Synaptic mechanisms of somatosensory circuit assembly

摘要 慢性疼痛是一种使人衰弱的疾病，比癌症、心脏病和糖尿病影响更多的美国人 加在一起。尽管存在这一重大的公共卫生问题，但有效的治疗方法很少，而且通常都是处方。 阿片类药物具有重大的滥用责任。翻译成绩不佳的一个可能原因是，我们仍然 缺乏对这些回路如何连接以处理感觉信息及其可塑性的详细了解 机械装置。在我们的初步实验中，我们已经确定了跨突触黏附的重要作用。 脊髓中调节体感突触功能的分子。在这里我们将确定反式- 影响体感突触形成的突触分子，了解突触前黏附 躯体感觉神经元中的分子指示脊髓中天然突触的形成和功能，以及 确定它们在协调伤害性回路组装以调节疼痛行为方面的作用。此提案将使用 体外突触诱导试验、条件性基因敲除和拯救方法的组合，外周 病毒电路追踪，光遗传切片记录，和体感表型，以了解如何反式 突触黏附分子调节躯体感觉回路的组装和功能。

Abstract Chronic pain is debilitating disease that affects more Americans than cancer, heart disease, and diabetes combined. Despite this significant public health problem, effective treatments are scarce and commonly prescribed opioids possess significant abuse liabilities. One possible reason for this poor translational success is that we still lack a detailed understanding of how these circuits are connected to process sensory information and their plasticity mechanisms. In our preliminary experiments we have identified important roles for trans-synaptic adhesion molecules in regulating somatosensory synapse function in the spinal cord. Here we will determine the trans- synaptic molecules that influence somatosensory synapse formation, understand how presynaptic adhesion molecules in somatosensory neurons instruct the formation and function of native synapses in the spinal cord, and establish their role in coordinating nociceptive circuit assembly to regulate pain behaviors. This proposal will use a combination of in vitro synapse induction assays, conditional gene knockout and rescue approaches, peripheral viral circuit tracing, optogenetic slice recordings, and somatosensory phenotyping to understand how trans- synaptic adhesion molecules regulate somatosensory circuit assembly and function.