Slow-wave sleep engages brainstem circuitry to prevent stress-induced anxiety.

The beneficial effects of sleep on anxiety are established, but the mechanisms remain unclear. We identify a GABAergic circuit from the parafacial zone (PZ) to the lateral parabrachial nucleus (LPB) neurons that project to the oval bed nucleus of the stria terminalis (ovBNST) as a node for slow-wave sleep (SWS)-mediated anxiolysis. Optogenetic activation of PZ GABAergic neurons following social defeat stress induces time-locked SWS and prevents anxiety. Multi-region Ca2+ recording reveals suppressed activity in LPB and ovBNST during natural and PZ-initiated SWS. The LPB-ovBNST pathway is required to drive wakefulness and anxiety, whereas the LPB-basal forebrain pathway promotes arousal without affecting anxiety. PZ neurons inhibit LPB calcitonin gene-related peptide (CGRP)-expressing neurons, which promote wakefulness and anxiety via ovBNST. This effect specifically requires LPB input to ovBNST corticotropin-releasing hormone (Crh) neurons. Thus, we define a PZVgat-LPBCGRP-ovBNSTCrh circuit essential for sleep-related anxiolysis, providing a potential therapeutic target for anxiety disorders.