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