Growth Factors and Memory Formation

描述（由申请人提供）：现代神经科学的最大挑战之一是了解大脑如何获取，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生长因子的可能作用，这些生长因子曾被认为主要在 大脑发育，在突触可塑性和记忆在成人。虽然这一想法确实是开创性的，但生长因子在记忆形成中的因果作用尚未建立。因此，这个研究项目的广泛的长期目标是详细阐明生长因子参与长期记忆形成和维持的机制。为了实现这一目标，我们将探讨两个相互关联的具体目标。在目的1中，我们将测试的假设，即生长因子信号在记忆的形成和其潜在的突触可塑性中起着至关重要的作用，并在目的2中，我们将测试的假设，即生长因子重新使用分子信号级联最初从事成人记忆的形成和突触可塑性的服务的发展。这两个目标与NIMH的健康相关使命直接相关，将解决心理健康方面的一个主要挑战：对参与正常记忆形成的大脑机制以及当记忆因疾病或损伤而受损时这些机制如何受损达成基本理解。因此，了解生长因子促进正常记忆形成的分子机制可以为各种健康相关的认知障碍提供重要和新颖的识别治疗靶点的手段。为了直接探索生长因子如何参与记忆形成，需要多个层次的分析（行为，细胞，突触和分子水平）。加州失智症是一个强大的模型系统来解决这个问题，因为它允许这样一个同时多层次的分析，以及一个时间依赖性的分析，当关键的变化发生，并在空间上分析的变化发生在不同地区的个别神经元。因此，这一建议的一个独特之处是我们使用的系统，有可能证明生长因子介导的记忆形成和潜在的突触机制的时间和空间特征之间的因果关系。

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.