Growth Factors and Memory Formation

描述(申请人提供)：现代神经科学中最大的挑战之一是理解大脑如何获取、存储和检索信息。在探索这一普遍问题方面，一个特别令人兴奋的新进展是最近确定了增长因素的可能作用，曾经被认为主要在 大脑发育，在成人的突触可塑性和记忆中。虽然这一想法确实具有开创性，但生长因子在记忆形成中的因果作用尚未确定。因此，这项研究的长期目标是从机制上详细阐明生长因子参与长期记忆形成和维持的方式。为了实现这一目标，我们将探讨两个相互关联的具体目标。在目标1中，我们将检验生长因子信号在记忆形成及其潜在的突触可塑性中起重要作用的假设，在目标2中，我们将检验生长因子重新利用最初参与发育的分子信号级联作用于成人记忆形成和突触可塑性的假设。这两个目标与NIMH与健康相关的任务直接相关，将解决精神健康方面的一个主要挑战：实现对参与正常记忆形成的大脑机制的基本了解，以及当记忆因疾病或伤害而受损时，这些机制是如何受损的。因此，了解生长因子促进正常记忆形成的分子机制可以为确定各种健康相关认知障碍的治疗靶点提供重要的新手段。为了直接探索生长因子如何参与记忆的形成，需要多层次的分析(行为、细胞、突触和分子水平)。Aplysia calfornica是解决这一问题的强大模型系统，因为它允许同时进行多水平分析，以及对关键变化发生的时间进行依赖分析，以及对单个神经元不同区域发生变化的位置进行空间分析。因此，这一提议的一个独特特征是我们使用了一个系统，该系统有可能证明生长因子介导的记忆形成与潜在突触机制的时间和空间特征之间的因果联系。

DESCRIPTION (provided by applicant): One of the greatest challenges in modern neuroscience is to achieve an understanding of how the brain acquires, stores and retrieves information. A particularly exciting new development in exploring this general question is the recent identification of the possible role of growth factors, once considered to function mainly in brain development, in synaptic plasticity and memory in the adult. While this idea is truly seminal, a causal role of growth factors in memory formation has yet to be established. Thus the broad, long-term goal of this research project is to elucidate in mechanistic detail the ways in which growth factors participate in the formation and maintenance of long-term memories. To achieve this goal we will explore two interrelated Specific Aims. In AIM 1 we will test the hypothesis that growth factor signaling plays an essential role in memory formation and its underlying synaptic plasticity, and in Aim 2 we will test the hypothesis that growth factors re-employ molecular signaling cascades originally engaged in development in the service of adult memory formation and synaptic plasticity. Of direct relevance to the health-related mission of the NIMH, these two Aims will address a major challenge in mental health: to achieve a basic understanding of the brain mechanisms that are engaged in normal memory formation, and how those mechanisms are impaired when memory is compromised by disease or injury. Thus, understanding the molecular mechanisms whereby growth factors contribute to normal memory formation can provide an important and novel means of identifying therapeutic targets for a variety of health related cognitive disorders. To directly explore how growth factors participate i memory formation requires multiple levels of analysis (behavioral, cellular, synaptic, and molecular levels). Aplysia californica is a powerful model system to address this question because it allows such a simultaneous multi-level analysis, as well as a time-dependent analysis of when critical changes occur, and a spatial analysis of where changes occur in different regions of individual neurons. Thus a unique feature of this proposal is our use of a system that has the potential to demonstrate causal linkages between growth factor-mediated memory formation and the temporal and spatial features of the underlying synaptic mechanisms.