Investigating mechanisms of homeostasis and plasticity in Drosophila

 描述（由申请人提供）：神经系统疾病影响世界各地每个国家的所有年龄组和社会阶层。在最基本的层面上，这些疾病中的许多是由电路、突触和神经元不能正常地适应其细胞环境的变化而导致神经元活动的不平衡引起的。为了治疗这些疾病，需要进行基础研究，以了解健康的神经元如何能够感知，补偿和保持适当的活动水平。这一提议将增加关于健康的神经系统如何能够在人类一生中保持可塑性的知识，同时在面对变化时保持功能连接。使用果蝇，其中许多基本的神经分子和蛋白质是保守的，提供了一个相对简单的，良好的表征系统，具有许多强大的遗传工具来操纵特定的神经元亚群。利用膜片钳电生理技术，可以直接记录果蝇幼虫运动神经元的放电特性和内在特性。这项工作将研究运动神经元如何感知其活动的变化，并启动一系列分子步骤，从钙开始，导致影响细胞兴奋性的通道和电导的变化。利用一种新技术，在神经元发育的敏感时期，光将激活神经元，并测量这种活动对神经元的影响。此外，果蝇中可用的遗传工具将被用来操纵钙通道的一部分，钙通道被认为是神经元感知自身活动所必需的。这项工作将是第一个在果蝇中研究如何增加神经元活动在特定的 发育期会影响单个神经元的兴奋性。它还直接解决了单个神经元如何能够感知和响应其局部环境的变化，以通过研究一种途径， 已经证明在包括哺乳动物在内的许多生物体中细胞兴奋性中是重要的。这项工作将有助于更好地了解有多少神经系统疾病可能随着时间的推移而发展和变化，例如癫痫。

 DESCRIPTION (provided by applicant): Neurological diseases affect all age groups and segments of society in every country around the world. Many of these diseases are, at the most basic level, caused by the inability of circuits, synapses, and neurons to normally adjust to changes in their cellular environment resulting in an imbalance in neuronal activity. To treat these disorders, basic research is needed to understand how healthy neurons are able to sense, to compensate for, and to maintain a proper activity level. This proposal will add to the body of knowledge about how a healthy nervous system is able to remain plastic throughout a human lifetime while also maintaining functional connections in the face of change. Using Drosophila, where many of the basic neural molecules and proteins are conserved, provides a relatively simple, well-characterized system that has many powerful genetic tools to manipulate specific sub-groups of neurons. Using patch clamp electrophysiology, motor neurons in larval Drosophila can be directly recorded from to measure the neuron's firing properties and intrinsic properties. This work will investigate how motor neurons sense changes in their activity and set in motion a series of molecular steps beginning with calcium that results in changes to channels and conductances that affect cell excitability. Using a new technique, neurons will be activated by light during sensitive periods of development and the effect of this activity on the neurons wil be measured. In addition, the genetic tools available in Drosophila will be used to manipulate parts of the calcium pathway believed to be essential for a neuron to sense its own activity. This work will be the first in Drosophila to investigate how increased neuronal activity during specific periods of development can affect the excitability of individual neurons. It also directly addresses how individual neurons are able to sense and respond to changes in their local environment to maintain a preferred level of excitability over time by investigating a pathway that has been shown to be important in cellular excitability in a number of organisms including mammals. This work will lead to a better understanding of how many neurological diseases may develop and change over time, such as epilepsy.