Mechanisms of Persistent Activity in a Neural Integrator

神经整合器持续活动的机制

• 批准号: 7649265
• 负责人: DAVID W TANK
• 金额: $ 39.52万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7649265
• 关键词: Action Potentials; Animals; Area; Behavior; Biophysics; Brain; Calcium; Cerebellum; Cognitive; Consultations; Correlation Studies; Data; Decision Making; Dendrites; Electrodes; Electron Microscopy; Electrophysiology (science); Eye; Face; Feedback; Funding; Generations; Generic Drugs; Goals; Goldfish; Grant; Health; Human; Hybrids; Image; In Vitro; Individual; Laboratories; Lead; Learning; Light; Measures; Memory; Mental disorders; Methods; Microscopy; Modeling; Modification; Monitor; Nature; Neurons; Neurosciences; Operative Surgical Procedures; Optical Methods; Positioning Attribute; Preparation; Property; Reading; Recording of previous events; Recurrence; Research; Research Personnel; Research Project Grants; Retinal; Role; Schizophrenia; Short-Term Memory; Signal Transduction; Stimulus; Synapses; Techniques; Test Result; Testing; Theoretical Studies; Time; United States National Institutes of Health; Vestibular nucleus structure; Work; base; extracellular; eye velocity; hindbrain; improved; in vivo; interest; motor control; neuromechanism; novel; oculomotor; programs; reconstruction; relating to nervous system; research study; simulation; two-photon; visual stimulus

DESCRIPTION (provided by applicant): Humans and other animals possess neural integrators, brain modules specialized for performing the mathematical operation of integrating a time-varying signal. This computation is important for certain behaviors such as motor control, navigation, and decision making. Transient stimuli to neural integrators produce sustained changes in rate of action potential discharge that persist for up to tens of seconds. Our past research suggests that this persistent neural activity, a correlate of the integrator's memory, is supported by both cellular and circuit mechanisms acting in concert. Our long-range goal is to understand the exact nature of these mechanisms through a collaborative research program combining experimental and theoretical studies of the goldfish oculomotor integrator. To more precisely localize the integrator, intracellular electrodes will be used in vivo to precisely stimulate and inhibit single neurons while extracellular recording methods are used to monitor the effects on other neurons in the circuit. The possibility that vestibular nuclei are part of the integrator will be tested using local pharmacological inactivation. Serial section electron microscopy, and paired recording in a novel in vitro preparation, will be used to improve our understanding of the synaptic connectivity of integrator neurons. Specific hypothesized cellular mechanisms of persistence will be tested using two-photon calcium imaging of dendrites. This information will be used to construct improved hybrid models of the integrator, incorporating dendritic biophysics as well as realistic synaptic connectivity. The role of the cerebellum in a recently discovered form of integrator plasticity will be tested by extracellular recording methods. Models of integrator plasticity based on synaptic learning rules will be developed. The proposed research should have broad significance for neuroscience. Persistent neural activity has been observed in many brain areas, not just in neural integrators, and therefore its mechanisms are of very general interest. Integration can be regarded as the simplest form of working memory, the ability to store information and actively manipulate it. Therefore, understanding how neurons integrate could shed light on how working memory is implemented by the brain. Many of the hypotheses in this proposal are generic to hypothesized circuit and cellular mechanisms of persistence in other brain areas; hence the results of testing them may be relevant to persistent neural activity in general. Health Relatedness: Persistent neural activity has consistently been observed in brain areas important in working memory, a central component of many cognitive abilities. Some mental disorders, such as schizophrenia, may involve deficits in working memory and neural integrators.

描述（由申请人提供）：人类和其他动物拥有神经积分器，专门用于执行积分时变信号的数学运算的大脑模块。这种计算对于某些行为很重要，例如运动控制，导航和决策。对神经整合器的瞬时刺激产生持续数十秒的动作电位放电速率的持续变化。我们过去的研究表明，这种持续的神经活动，与整合者的记忆相关，是由细胞和电路机制共同支持的。我们的长期目标是通过一个合作研究项目，结合金鱼眼动积分器的实验和理论研究，了解这些机制的确切性质。为了更精确地定位积分器，将在体内使用细胞内电极来精确地刺激和抑制单个神经元，同时使用细胞外记录方法来监测对回路中其他神经元的影响。前庭核是整合器的一部分的可能性将使用局部药理学灭活进行测试。连续切片电子显微镜，并在一种新的体外制备成对记录，将被用来提高我们的理解的整合神经元的突触连接。具体假设的细胞机制的持久性将使用双光子钙成像树突进行测试。这些信息将被用来构建改进的混合模型的积分器，结合树突生物物理学以及现实的突触连接。小脑在最近发现的整合可塑性形式中的作用将通过细胞外记录方法进行测试。将开发基于突触学习规则的积分可塑性模型。这项研究对神经科学具有广泛的意义。持续的神经活动已经在许多大脑区域中观察到，而不仅仅是在神经整合者中，因此其机制非常普遍。整合可以被视为工作记忆的最简单形式，即存储信息并主动操纵信息的能力。因此，了解神经元如何整合可以揭示大脑如何实现工作记忆。在这个提议中的许多假设是通用的假设电路和细胞机制的持久性在其他脑区，因此测试他们的结果可能是相关的持久性神经活动一般。健康相关性：持续的神经活动一直被观察到在大脑区域的重要工作记忆，许多认知能力的核心组成部分。一些精神障碍，如精神分裂症，可能涉及工作记忆和神经整合的缺陷。