Genetic and Synaptic Mechanisms of State Representation Impairments in Mice

小鼠状态表征损伤的遗传和突触机制

• 批准号: 10377365
• 负责人: Patrick Rothwell
• 金额: $ 51.12万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10377365
• 关键词: 16p11.2; 22q11.2; Ablation; Algorithms; Automobile Driving; Behavior; Behavior monitoring; Behavioral; Biological; Brain; Cells; Characteristics; Chronic; Complex; Computer Analysis; Computer Models; Copy Number Polymorphism; Coupled; Data; Disease; Enterobacteria phage P1 Cre recombinase; Equilibrium; Exhibits; Expectancy; Failure; Functional disorder; Genes; Genetic; Genetic Models; Genetic Variation; Genotype; Heterogeneity; Human; Impairment; Implanted Electrodes; Individual; Interneurons; Knockout Mice; Link; Measurement; Measures; Medial; Methods; Modeling; Mus; Mutant Strains Mice; Mutation; N-Methyl-D-Aspartate Receptors; NMDA receptor A1; Neuronal Plasticity; Neurons; Patients; Pattern; Pharmacology; Phenotype; Physiology; Prefrontal Cortex; Process; Psychoses; Publishing; Pyramidal Cells; Receptor Signaling; Reversal Learning; Rodent; Slice; Synapses; Synaptic Transmission; Syndrome; System; Testing; Translating; Variant; Virus; Weight; base; behavior measurement; behavioral impairment; behavioral phenotyping; cognitive testing; conditional knockout; design; disease phenotype; excitatory neuron; experience; experimental study; genetic manipulation; genetic variant; genome-wide; in vivo; information processing; inhibitory neuron; network models; neural circuit; neurophysiology; nonhuman primate; optogenetics; patch clamp; patient population; promoter; relating to nervous system; synaptic function

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.

项目概要：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 神经生理学，捕捉内侧前额叶皮层（mPFC）微电路功能障碍的核心特征 这可能与精神病中的信息处理失败有关。我们中心的组织前提是 精神病涉及功能失调的状态表征过程，我们将在 行为水平使用点模式期望（DPX）任务和Bandit概率反转 学习任务。在已发表的非人类灵长类动物前额叶皮层神经生理学研究结果的指导下， 在全身性NMDA受体阻断后，我们建议测量神经元的协调活动， 在执行这两项任务的小鼠的内侧前额叶皮层中。 在目的1中，我们将使用遗传操作选择性地删除NMDA受体从媒体， 前额叶皮层，同时也测试了相同的NMDA受体的药理学操作，用于 项目1.在目标2中，我们将研究携带三种最常见遗传变异的小鼠品系， 与精神病相关的基因组意义行为和神经生理学数据将 传递到预防性核心，进行相同的因果发现分析， 在所有项目中使用的计算建模。在目标3中，我们将探索突触功能， 内侧前额叶皮层的每一个突变小鼠线，以确定是否差异的突触 微电路（即，兴奋性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用于评估和告知神经生理学- 水平吸引子网络模型，其中包括突触权重作为关键参数。我们的核心假设 突变小鼠将表现出突触功能障碍和mPFC神经生理学的相关变化， 我们预计会对各州的代表程序产生负面影响。我们希望观察到 不同遗传操作的异质性损伤，反映了 患者人群（项目3和4），并为计算建模和因果关系提供素材 发现分析。在我们的中心，这些实验提供了一个独特的机会， 测量和操纵疾病相关的功能障碍和治疗相关的可塑性， 内侧前额叶皮层微电路，同时通过计算 分析。