Mechanisms of Persistent Activity in a Neural Integrator

描述(申请人提供)：人类和其他动物拥有神经积分器，即专门用于执行积分时变信号的数学运算的大脑模块。此计算对于某些行为非常重要，例如运动控制、导航和决策。对神经积分器的瞬时刺激导致动作电位放电率的持续变化，持续时间长达数十秒。我们过去的研究表明，这种持续的神经活动，与积分者的记忆相关，得到了细胞机制和电路机制的共同支持。我们的长期目标是通过一个合作研究项目来了解这些机制的确切性质，该项目结合了金鱼动眼运动积分器的实验和理论研究。为了更准确地定位积分器，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对电路中其他神经元的影响。前庭核团是积分器的一部分的可能性将通过局部药理学灭活来测试。连续切片电子显微镜和一种新的体外准备中的配对记录将用于提高我们对整合神经元突触连接的理解。将使用树突的双光子钙成像来测试特定的假想的持久性细胞机制。这些信息将被用来构建集成器的改进混合模型，包括树突生物物理学以及现实的突触连接。小脑在最近发现的一种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器可塑性模型。这项拟议的研究应该对神经科学具有广泛的意义。在许多大脑区域都观察到了持续的神经活动，而不仅仅是在神经整合器中，因此其机制引起了非常广泛的兴趣。整合可以被认为是工作记忆的最简单形式，即存储信息并主动操作信息的能力。因此，了解神经元是如何整合的，可以帮助我们了解大脑是如何实现工作记忆的。这项建议中的许多假说对于其他大脑区域持续存在的假说电路和细胞机制是通用的；因此，它们的测试结果可能与一般的持续神经活动有关。与健康相关：在工作记忆的大脑重要区域一直可以观察到持续的神经活动，工作记忆是许多认知能力的中心组成部分。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.