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。这依赖于 能够区分不同的环境并制定最大化回报(或最小化)的策略 惩罚)以一种特定于上下文的方式。这种改变行为的能力的崩溃取决于 环境在痴呆症和阿尔茨海默病中是突出的。我们的中心目标是确定特定的 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。 我们关注的是海马体，这是区分环境的关键区域，也是 编码某些类型的行为。我们的中心假设是，细胞类型的特定抑制电路调节 编码目标导向行为的金字塔网络动态。具体地说，我们在体内使用双光子 钙显像法显示小鼠海马CA1区神经元基因亚群的活性 在虚拟现实(VR)环境中完成目标导向的任务，使用水奖励作为动力(Arriaga 和han，J.Neurosc.，2017)。通过这个系统，我们最近发现小白蛋白(PV)-和 生长抑素(SOM)表达的抑制性中间神经元在新的环境中受到强烈抑制， 随着任务绩效的增加，活动在几天内逐渐恢复(Arriaga和han，eLife，2019年)。在目标1中， 我们将使用成像、行为以及相关功能和免疫标记显微镜的组合来 定义在新环境中激活的假定的去抑制性VIP+神经元。在目标2中，我们将定义动力学 在以目标为导向的行为中，兴奋性网络在新环境中的重组。If抑制活性 在兴奋性网络中控制信息编码的主要作用，我们应该看到类似的 两个网络的活动动态的动力学，即几天的缓慢稳定。我们将跟踪个人 锥体神经元在新环境中任务投入行为中的活动动力学 兴奋性网络。为了促进这一目标，我们开发了一个基于神经网络的解码器，它跟踪 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 目标行为和金字塔的抑制抑制和去抑制激活的必要性 网络重新配置。我们将通过化学遗传学恢复抑制的SOM+和PV+中间神经元来测试这一点 在新的环境中活动(单独)或使PV+神经元沉默，并将任务绩效与 控制小鼠。为了阐明抑制活性操纵下游可能的电路机制，我们将 图像兴奋性神经元活性以评估目标2中定义的网络重组的改变。 贡献是显著的，因为它承诺将细胞类型特定的抑制活性与新颖性诱导联系起来， 体内锥体网络重组和目标导向行为。这些研究可能会导致新的电路- 有针对性地加强网络功能以治疗与以下相关的行为障碍 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.