Lateral hypothalamic orexin→VTA projection regulates consolation via orexin receptor 1 in male mice

Consolation, a prosocial behavior in which individuals comfort distressed conspecifics, is regarded as a fundamental expression of empathy. Orexin (OX) neurons in the lateral hypothalamus (LH) have been implicated in empathic processes, but the specific circuitry and receptor subtypes through which they modulate consolation remain unknown. Here, we investigated the role of LH^OX neurons and their projection to the ventral tegmental area (VTA) in regulating consolation-like behavior in male mice. We found that consolation toward a defeat induced stressed partner was accompanied by reduced c-Fos expression in LH^OX neurons. Using chemogenetic manipulations, we demonstrated that activation of LH^OX neurons, or specifically the LH^OX→VTA projections, decreased consolation-like allogrooming. Furthermore, intra-VTA injection of the orexin receptor 1 (OX1R) antagonist SB-334867, but not the OX2R antagonist Seltorexant, rescued the allogrooming deficit induced by pathway activation, identifying VTA OX1R as the critical receptor subtype. These effects occurred without alterations in anxiety-like behavior or general sociability. Collectively, these findings reveal that the LH^OX→VTA pathway, acting through OX1R, contributes to the regulation of consolation, establishing a receptor-specific circuit mechanism for orexinergic modulation of empathy-related prosocial behavior.