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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\n                    <jats:italic>Camk2\u03b1, Rspo2<\/jats:italic>\n                    , and\n                    <jats:italic>Hcrtr1<\/jats:italic>\n                    , which enhance stress-vulnerable behaviors via Orx\n                    <jats:sub>1<\/jats:sub>\n                    R activity, and are inhibited directly by Orx\n                    <jats:sub>2<\/jats:sub>\n                    R activation on\n                    <jats:italic>Gad1, Hcrtr2, Cck<\/jats:italic>\n                    GABAergic neurons. Our results have suggested stress circuitry in BLA is modulated by Orx\n                    <jats:sub>1<\/jats:sub>\n                    R and Orx\n                    <jats:sub>2<\/jats:sub>\n                    R activity, which counterbalance stress responsivity via\n                    <jats:italic>Rspo2<\/jats:italic>\n                    -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\n                    <jats:sub>1<\/jats:sub>\n                    R antagonist and Orx\n                    <jats:sub>2<\/jats:sub>\n                    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\n                    <jats:italic>Rspo2<\/jats:italic>\n                    and an increase in\n                    <jats:italic>Hcrtr2<\/jats:italic>\n                    gene expression in aBLA of SORCO-treated Stay mice, and an increase in\n                    <jats:italic>Akt3<\/jats:italic>\n                    and\n                    <jats:italic>Mtor<\/jats:italic>\n                    transcription in Stay mice treated with an Orx\n                    <jats:sub>2<\/jats:sub>\n                    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.\n                  <\/jats:p>","DOI":"10.1038\/s41386-026-02468-1","type":"journal-article","created":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T23:27:10Z","timestamp":1781998030000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Selective orexin receptor cross-over treatment increases resilience and expression of neuroplastic signaling genes"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6216-2899","authenticated-orcid":false,"given":"Megan M.","family":"John","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9549-4917","authenticated-orcid":false,"given":"J. 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