Abstract Social stress, beneficial for evaluating threats and resource opportunities, influences the development of anxious and depressive disorders. Stress responses are initiated via a pro-stress circuit in the anterior region of the basolateral amygdala (aBLA). This circuit contains pyramidal glutamatergic neurons that express genetic markers Camk2α, Rspo2 , and Hcrtr1 , which enhance stress-vulnerable behaviors via Orx 1 R activity, and are inhibited directly by Orx 2 R activation on Gad1, Hcrtr2, Cck GABAergic neurons. Our results have suggested stress circuitry in BLA is modulated by Orx 1 R and Orx 2 R activity, which counterbalance stress responsivity via Rspo2 -positive glutamatergic neurons in aBLA, but whether these effects are consistent with systemic delivery is unknown. These receptor-dependent biases contribute to behavioral, physiological and molecular outcomes associated with psychiatric disorders, such as anxiety, depression, and post-traumatic stress disorder. Administration of a selective orexin receptor cross-over (SORCO; Orx 1 R antagonist and Orx 2 R agonist combination) treatment alleviates anxiogenic behavioral outputs in socially stressed mice, by decreasing escape latency in stress-vulnerable (Stay) mice (phenotypic reversal; vulnerable to resilient), and reducing the time spent freezing in response to the presence of a social aggressor (socially induced) in stress resilient (Escape) mice. Behavioral results coincided with a decrease in Rspo2 and an increase in Hcrtr2 gene expression in aBLA of SORCO-treated Stay mice, and an increase in Akt3 and Mtor transcription in Stay mice treated with an Orx 2 R agonist (YNT-185). Our findings indicate that a combination of OrxR drugs (SORCO) provides potentially therapeutic outcomes through modifications of stress neurocircuitry, triggered by increasing expression of genes associated with neuroplasticity.
John et al. (Sat,) studied this question.