit double conditioning-induced corticosterone secretion, more contextual fear conditioning, and reduced social preference. Systemic and intra-BLA injections of Orx2R or α2 antagonists resulted in slower escape (EscapeS), increased social avoidance, as well as increased cued and contextual freezing in stress-vulnerable females. Neurons in BLA express Orx2R mRNA (Hcrtr2) predominantly in cholecystokinin-positive GABA neurons. In slower escape (EscapeS) females expression of Hcrtr2 and Adra2a in BLA is elevated.

Conclusions

Female and male mice exposed to social stress exhibit distinct behavioral adaptations, but similarly, separate into resilient and susceptible subpopulations. Inhibiting Orx2R promotes stress-vulnerable behavior in females, and modifies transcription in BLA microcircuits, suggesting a role for Orx2R defining stress behavior.