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神经回路动力学的细胞和网络机制，这些机制导致认知和行为。这样一幅机械性的图景将显著提高我们理解并潜在地解决精神和神经学疾病(包括精神分裂症、癫痫和自闭症)的细胞和电路功能障碍的能力。为了实现这一理解，需要新的工具来测量和扰乱行为过程中广泛神经群体中细胞和亚细胞分辨率的神经活动。这项更新建议中的工作通过增强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，这些仪器和方法是在过去的资助期间由PI的实验室开发的，用于头戴约束的小鼠在虚拟现实中导航。当实施时，我们提出的目标将提供几个新的能力。首先，通过使用同时成像和细胞分辨率光遗传刺激，不仅可以测量正在进行的行为中的神经活动的特定模式，而且可以通过实验操作在虚拟现实(VR)中导航的小鼠。该系统将用于研究突触输入和海马区位置细胞放电模式下的可塑性。这种能力还可以形成一种通用的方法，用于绘制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，将有可能将细胞分辨率光学方法应用于一些被广泛研究的大脑深部区域，这些区域使用当前的技术在光学上是无法到达的，包括内侧前额叶皮质。此外，我们的方法将使同时成像多个海马区成为可能，一起从输入到输出跨越整个海马区电路。第三，将有可能在光学上测量功能微电路内神经调制输入的动力学，以及在行为过程中测量到功能识别神经元的突触输入的活动。这将使得能够直接测试关于这些输入对细胞和电路计算的贡献的假设。作为第一个应用，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质的多巴胺能输入。我们还将测量在虚拟导航过程中，突触输入到海马区细胞的空间放电特性。总体而言， 新的能力将提供一种改进的手段，以发现和表征神经编码和动力学基础上的细胞和网络机制。

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.