Mechanisms of Persistent Activity in a Neural Integrator

描述（由申请人提供）：人类和其他动物拥有神经积分器，专门用于对时变信号进行数学运算的大脑模块。这种计算对于某些行为很重要，比如运动控制、导航和决策。对神经整合器的短暂刺激会产生持续的动作电位放电速率变化，这种变化可持续数十秒。我们过去的研究表明，这种持续的神经活动，与积分器的记忆相关，是由细胞和电路机制共同作用的。我们的长期目标是通过对金鱼动眼力整合器的实验和理论研究相结合的合作研究项目，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刺激和抑制单个神经元，同时使用细胞外记录方法来监测电路中对其他神经元的影响。前庭核是整合器的一部分的可能性将通过局部药物失活进行测试。连续切片电子显微镜，并在一种新的体外制备成对记录，将用于提高我们对积分神经元突触连接的理解。特定的假设的细胞机制的持久性将测试使用双光子钙成像树突。这些信息将用于构建改进的整合器混合模型，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器可塑性形式中的作用将通过细胞外记录方法进行测试。基于突触学习规则的积分器可塑性模型将被开发。本研究对神经科学具有广泛的意义。持续的神经活动已被观察到在许多大脑区域，而不仅仅是在神经整合，因此其机制是非常普遍的兴趣。整合可以被看作是工作记忆的最简单形式，即存储信息和主动操作信息的能力。因此，了解神经元如何整合可以阐明大脑是如何实现工作记忆的。该提案中的许多假设与其他脑区持续存在的假设电路和细胞机制是通用的；因此，测试它们的结果可能与一般的持续性神经活动有关。健康相关性：持续的神经活动一直被观察到在工作记忆中重要的大脑区域，这是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器的缺陷。

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.