Cellular and molecular mechanisms that temporally and spatially restrict synaptic

描述（由申请人提供）：血清素是一种神经递质，可调节多种行为和生理过程，包括进食、运动、繁殖、呼吸、睡眠和情绪。血清素能神经元在发育、形态可塑性和功能方面都是独特的。它们在特定的目标区域上精心设计复杂的轴突枢纽。这一发展的重要性反映在许多精神和认知障碍中，这些障碍的根源在于血清素能回路的不适当发展。5 -羟色胺神经递质也能够反馈到5 -羟色胺能神经元上，以可塑性地重塑轴突和突触前释放位点。调节5 -羟色胺能轴突和突触的发育和可塑性的分子机制尚不清楚，这是本建议的目的。5 -羟色胺能途径在整个进化过程中都是保守的。我们最近开发了一个系统，使我们能够在线虫的单细胞分辨率下实时测定血清素能神经元的形态发生和突触发生。我们计划利用这个系统来回答以下问题：1)在空间上限制血清素能轴突树突的细胞和分子机制是什么？2)控制血清素能突触组装的分子机制是什么？3)控制血清能突触可塑性的分子机制是什么？总之，这里提出的方法将使我们能够解剖调节血清素能突触发育和可塑性的分子机制。考虑到5 -羟色胺能回路的保守性，我们期望在这些研究中发现的机制能告诉我们5 -羟色胺能回路在发育和疾病中是如何受到生理调节的。

DESCRIPTION (provided by applicant): Serotonin is a neurotransmitter that modulates a wide range of behaviors and physiological processes, including feeding, movement, reproduction, respiration, sleep and affect. Serotonergic neurons are unique in terms of their development, morphological plasticity and function. They elaborate complex axon arbors over specific target regions. The importance of this development is reflected in the numerous psychiatric and cognitive disorders that have their roots in the improper development of serotonergic circuits. The serotonin neurotransmitter is also able to feed back onto serotonergic neurons to plastically reshape the axon arbors and presynaptic release sites. The molecular mechanisms that regulate the development and plasticity of serotonergic axon arbors and synapses are not yet understood, and are the purpose of this proposal. Serotonergic pathways are well conserved throughout evolution. We recently developed a system that allows us to assay serotonergic neuron morphogenesis and synaptogenesis in vivo, in real time and with single cell resolution in C. elegans. We plan to use this system to answer the following questions: 1) What are the cellular and molecular mechanisms that spatially restrict serotonergic axon arborization? 2) What are the molecular mechanisms the control serotonergic synapse assembly? and 3) What are the molecular mechanisms that control sertotonergic synapse plasticity? In summary, the approaches proposed here will allow us to dissect the molecular mechanisms that regulate serotonergic synapse development and plasticity. Given the conserved nature of serotonergic circuits, we expect the mechanisms uncovered in these studies to inform how serotonergic circuits are physiologically regulated in development and disease.