Hebbian Long-Term Potentiation and Learning in Aplysia

海兔的赫布长时程增强和学习

• 批准号: 7013970
• 负责人: DAVID L GLANZMAN
• 金额: $ 34.43万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-03 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7013970
• 关键词: AMPA receptors; Aplysia; NMDA receptors; association learning; behavioral /social science research tag; conditioning; electrophysiology; long term potentiation; memory; motor neurons; neural plasticity; protein kinase; protein localization; reflex; serotonin; synapses; voltage /patch clamp

DESCRIPTION (provided by applicant): Perhaps the most basic form of associative learning, classical conditioning has been the subject of scientific investigation for a century. Nevertheless, the neurobiological mechanisms underlying classical conditioning remain poorly understood. The goal of the proposed research is to use a simple reflex that exhibits classical conditioning, and can be studied using reductionist neurobiological tools. Many of the neurons that underlie this reflex have been identified. In particular, the sensory and motor neurons for the reflex have been identified in the central nervous system (CNS). Moreover, the sensory and motor neurons can be individually dissociated from the CNS and placed into cell culture. This makes possible in vitro electrophysiological and molecular investigations of learning-related neuronal plasticity. In vitro studies of synaptic plasticity will be combined with studies of classical condititioning in semi-intact preparations that permit simultaneous electrophysiological and behavioral manipulation and measurement. A major focus of the proposed research will be on the roles of postsynaptic glutamate receptors, particularly NMDA and AMPA receptors, in classical conditioning. One potential mechanism for classical conditioning is modulation of the intracellular trafficking of AMPA receptors by the monoamine serotonin (5-HT). The cellular and molecular mechanisms of 5-HT-dependent modulation of AMPA receptor trafficking will be investigated in both neurons in culture and in the CNS. Pharmacological agents that block modulation of AMPA receptor trafficking will be used to identify the protein kinases involved in this modulation. Whether modulation of AMPAR receptor trafficking depends upon protein synthesis will also be studied. Immunohistochemical techniques will be used to label AMPA receptors, both in vitro and in the CNS. This will permit the direct visualization of changes in AMPA receptor distribution and number due to 5-HT and to learning. Furthermore, in situ hybridization will be used to determine whether long-term (>=24 hr) classical conditioning depends upon increased expression of genes for AMPA and NMDA receptors. Finally, the interactions between 5-HT-dependent processes and NMDA receptor-dependent processes during classical conditioning will be examined. The results of the project will clarify the basic neurobiology of learning, and will thereby facilitate the development of treatments for diseases of memory, such as Alzheimer's.

描述（由申请人提供）：也许是协会学习的最基本形式，经典条件一直是一个世纪的科学研究主题。然而，经典条件的基础神经生物学机制仍然很少理解。拟议的研究的目的是使用一种表现出经典条件的简单反射，并可以使用还原主义神经生物学工具进行研究。已经确定了这种反射的许多神经元。特别是，在中枢神经系统（CNS）中鉴定出了反射的感觉和运动神经元。此外，感觉和运动神经元可以与中枢神经系统单独解离并放入细胞培养物中。这使得与学习相关的神经元可塑性的体外电生理和分子研究成为可能。突触可塑性的体外研究将与半独立制剂中的经典屈服进行研究，以同时进行电生理和行为操纵和测量。拟议的研究的主要重点将是突触后谷氨酸受体（尤其是NMDA和AMPA受体）在经典条件中的作用。经典调节的一种潜在机制是调节单胺5-羟色胺（5-HT）对AMPA受体的细胞内运输。将在培养和中枢神经系统中的神经元中研究5-HT依赖性调节的5-HT依赖性调节的细胞和分子机制。阻断AMPA受体运输的调节的药理学剂将用于鉴定与该调节有关的蛋白激酶。还将研究AMPAR受体运输的调节是否取决于蛋白质的合成。免疫组织化学技术将用于在体外和中枢神经系统中标记AMPA受体。这将允许直接可视化AMPA受体分布的变化和由于5-HT和学习而导致的数量。此外，原位杂交将用于确定长期（> = 24小时）经典条件是否取决于AMPA和NMDA受体的基因表达增加。最后，将检查在经典调节过程中5-HT依赖性过程与NMDA受体依赖性过程之间的相互作用。该项目的结果将阐明学习的基本神经生物学，从而有助于发展记忆疾病的治疗方法，例如阿尔茨海默氏症。