Project Summary Social touch is rewarding, motivating social interactions and relationships, and can act as a stress buffer, regulating the body’s responses to short-term challenges. However, the skin-to-brain neuronal circuits by which touch is rewarding and promotes stress resilience remain unknown. Discovery of specific peripheral neurons that play a role in the rewarding and/or anxiolytic nature of touch would be the first step in elucidating such a circuit. Peripheral mechanoreceptors called C-tactile (CT afferents) in humans are implicated in soothing, comforting touch. However, the molecular identity of the neurons responsible for the rewarding and calming effects of touch remain unknown. In mice, an anatomically analogous and functionally similar population of mechanoreceptors to CT afferents express mas-related G-protein coupled receptor B4 (MrgprB4). With this genetic handle, we can target a single molecular subset of mammalian sensory neurons implicated in social touch, and investigate its role in reward and stress attenuation. In fact, my preliminary data suggest that transdermal optogenetic activation of MrgprB4 neurons is rewarding and ablation of MrgprB4 neurons increases susceptibility to stress. Therefore, I hypothesize that activation of MrgprB4 neurons directly activates brain reward circuitry and is sufficient to attenuate the stress response. I will test this hypothesis in two specific aims. In Aim 1, I will determine whether activation of MrgprB4 neurons is necessary and sufficient for touch- dependent activation of the reward system. To test the sufficiency, I will determine whether optogenetic activation of MrgprB4 neurons stimulates dopamine release in the nucleus accumbens. To test necessity, I will determine whether a tactile stimulus that typically stimulates dopamine release in the nucleus accumbens (gentle stroking of the back) stimulates dopamine release in mice with MrgprB4 neurons ablated. These experiments will determine whether activation of a single subset of peripheral neurons is responsible for touch- dependent activation of reward circuits in vivo. In Aim 2, I will determine whether optogenetic activation of MrgprB4 neurons is sufficient to attenuate the stress response, using behavioral assays and corticosterone measurements. The proposed work will define the role of MrgprB4+ neurons in the rewarding and anxiolytic nature of touch in rodents, laying the groundwork for future studies aimed at uncovering the human skin-to- brain circuit that mediates these benefits of touch, which could lead to the development of novel therapeutics for anxiety and depression.