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

基本信息

批准号：
10597071
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
项目类别：
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/10597071
关键词：
16p11.2 22q11.2 Ablation Algorithms Automobile Driving Behavior Behavior monitoring Behavioral Biological Brain Cells Characteristics Chronic Compensation 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 Heterozygote 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 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 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 neural circuit neurophysiology nonhuman primate optogenetics patch clamp patient population pharmacologic promoter synaptic function

项目摘要

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.

项目摘要：项目2 项目2的目的是将小鼠用作实验系统来研究细胞和突触捕获内侧前额叶皮层（MPFC）微电路功能障碍的核心特征的神经生理学这可能与精神病的信息处理失败有关。我们中心的组织前提是该精神病涉及功能失调的状态表示过程，我们将跨物种研究使用点模式预期（DPX）任务和BANDIT概率逆转的行为级别学习任务。在非人类灵长类动物的前额叶皮层中发表的神经生理学发现的指导全身性NMDA受体阻滞后，我们建议测量神经元的协调活性小鼠的内侧前额叶皮层中的合奏执行这两个任务。在AIM 1中，我们将使用遗传操作从内侧选择性删除NMDA受体前额叶皮层，同时还测试了使用的NMDA受体的相同药理操作项目1。在AIM 2中，我们将研究带有三种最常见遗传变异的鼠标线与精神病有关，具有全基因组意义。行为和神经生理学数据将是传递到计算核心，进行相同的因果发现分析和所有项目都使用的计算建模。在AIM 3中，我们将在每条突变小鼠系的内侧前额叶皮层，以确定突触中的差异是否存在微电路（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 - 等级吸引者网络模型，其中包括突触权重作为关键参数。我们的中心假设是否突变小鼠会表现出突触功能障碍和MPFC神经生理学的相关变化，这我们期望对各种国家代表过程产生负面影响。我们希望观察跨不同遗传操作的异质损伤，反映了存在的异质性患者人群（项目3和4），并为计算建模和因果关系提供饲料发现分析。在我们的中心内，这些实验为精确提供了独特的机会测量和操纵与疾病有关的功能障碍和与治疗相关的可塑性内侧前额叶皮层微电路，同时通过计算转化跨物种的结果分析。