Molecular Codes For Neuronal Homeostasis

描述(申请人提供)：神经科学中最深层和最核心的问题之一是神经元和回路如何设法平衡对可塑性的需求与神经元和回路稳定性的要求。这个项目的研究人员在过去20年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，这些机制可以在活动设定点附近稳定神经元的兴奋性。稳态可塑性的研究现已发展到一个大而多样的领域，大量文献描述了神经元兴奋性和突触强度的稳态调节的现象学。然而，尽管取得了很大进展，但理解神经元活动的动态平衡调节的概念框架的关键要素仍然完全不清楚。在这个提案中，我们希望解决该领域的四个悬而未决的问题：1)神经元活动设定点是如何建立的，设定点成分的分子同一性是什么？2)不同神经元中不同的设定点是如何建立的？3)设定点机制的下游目标是什么，以及这些目标是如何组织起来的，以有效地协调不同形式的稳态可塑性？最后，网络关系如何影响设定值？该计划项目将汇集协同企业中动态平衡可塑性领域的四位顶尖研究人员，以确定如何建立活动设置点。我们的前提是，这个过程对所有神经系统来说都是如此基础，以至于它下面的功能结构很可能在进化上是保守的。因此，我们现在提出一套协作和协同的实验，利用不同脊椎动物和无脊椎动物制剂的优势来揭示调节活动设定点的动态平衡的传感器和效应器的分子身份。这里描述的实验将测试关于神经科学中真正根本的问题是如何解决的新假设，从长远来看，可能会产生一套新的策略，用于干预许多神经疾病，这些疾病是由体内平衡和代偿机制受损引起的。

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.