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

Stress and anxiety are well-known modulators of both physiological and pathological itch. Acute stress suppresses itch, while chronic stress exacerbates it. These effects are mediated by neural circuits within the brain, though the precise mechanisms remain poorly understood. In this study, we investigate the role of neurons in the stress-sensitive lateral hypothalamic area (LHA) in modulating itch. Using neural activity-dependent genetic labeling and chemogenetic tools, we selectively engaged a population of LHA neurons (LHA ^stress-TRAP neurons) responsive to stress. Transient stimulation of these neurons induced anxiety-like behaviors, conditioned place aversion, and suppressed acute (chloroquine-induced) and chronic (psoriatic) itch. Conversely, the inhibition of the LHA ^stress-TRAP neurons enhanced acute and chronic itch. Interestingly, LHA ^stress-TRAP neurons did not respond to acute itch stimuli, but their activity was temporally correlated with scratching episodes in mice with psoriasis. Ex vivo whole-cell patch-clamp recordings revealed that these neurons exhibit heightened excitability in psoriatic animals. Anterograde viral tracing demonstrated that LHA ^stress-TRAP neurons project to brainstem regions implicated in itch modulation, including the periaqueductal gray (PAG), rostral ventromedial medulla (RVM), and lateral parabrachial nucleus (LPBN). Furthermore, chemogenetic activation and optogenetic silencing of LHA ^stress-TRAP axon terminals revealed that bidirectional modulation of itch is primarily mediated through projections to the PAG. Together, these findings identify a previously unrecognized central mechanism by which stress modulates itch, centered on a specific population of LHA neurons and their downstream brainstem targets.