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

项目总结 社交接触的有益性质对于交流身体和情感支持至关重要，甚至可以 通过触摸的治疗方式来缓解焦虑，比如按摩。触摸诱导的从属情绪和焦虑症 益处通常归因于脑室旁核释放催产素(OT)荷尔蒙 下丘脑(PVH)。然而，社交接触和OT之间的潜在神经生物学关系 释放，包括将这一信息传递给中枢神经的外周机械感受器 系统，是未知的。被称为C-触觉传入的外周机械感受器(CT传入)检测中风触摸 在人类身上。然而，在社交场景中，CT传入的激活是否是中枢OT释放的基础仍然存在 不清楚，主要是因为CT传入的实验操作被证明是具有挑战性的。在小鼠身上，一种 解剖学上相似的机械感受器群体的标志是Mas相关的G蛋白的表达 偶联受体B4(MrgB4)，提供了一个剖析遗传上的社会接触机制的门户 易驯服的模式生物。事实上，我的初步数据表明，MRgB4的透皮光遗传激活- 家系神经元增加PVH内催产素的表达，增加内侧视前区CFos的表达 (在女性性行为期间是活跃的)，并引起姿势的变化，这可能代表一种反应 受社会机械压力的影响。因此，我假设，MRGB4系神经元的激活在 触觉依赖的社会行为，并足以激活下丘脑OT神经元。我将检验这一假设 有两个具体的目标。在目标1中，我将确定mrgB4系神经元是否对 性行为，一种高度依赖触摸的社会行为。为了测试这些神经元对性行为的必要性 行为，我将评估具有基因消融的mrgB4系神经元的女性是否表现出性功能缺陷 与产仔对照相比，对雄性坐骑的接受性。在一个补充实验中，我确定是否 MRgB4系神经元的化学生成激活足以促进性感受性。这两个 实验将确定mrgB4系神经元在高度依赖触摸的社会行为中的作用。在AIM 2我将确定光遗传刺激或自然触觉刺激是否激活自由行为中的OT+PVH神经元 老鼠。为了确定所观察到的OT mRNA的增加是否代表了MRgB4系神经元诱导的激活 对于活体中的OT神经元，我将使用纤维光度法记录来自OT+PVH神经元的同步 背部mrgB4系神经元的光发生激活。为评估OT+PVH神经元与 社会接触，我将使用纤维光度法记录女性性行为过程中OT+PVH神经元的变化。 总的来说，这一提议将定义一群分子定义的机械感受器在社会中的作用 触摸和OT+神经元活动，从而解决触摸和OT释放之间缺失的联系。 了解社交接触的神经生物学中介最终将促进新奇的发现 体感介导的抗焦虑方法的治疗靶点。

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.