Developmental and Molecular Logic of Synaptic Partner Specificity

项目摘要 单个神经元组装成相互连接的网络是感知外部刺激的关键 和行为反应的诱导。当这种回路被破坏时，如在慢性疼痛和外周 神经病变，其影响可能对生活质量产生破坏性影响。大多数的疼痛研究 集中在外周体感神经元的功能特性，但驱动的因素， 这些神经元与中央中间神经元的适当连接也可以导致新的治疗途径。 在大脑中，有一个密集的传入神经元轴突和接受神经元树突的神经网络，但不是所有的 神经元之间可以相互交流。例如，对轻触有反应的感觉神经元必须 从对粗糙触摸有反应的感觉神经元中识别出不同的伙伴神经元。因此， 以促进选择性神经元伴侣匹配，这确保了给定的感觉输入将导致 可预测的、适当的输出响应。尽管这一中心，以确保可重复的反应，很少是 了解神经元如何选择特定的伙伴来形成突触。更好地了解 驱动突触伴侣选择的发育和分子机制可能有助于揭示 它们被破坏并驱动了一些疼痛神经病的病因。这项建议旨在提供一个入侵 开始发现参与伴侣选择的发育机制和基因， 可能是揭示神经元连接的分子逻辑的关键。该提案将调查 连接在一个紧凑的神经系统，果蝇黑腹果蝇，由于多个 优势包括单个神经元的遗传控制，刻板的连接，以及评估方法 突触伴侣选择虽然在进化上相隔数亿年，但大约75%的 基因在功能上与D.黑腹菌对人类的影响，很可能即使基因 在D.黑腹动物选择伴侣没有人类同源物，神经元的整体逻辑如何 这些物种中会有选择性的伴侣最近的发现已经开始定义一个网络， 已知连通性的神经元在D.黑腹神经系统，这项研究将主要集中在 两个伙伴神经元，使用网络中的其他神经元来测试对其他神经元的泛化问题。 突触伴侣在第一个目标中，在许多潜在的基因中建立特异性的功能机制， 合伙人会被审问在第二个目标中，介导这种突触识别的单个分子 将被探索。总之，这两个互补的发展和分子实验集将 允许测试粘附分子的组合编码指示特异性的总体假设 突触伴侣匹配 !

PROJECT SUMMARY The assembly of individual neurons into interconnected networks is essential for sensation of external stimuli and induction of a behavioral response. When this circuitry is disrupted as in chronic pain and peripheral neuropathies, the effects can have a debilitating effect on quality of life. The majority of pain research has focused on functional properties of the peripheral somatosensory neurons, but the factors that drive the appropriate connectivity of these neurons to central interneurons could also lead to new avenues for treatment. In the brain, there is a dense neuropil of incoming neuronal axons and receptive neuronal dendrites, yet not all neurons can communicate with one another. For instance, sensory neurons responsive to light touch must identify distinct partner neurons from sensory neurons responsive to harsh touch. Thus, there is high impetus to promote selective neuronal partner matching, which ensures that a given sensory input will lead to a predictable, appropriate output response. Despite this centrality to ensuring reproducible reactions, little is known about how neurons select specific partners for synapse formation. A better understanding of developmental and molecular mechanisms that drive synaptic partner choice could help to uncover processes that are disrupted and driving the etiology of some pain neuropathies. This proposal aims to provide an inroad to initiate discovery of developmental mechanisms and genes that are involved in partner choice, and that could be key to revealing the molecular logic used in neuronal connectivity. This proposal will investigate connectivity in a compact nervous system, that of the fruit fly Drosophila melanogaster, due to multiple advantages including genetic control of individual neurons, stereotyped connectivity, and methods to assess synaptic partner choice. Although separated evolutionarily by hundreds of millions of years, about 75% of genes are functionally conserved from D. melanogaster to humans, and it is likely that even if the genes identified in D. melanogaster partner choice do not have human homologs, the overall logic of how neurons select partners will be preserved across these species. Recent discoveries have begun to define a network of neurons of known connectivity in the D. melanogaster nervous system, and this study will focus primarily on two partner neurons, using additional neurons in the network to test questions of generalizability to other synaptic partners. In the first aim, functional mechanisms for establishing specificity among numerous potential partners will be interrogated. In the second aim, the individual molecules that mediate this synaptic recognition will be explored. Together, these two complementary developmental and molecular sets of experiments will allow the testing of the overall hypothesis that a combinatorial code of adhesion molecules instructs specificity in synaptic partner matching. !