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）：也许是最基本的形式联想学习，经典条件反射一直是科学研究的主题为世纪。然而，经典条件反射背后的神经生物学机制仍然知之甚少。这项研究的目的是使用一种表现出经典条件反射的简单反射，并且可以使用还原论的神经生物学工具进行研究。许多神经元的基础，这种反射已被确定。特别地，在中枢神经系统（CNS）中已经确定了用于反射的感觉神经元和运动神经元。此外，感觉神经元和运动神经元可以单独地从CNS分离并置于细胞培养物中。这使得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经典的半完整的制剂，允许同时电生理和行为的操纵和测量的条件作用的研究相结合。拟议的研究的一个主要重点将是突触后谷氨酸受体，特别是NMDA和AMPA受体，在经典条件反射中的作用。经典条件反射的一个潜在机制是通过单胺5-羟色胺（5-HT）调节AMPA受体的细胞内运输。AMPA受体运输的5-HT依赖性调节的细胞和分子机制将在培养的神经元和CNS中进行研究。阻断AMPA受体运输调节的药理学试剂将用于鉴定参与这种调节的蛋白激酶。AMPAR受体运输的调节是否依赖于蛋白质合成也将被研究。免疫组织化学技术将被用来标记AMPA受体，在体外和中枢神经系统。这将允许直接可视化AMPA受体分布和数量的变化，由于5-HT和学习。此外，原位杂交将用于确定长期（>=24小时）经典条件反射是否依赖于AMPA和NMDA受体基因表达的增加。最后，5-HT依赖性过程和NMDA受体依赖性过程之间的相互作用将在经典条件反射检查。该项目的结果将阐明学习的基本神经生物学，从而促进阿尔茨海默氏症等记忆疾病治疗方法的开发。