Genetic and Synaptic Mechanisms of State Representation Impairments in Mice

项目总结：项目2 项目2的目的是使用小鼠作为实验系统来研究细胞和突触 捕捉内侧前额叶皮质(MPFC)微回路功能障碍核心特征的神经生理学 这可能与精神病患者的信息处理失灵有关。我们中心的组织前提是 这种精神病涉及功能失调的状态表征过程，我们将在 使用点模式预期(DPX)任务和Bandit概率反转的行为水平 学习任务。非人灵长类前额叶皮质神经生理学发现的指导 在全身性NMDA受体阻断后，我们建议测量神经元的协调活动 在执行这两个任务的小鼠的内侧前额叶皮质中的集合。 在目标1中，我们将使用基因操作来选择性地从内侧脑组织中删除NMDA受体 前额叶皮质，同时也测试NMDA受体的相同药理操作 项目1.在目标2中，我们将研究携带三种最常见的遗传变异的小鼠品系 与精神病有关，具有全基因组意义。行为和神经生理学数据将 传递到计算核心，以进行相同的因果发现分析和 在所有项目中使用计算建模。在目标3中，我们将探讨大鼠脑内突触功能。 每一突变系小鼠的内侧前额叶皮质，以确定突触是否存在差异 微回路(即兴奋性神经元和抑制性神经元之间的局部连接)与行为和 疾病表型。来自突触水平的数据将被用于评估和告知神经生理学- 水平吸引子网络模型，该模型将突触权重作为关键参数。我们的中心假设 突变小鼠将表现出突触功能障碍和相关的mPFC神经生理学变化，这 我们预计将对各种国家代表程序产生负面影响。我们期待着观察 跨不同遗传操作的异质性损伤，反映了 患者群体(项目3和4)，并为计算建模和因果关系提供素材 发现分析。在我们中心内，这些实验提供了一个独特的机会 疾病相关功能障碍和治疗相关可塑性的测量和操作 内侧前额叶皮质微电路，同时通过计算跨物种转换结果 分析。

PROJECT SUMMARY: PROJECT 2 The purpose of PROJECT 2 is to use mice as an experimental system to investigate cellular and synaptic neurophysiology that captures core features of medial prefrontal cortex (mPFC) microcircuit dysfunction that may be related to information processing failures in psychosis. The organizing premise of our Center is that psychosis involves dysfunctional state representation processes, which we will study across species at the behavioral level using the Dot Pattern Expectancy (DPX) task and the Bandit probabilistic reversal learning task. Guided by published neurophysiology findings in the prefrontal cortex of nonhuman primates after systemic NMDA receptor blockade, we propose to measure the coordinated activity of neuronal ensembles in the medial prefrontal cortex of mice performing these two tasks. In Aim 1, we will use genetic manipulations to selectively delete NMDA receptors from the medial prefrontal cortex, while also testing the same pharmacological manipulation of NMDA receptors used in PROJECT 1. In Aim 2, we will study mouse lines carrying the three most common genetic variants associated with psychosis with genome-wide significance. Behavior and neurophysiology data will be passed to the COMPUTATIONAL CORE, to conduct the same causal discovery analyses and computational modeling used across all PROJECTS. In Aim 3, we will probe synaptic function in the medial prefrontal cortex of each mutant mouse line, to determine whether differences in the synaptic microcircuit (i.e., local connections between excitatory and inhibitory neurons) are related to behavioral and disease phenotypes. Data from the synaptic level will be used to evaluate and inform the Neurophysiology- Level attractor network model, which includes synaptic weights as key parameters. Our central hypothesis is that mutant mice will exhibit synaptic dysfunction and related changes in mPFC neurophysiology, which we expect to have a negative impact on various state representation processes. We expect to observe heterogeneous impairments across different genetic manipulations, mirroring the heterogeneity present in patient populations (PROJECTS 3 & 4), and providing fodder for computational modeling and causal discovery analyses. Within our Center, these experiments provide a unique opportunity for precise measurement and manipulation of both disease-related dysfunction and treatment-related plasticity in the medial prefrontal cortex microcircuit, while translating results across species through computational analyses.