Neural circuit imaging and stimulation at cellular resolution in virtual reality

描述（由申请人提供）：神经科学的一个基本目标是了解引起认知和行为的神经回路动力学的细胞和网络机制。这样一个机械的图片将显着提高我们的能力，以了解和潜在的解决细胞和电路功能障碍的基础精神和神经疾病，包括精神分裂症，癫痫和自闭症。为了实现这一理解，需要新的工具，可以测量和干扰神经活动，在细胞和亚细胞分辨率，在广泛的神经群体的行为。这项更新提案中的工作通过增强PI实验室在过去的资助期间开发的一套强大的光学和行为仪器和方法的能力来满足这一需求，用于在虚拟现实中导航的头部受限小鼠。一旦实施，我们提出的目标将提供几种新的能力。首先，通过在虚拟现实（VR）中导航的小鼠中同时使用成像和细胞分辨率光遗传学刺激，不仅可以测量，而且可以实验性地操纵正在进行的行为期间的特定神经活动模式。该系统将被应用于研究海马中的突触输入和可塑性潜在的位置细胞放电模式。这种能力也可以形成一种通用的方法，用于映射神经元之间的功能连接，这些神经元的放电特性在行为过程中已经被表征。其次，将有可能在一些广泛研究的使用当前技术光学无法访问的深层脑区域（包括内侧前额叶皮层）中应用细胞分辨率光学方法。此外，我们的方法将使同时对多个海马区进行成像成为可能，这些海马区一起跨越从输入到输出的整个海马电路。第三，将有可能光学测量功能微电路内神经调节输入的动态，以及测量行为期间功能识别神经元的突触输入的活动。这将使直接测试的假设，这些输入的贡献，使细胞和电路计算。作为第一个应用程序，我们将在学习过程中以精细的时空分辨率测量内侧前额叶皮层的多巴胺能输入。我们还将测量虚拟导航过程中海马位置细胞突触输入的空间放电特性。总体上 新的能力将提供一种改进的手段来发现和表征神经编码和动力学基础的细胞和网络机制。

DESCRIPTION (provided by applicant): A fundamental goal of neuroscience is to understand the cellular and network mechanisms of neural circuit dynamics that give rise to cognition and behavior. Such a mechanistic picture would significantly enhance our ability to understand and potentially address the cellular and circuit dysfunctions that underlie psychiatric and neurologica disorders, including schizophrenia, epilepsy, and autism. To achieve this understanding, new tools are needed that can measure and perturb neural activity, at cellular and subcellular resolution, in a wide range of neural populations during behavior. Work in this renewal proposal addresses this need by enhancing the capabilities of a powerful set of optical and behavioral instrumentation and methods, developed in the PI's laboratory during the past funding period, for head-restrained mice navigating in virtual reality. When implemented, our proposed aims will provide several new capabilities. First, it will be possible to not only measure, but also experimentally manipulate, specific patterns of neural activity during ongoing behavior by using simultaneous imaging and cellular-resolution optogenetic stimulation in mice navigating in virtual reality (VR). The system will be applied to study synaptic inputs and plasticity underlying place-cell firing patterns in the hippocampus. This capability could also form a general-purpose method for mapping functional connectivity between neurons whose firing properties have been characterized during behavior. Second, it will be possible to apply cellular resolution optical methods in a number of widely studied deep brain regions that are optically inaccessible using current techniques, including medial prefrontal cortex. In addition, our methods will make it possible to image multiple hippocampal areas simultaneously, together spanning the entire hippocampal circuit from input to output. Third, it will be possible to optically measure the dynamics of neuromodulatory inputs within functioning microcircuits, as well as to measure the activity of synaptic inputs to functionally identified neurons during behavior. This will enable direct tests of hypotheses about the contributions these inputs make to cellular and circuit computations. As a first application, we will measure dopaminergic inputs to medial prefrontal cortex at fine spatio-temporal resolution during learning. We will also measure the spatial firing properties of synaptic inputs to hippocampal place cells during virtual navigation. In general, the new capabilities will provide an improved means to discover and characterize the cellular and network mechanisms that underlie neural coding and dynamics.