Lateral hypothalamus directs stress-induced modulation of acute and psoriatic itch.

Stress modulates itch, with acute stress suppressing and chronic stress exacerbating pruritus, yet the underlying neural mechanisms remain unclear. In this study, we investigate the role of lateral hypothalamic area (LHA) neurons in stress-induced itch modulation. Using neural-activity-dependent genetic labeling and chemogenetic tools, we selectively engaged a stress-sensitive population of LHA neurons (LHAstress-TRAP neurons). Transient activation of these neurons elicited anxiety-like behavior and place aversion while suppressing both acute (chloroquine-induced) and chronic (psoriatic) itch; conversely, their inhibition potentiated itch. Notably, these neurons were not activated by acute itch but displayed activity correlated with scratching in psoriatic mice and exhibited enhanced intrinsic excitability ex vivo. Anterograde tracing revealed projections to key brainstem itch-modulatory regions, including the periaqueductal gray (PAG), rostral ventromedial medulla (RVM), and lateral parabrachial nucleus (LPBN). Projection-specific manipulations demonstrated that itch modulation is predominantly mediated via the PAG. Together, these findings uncover a central stress-itch circuit centered on LHA neurons and their brainstem targets.