GENETIC, PHYSIOLOGICAL, AND BEHAVIORAL STUDIES OF MEMORY

描述：(改编自申请者的摘要)这是一份建立西尔维奥·孔特神经科学研究中心(CCNR)的申请，研究记忆的遗传、生理和行为研究。该中心的长期目标是阐明哺乳动物学习和记忆的分子、细胞和神经元整体机制。中央人民广播电台从三个层面着手解决这一问题。首先，它试图了解海马体和新皮质中突触可塑性的基本机制，以及这些是如何在发育和区域上进行调节的。其次，该中心试图了解海马体和新皮质中的神经元活动如何代表有关外部世界的信息，这些信息如何与之前的经验进行比较，以及这些表征如何整合到长期记忆中。第三，该中心试图将学习的突触可塑性和神经元相关性与记忆的行为测量联系起来。突触可塑性的基本机制将通过将电生理技术应用于来自海马区的脑片以及具有几个特定空间靶向遗传损伤的小鼠(基因敲除小鼠)的视觉和颞下皮质来研究。一种新的电生理学技术，可以分析培养神经元的单个可视化突触，也将用于这些小鼠的分析。为了了解神经元活动如何代表习得信息，该中心将通过将新的多路四极管记录技术应用于承担各种记忆任务的猴子或啮齿动物，寻求确定海马区、颞下皮质和前额叶皮质神经元整体活动的变化。最后，为了将学习的突触可塑性和神经元与记忆的行为测量联系起来，该中心利用了小鼠局部和时间选择性遗传干扰的新方法，其中一些已经在中心开发(海马区选择性)，而另一些(新皮质和新皮质分区特异性)被提议作为核心项目开发。这项拟议的研究是真正的跨学科研究，涵盖小鼠的分子遗传学，大鼠和小鼠的脑片和培养神经元的电生理学，以及执行特定记忆任务的猴子、大鼠和基因工程小鼠的多电极记录。来自三个机构的六名调查人员和作为分包商的第七名调查人员，每个人都拥有免费和公认的专业知识和最先进的实验技术，将在CCNR框架内联手并广泛合作。该中心的研究与心理健康和疾病高度相关，因为记忆力障碍是衰老和重大神经疾病(如精神分裂症、阿尔茨海默病和帕金森氏病)的标志。

DESCRIPTION: (Adapted from the applicant's abstract) This is an application to establish a Silvio O. Conte Center for Neuroscience Research (CCNR) on GENETIC, PHYSIOLOGICAL, AND BEHAVIORAL STUDIES OF MEMORY. The long-term objective of the Center is to elucidate the molecular, cellular, and neuronal ensemble mechanisms of mammalian learning and memory. The CCNR attacks the problem at three levels. First, it seeks to understand the elementary mechanisms of synaptic plasticity in the hippocampus and neocortex, and how these are developmentally and regionally regulated. Second, the Center seeks to understand how neuronal activity in the hippocampus and neocortex represents information about the outside world, how this information is compared with previous experience, and how these representations are consolidated into long-term memory. Third, the Center seeks to connect the synaptic plasticity and the neuronal correlates of learning with behavioral measures of memory. The elementary mechanisms of synaptic plasticity will be studied by applying electrophysiological techniques to brain slices derived from the hippocampus and the visual and inferotemporal cortices of mice with several specific spatially targeted genetic lesions (knockout mice). A novel electrophysiological technique that permits the analysis of single visualized synapses of cultured neurons will also be used for the analysis of these mice. In order to understand how neuronal activity represents learned information, the Center will seek to identify alterations in the activity of neuronal ensembles in the hippocampus, inferotemporal cortex, and prefrontal cortex by applying the novel multiple tetrode recording techniques to monkeys or rodents that are undertaking various memory tasks. Finally, in order to connect synaptic plasticity and neuronal correlates of learning with behavioral measures of memory, the Center takes advantage of the new methods of regionally and temporally selective genetic disruptions in mice, some of which have already been developed in the Center (hippocampus CAI-selective) while others (neocortex and neocortical subregion-specific) are proposed to be developed as a core project. The proposed research is truly interdisciplinary covering molecular genetics of mice, electrophysiology of brain slices and cultured neurons from rats and mice, and multiple electrode recordings of monkeys, rats, and genetically engineered mice performing specific memory tasks. Six investigators from three institutions and the seventh investigator as a subcontractor, each possessing complimentary and well-recognized expertise and state of the art experimental technologies will join forces and collaborate extensively in the CCNR framework. The Center's research is highly relevant to mental health and illness because mnemonic impairments are a hallmark of aging and major neurological diseases such schizophrenia, Alzheimer's disease and Parkinson's disease.