Hypothalamic circuitry underlying stress-induced insomnia and peripheral immunosuppression.

The neural substrates of insomnia/hyperarousal induced by stress remain unknown. Here, we show that restraint stress leads to hyperarousal associated with strong activation of corticotropin-releasing hormone neurons in the paraventricular nucleus of hypothalamus (CRH) and hypocretin neurons in the lateral hypothalamus (Hcrt). CRH neurons directly innervate Hcrt neurons, and optogenetic stimulation of LH-projecting CRH neurons elicits hyperarousal. CRISPR-Cas9-mediated knockdown of the gene in CRH neurons abolishes hyperarousal induced by stimulating LH-projecting CRH neurons. Genetic ablation of Hcrt neurons or gene knockdown significantly counteracts restraint stress-induced hyperarousal. Single-cell mass cytometry by time of flight (CyTOF) revealed extensive changes to immune cell distribution and functional responses in peripheral blood during hyperarousal upon optogenetic stimulation of CRH neurons simulating stress-induced insomnia. Our findings suggest both central and peripheral systems are synergistically engaged in the response to stress via CRH circuitry.