Molecular Codes For Neuronal Homeostasis

描述（由申请人提供）：神经科学中最深刻和最核心的问题之一是神经元和电路如何平衡对可塑性的需求与神经元和电路稳定性的要求。在过去的二十年中，研究人员在这个项目上的开创性工作已经确定，神经元和电路通过参与一套稳态可塑性机制来解决这个稳定性问题，这些机制可以稳定神经元在活动设定点附近的兴奋性。稳态可塑性的研究现在已经发展成为一个庞大而多样的领域，并且存在大量描述神经元兴奋性和突触强度的稳态调节现象学的文献。然而，尽管取得了很大进展，但理解神经元活动的稳态调节的概念框架的关键要素仍然完全不清楚。在本提案中，我们希望解决该领域的四个突出问题：1)神经元活动设定点是如何建立的，设定点组件的分子身份是什么？2)如何在不同的神经元中建立不同的设定点？3)设定点机制的下游目标是什么，这些目标是如何组织起来以有效地协调不同形式的稳态可塑性的？最后4)网络关系如何影响设定点？该项目将在一个协同企业中召集四位自稳态可塑性领域的顶尖研究人员，以确定如何建立活动设定值。我们的前提是，这个过程是所有神经系统的基础，它的功能结构很可能是进化上保守的。因此，我们现在提出了一套协作和协同的实验，将利用不同脊椎动物和无脊椎动物制剂的优势，揭示调节活动设定点稳态的传感器和效应器的分子特性。这里所描述的实验将测试关于如何解决神经科学中一个真正基本问题的新假设，从长远来看，可能会产生一套新的策略，用于干预由体内平衡和代偿机制受损引起的许多神经系统疾病。

DESCRIPTION (provided by applicant): One of the deepest and most central problems in neuroscience is how neurons and circuits manage to balance the need for plasticity with the requirements of neuronal and circuit stability. Pioneering work over the past two decades from the investigators on this program project has established that neurons and circuits solve this stability problem by engaging a set of homeostatic plasticity mechanisms that act to stabilize neuronal excitability around an activity set-point. The study of homeostatic plasticity has now blossomed into a large and diverse field, and a substantial body of literature describing the phenomenology of homeostatic regulation of neuronal excitability and synaptic strength now exists. However, despite much progress, key elements of the conceptual framework for understanding homeostatic regulation of neuronal activity remain completely obscure. In this proposal, we wish to address four outstanding questions in the field: 1) How are neuronal activity set-points built, and what are the molecular identities of the set-point components? 2) How are different set-points in different neurons established? 3) What are the downstream targets of the set-point machinery, and how are these organized to effectively coordinate different forms of homeostatic plasticity? And finally 4), how do network relationships influence set-points? This program project will bring together four of the top researchers in the field of homeostatic plasticity in a synergistic enterprise to determine how activity set-points are built. Our premise is that this process is so fundamental to all nervous systems that it is likely that th functional structures underlying it are evolutionarily conserved. Therefore, we now propose a collaborative and synergistic set of experiments that will leverage the advantages of different vertebrate and invertebrate preparations to uncover the molecular identity of the sensors and effectors that regulate homeostasis of activity set-points. The experiments described here will test novel hypotheses about how a truly fundamental problem in neuroscience is solved, and in the long term are likely to result in a set of new strategies for interventions in numerous neurological disorders that result from impaired homeostatic and compensatory mechanisms.