Cellular and molecular mechanisms that modulate synaptic function and plasticity

关于改变突触生理的特定分子变化是如何启动的，知识上的差距仍然存在 活着的动物的特殊行为偏好和记忆。关于细胞生物学的知识 突触在记忆的激活中被改变对于我们理解如何 神经系统的组成部分聚集在一起，产生其功能输出和行为。这个 这项提议的总体目标是确定线虫如何在温敏神经元之间突触 AFD及其唯一的突触后伙伴(AIY)被经验修改以表达习得的温度 偏好。我们的中心假设是在AFD中温度偏好记忆是通过 突触前可塑性，而突触前可塑性又受依赖于nPKC/etA(nPKCε)的蛋白激酶C调节 机械装置。我们的假设是基于我们的初步研究和发表的研究结果，这些发现表明 改变单个神经元中的nPKCε活性足以改变细胞的温度偏好 有机体，而不考虑以前的经验。我们发现npkcε定位于突触前部位并发生改变。 将AFD感觉信息传递给其突触后伙伴(AIY)。拟议目标的理由 我们可以利用线虫紧凑的神经回路来分析保守的分子，如nPKCε， 调节突触前可塑性以调节经验依赖的适应行为。我们建议使用 遗传学、细胞生物学、药理学、行为学和钙成像方法来实现我们的三个目标 具体目标：(1)确定nPKCε在调节AFD：AIY化学突触中的作用；(2)确定 调节nPKCε激活的分子机制；以及(3)识别突触前可塑性机制 受npkcε调控。在成功完成拟议的目标后，我们预计贡献将是 详细的分子和细胞生物学知识，了解温度偏爱记忆是如何在 体内通过保守的nPKCε通路调节突触前可塑性。技术上的 这一提案中的概念创新通过提供对记忆中心的访问打开了新的视野 在活体动物中的驱动和细胞生物分辨率。我们预计，因为分子 保护被检查的路径，基于这些创新在我们理解上的进步 将导致具有广泛生物学意义的可转置课程。

A gap in knowledge remains regarding how specific molecular changes that alter synaptic physiology actuate particular behavioral preferences and memories in living animals. Knowledge on how the cell biology of synapses is altered in the actuation of memories is of critical importance in our aspiration to understand how the building blocks of the nervous system come together to produce its functional output, behaviors. The overall objective of this proposal is to determine how C. elegans synapses between the thermosensory neuron AFD and its only postsynaptic partner (AIY) are modified by experiences to express a learned temperature preference. Our central hypothesis is that temperature preference memory is actuated in AFD through presynaptic plasticity, which is in turn regulated through Protein Kinase C epsilon/eta (nPKCε)-dependent mechanisms. Our hypothesis is based on our preliminary studies and published findings that indicate that altering nPKCε activity in a single neuron (AFD) is sufficient to change the temperature preference of the organism regardless of previous experience. We found that nPKCε localizes near presynaptic sites and alters transmission of AFD sensory information to its postsynaptic partner (AIY). The rationale of the proposed aims is that we can use the compact neural circuitry of C. elegans to dissect how conserved molecules, like nPKCε, regulate presynaptic plasticity to modulate experience-dependent adaptive behaviors. We propose to use genetic, cell biological, pharmacological, behavioral and calcium imaging approaches to achieve our three specific aims: (1) Identify the role of nPKCε in modulating the AFD:AIY chemical synapse; (2) Identify the molecular mechanisms that regulate nPKCε activation; and (3) Identify the presynaptic plasticity mechanism regulated by nPKCε. Upon successful completion of the proposed aims we expect the contribution to be a detailed molecular and cell biological understanding of how the temperature preference memory is actuated in vivo through the regulation of presynaptic plasticity mediated by the conserved nPKCε pathways. The technical and conceptual innovations in this proposal open up new horizons by providing access to the hubs of memory actuation in living animals and with cell biological resolution. We anticipate, because of the molecular conservation of the examined pathways, that advancements in our understanding based on these innovations will result in transposable lessons of broad biological significance.