Neural mechanism of rebooting the unconsciousness caused by midazolam

The advent of midazolam has significant implications for modern clinical practice. The hypnotic and sedative effects of midazolam give it a wide range of clinical utility. However, the specific mechanisms underlying the modulation of altered consciousness by midazolam remain unknown. Herein, using pharmacology, optogenetics, chemogenetics, fiber photometry, and gene knockdown, we revealed the role of locus coeruleus (LC)-ventrolateral preoptic nucleus (VLPO) noradrenergic neural circuit in regulating midazolam-induced altered consciousness. This effect was mediated by α1 adrenergic receptors. Moreover, gamma-aminobutyric acid receptor type A (GABAA-R) is a mechanistically important binding site in the LC for midazolam. Our findings will provide novel insights into the neural circuit mechanisms underlying the recovery of consciousness after midazolam administration and will help guide the timing of clinical dosing and propose effective intervention targets for timely recovery from midazolam-induced loss of consciousness.