Stress-Activated Lateral Hypothalamic Neurons Suppress Itch

Abstract

The bidirectional relationship between stress and itch represents a critical but incompletely understood aspect of pruritic skin disorders that affects millions of patients worldwide. This thesis identifies a specific population of lateral hypothalamus neurons activated by restraint stress (LHStress neurons) that play a crucial role in stress-modulation of itch. Using the TRAP2 system in mice, we demonstrate that acute restraint stress significantly suppresses scratching behavior in both acute chloroquine-induced (P = 0.0092, n = 8) and chronic imiquimod-induced (P = 0.0053, n = 7) itch models. Chemogenetic activation of LHStress neurons reduced scratching in both models (P < 0.005), while silencing these neurons increased scratching behavior (P < 0.02) and abolished stress-induced itch suppression. Through viral tracing and targeted manipulations, we identified the LHStress→lateral/ventrolateral periaqueductal gray pathway as both necessary and sufficient for stress-induced itch suppression. Notably, LHStress neurons exhibited significant plasticity during chronic itch, developing novel scratch-related activity patterns (P = 0.0113, n = 10) and increased intrinsic excitability not observed in acute conditions. These findings reveal a specific neural circuit mechanism underlying stress-itch interactions and provide a framework for understanding why stress often exacerbates pruritic disorders in clinical settings. The identification of experience-dependent plasticity in these circuits offers potential targets for therapeutic intervention aimed at breaking the vicious cycle between stress and itch that characterizes many chronic pruritic conditions.