Identifying the role of MrgprB4-lineage neurons in social touch and oxytocin circuit activation

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PROJECT SUMMARY The rewarding nature of social touch is critical for communicating physical and emotional support, and can even be anxiolytic in therapeutic forms of touch such as massage. Touch-induced affiliative emotions and anxiolytic benefits are generally attributed to the release of the hormone oxytocin (OT) from the paraventricular nucleus of the hypothalamus (PVH). However, the underlying neurobiological relationship between social touch and OT release, including the class of peripheral mechanoreceptors that convey this information to the central nervous system, is unknown. Peripheral mechanoreceptors called C-tactile afferents (CT afferents) detect stroking touch in humans. However, whether activation of CT afferents underlies central OT release in social scenarios remains unclear, largely because experimental manipulation of CT afferents has proved challenging. In mice, an anatomically analogous population of mechanoreceptors are marked by expression of mas-related G-protein coupled receptor B4 (MrgB4), providing a gateway to dissect mechanisms of social touch in a genetically tractable model organism. In fact, my preliminary data suggest that transdermal optogenetic activation of MrgB4- lineage neurons increases oxytocin expression in the PVH, cFos expression in the medial preoptic area (mPOA) (which is active during female sexual behavior), and induces a change in posture that could represent a reaction to social mechanical pressure. Therefore, I hypothesize that activation of MrgB4-lineage neurons mediates touch-dependent social behaviors and is sufficient to activate hypothalamic OT neurons. I will test this hypothesis in two specific aims. In Aim 1 I will determine whether MrgB4-lineage neurons are necessary and sufficient for sexual behavior, a highly touch-dependent social behavior. To test the necessity of these neurons for sexual behavior, I will assess whether females with genetically ablated MrgB4-lineage neurons exhibit a deficit in sexual receptivity to male mounts compared to littermate controls. In a complementary experiment, I determine whether chemogenetic activation of the MrgB4-lineage neurons is sufficient to facilitate sexual receptivity. These two experiments will define the role of MrgB4-lineage neurons in a highly touch-dependent social behavior. In Aim 2 I will determine whether optogenetic or natural tactile stimulation activates OT+ PVH neurons in freely behaving mice. To determine if the observed increase in OT mRNA represents a MrgB4-lineage neuron-induced activation of OT neurons in vivo, I will use fiber photometry to record from OT+ PVH neurons during simultaneous optogenetic activation of MrgB4-lineage neurons in the back. To assess the relevance of OT+ PVH neurons to social touch, I will use fiber photometry to record from OT+ PVH neurons in females during sexual behavior. Collectively, this proposal will define the role of a population of molecularly-defined mechanoreceptors in social touch and OT+ neuron activity, thereby addressing the missing link between touch and OT release. Understanding the neurobiological mediators of social touch will ultimately facilitate discovery of novel therapeutic targets for somatosensory-mediated anxiolytic approaches.