Cellular and molecular mechanisms that temporally and spatially restrict synaptic

描述(申请人提供)：5-羟色胺是一种神经递质，调节广泛的行为和生理过程，包括摄食、运动、生殖、呼吸、睡眠和影响。5-羟色胺能神经元在发育、形态可塑性和功能方面都是独一无二的。他们在特定的目标区域精心制作了复杂的轴突乔木。这种发展的重要性反映在许多精神和认知障碍上，这些障碍的根源是5-羟色胺能回路的不正常发育。5-羟色胺神经递质也能够反馈到5-羟色胺能神经元，以可塑性重塑轴突树枝和突触前释放部位。调节5-羟色胺能轴突和突触发育和可塑性的分子机制尚不清楚，这也是本研究的目的。5-羟色胺能通路在整个进化过程中被很好地保守。我们最近开发了一种系统，使我们能够在体内、实时和单细胞分辨率下分析线虫体内5-羟色胺能神经元的形态发生和突触发生。我们计划使用这个系统来回答以下问题：1)在空间上限制5-羟色胺能轴突树枝形成的细胞和分子机制是什么？2)控制5-羟色胺能突触组装的分子机制是什么？3)控制5-羟色胺能突触可塑性的分子机制是什么？综上所述，本文提出的方法将使我们能够剖析调节5-羟色胺能突触发育和可塑性的分子机制。鉴于5-羟色胺能回路的保守性，我们希望这些研究中发现的机制能够揭示5-羟色胺能回路如何在发育和疾病中进行生理调节。

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.