Neural circuit mechanisms for goal-oriented behavior in novel environments

项目摘要 人类和其他动物一样，经常根据环境背景改变行为。这取决于 区分环境并制定最大化奖励（或最小化）策略的能力 以特定的方式进行惩罚。这种改变行为的能力的崩溃， 在痴呆症和阿尔茨海默病中，环境是突出的。我们的主要目标是确定具体的 在新环境中获得目标导向行为所需的神经元回路和活动动力学。 我们把重点放在海马体上，这是一个区分环境的关键区域， 编码某种行为我们的中心假设是，细胞类型特异性抑制回路调节 金字塔形的网络动态编码目标导向的行为。具体来说，我们使用体内双光子 钙成像，以显示遗传定义的海马CA 1神经元亚群的活性， 在虚拟现实（VR）环境中完成目标导向的任务，使用水奖励激励（Arriaga 和Han，J. Neurosci.，2017年）。利用这个系统，我们最近发现小清蛋白（PV）和 生长抑素（SOM）表达抑制性中间神经元在新的环境中受到强烈抑制， 随着任务表现的增加，活动在几天内逐渐恢复（Arriaga和Han，eLife，2019）。在目标1中， 我们将使用成像、行为、相关功能和免疫标记显微镜的组合， 定义在新环境中激活的假定的去抑制VIP+神经元。在目标2中，我们将定义 兴奋性网络重组在新环境中的目标导向行为。如果抑制活性 在控制兴奋性网络中的信息编码中起着重要作用，我们应该看到类似的 两个网络之间的活动动力学，即几天内缓慢稳定。我们将跟踪个人 锥体神经元在新的环境中的任务参与行为，以确定活动动力学的 兴奋网络为了实现这一目标，我们开发了一种基于神经网络的解码器， 个体神经元对群体位置编码的贡献。在目标3中，我们将确定 目标导向行为抑制抑制和去抑制激活的必要性 网络重构我们将通过化学发生学恢复抑制性SOM+和PV+中间神经元来测试这一点。 活动（单独），或沉默PV+神经元，在新的环境中，并比较任务性能与 对照小鼠。为了阐明抑制活动操纵下游可能的回路机制，我们将 对兴奋性神经元活动进行成像，以评估目标2中定义的网络重组中的变化。这 贡献是重要的，因为它承诺将细胞类型特异性抑制活性与新颖性诱导的， 锥体网络重组和体内目标导向行为。这些研究可能会导致新的电路- 有针对性的方法，以增强网络功能，治疗与以下疾病相关的行为障碍： 许多认知障碍和神经退行性疾病。

Project Summary Humans, like other animals, regularly modify behavior based on environmental context. This relies on the ability to discriminate between environments and develop strategies for maximizing rewards (or minimizing punishment) in a context-specific manner. A breakdown in this ability to change behavior depending on environment is prominent in dementia and Alzheimer's disease. Our central objective is to identify the specific neuronal circuits and activity dynamics required for acquiring goal-oriented behaviors in novel environments. We focus on the hippocampus, a region critical for discriminating between environments and necessary for encoding certain types of behavior. Our central hypothesis is that cell-type specific inhibitory circuits regulate the pyramidal network dynamics that encode goal-oriented behavior. Specifically, we use in vivo two-photon calcium imaging to visualize the activity of genetically-defined subsets of hippocampal CA1 neurons as mice complete goal-oriented tasks in virtual reality (VR) environments, using water rewards for motivation (Arriaga and Han, J. Neurosci., 2017). With this system, we recently found that both parvalbumin (PV)- and somatostatin (SOM)-expressing inhibitory interneurons are strongly suppressed in novel environments, with gradual recovery of activity over days as task performance increases (Arriaga and Han, eLife, 2019). In Aim 1, we will use a combination of imaging, behavior, and correlative functional and immunolabeling microscopy to define putative disinhibitory VIP+ neurons activated in novel environments. In Aim 2, we will define the kinetics of excitatory network reorganization in novel environments during goal-oriented behavior. If inhibitory activity plays a major role in controlling the encoding of information in excitatory networks, we should see similar kinetics in activity dynamics across the two networks, i.e. slow stabilization over days. We will track individual pyramidal neurons during task-engaged behavior in novel environments to define activity dynamics of the excitatory network. To facilitate this goal, we have developed a neural network-based decoder that tracks the contribution of individual neurons to population position coding across days. In Aim 3, we will determine the necessity of inhibition suppression and disinhibition activation for goal-oriented behavior and pyramidal network reconfiguration. We will test this by chemogenetically restoring inhibitory SOM+ and PV+ interneuron activity (separately), or silencing PV+ neurons, in novel environments and compare task performance with control mice. To illuminate possible circuit mechanisms downstream of inhibitory activity manipulation, we will image excitatory neuron activity to evaluate alterations in network reorganization as defined in Aim 2. This contribution is significant because it promises to link cell type-specific inhibitory activity with novelty-induced, pyramidal network reorganization and goal-oriented behavior in vivo. These studies may lead to new circuit- targeted approaches to enhance network function for the treatment of behavioral impairment associated with many cognitive disorders and neurodegenerative diseases.