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：
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
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/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

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的目的是使用小鼠作为实验系统来研究细胞和突触捕捉内侧前额皮质 (mPFC) 微电路功能障碍核心特征的神经生理学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，我们将在以下跨物种研究这一过程使用 Dot Pattern Expectancy (DPX) 任务和 Bandit 概率反转的行为级别学习任务。以已发表的非人类灵长类动物前额皮质神经生理学研究结果为指导系统性 NMDA 受体阻断后，我们建议测量神经元的协调活动执行这两项任务的小鼠内侧前额叶皮层中的集合。在目标 1 中，我们将使用基因操作选择性地删除内侧 NMDA 受体前额皮质，同时还测试了与 NMDA 受体相同的药理操作项目 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具有全基因组意义的精神病相关。行为和神经生理学数据将传递到计算核心，进行相同的因果发现分析和所有项目都使用计算模型。在目标 3 中，我们将探讨突触功能每个突变小鼠品系的内侧前额皮质，以确定突触是否存在差异微电路（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通知神经生理学- 水平吸引子网络模型，其中包括突触权重作为关键参数。我们的中心假设突变小鼠会表现出突触功能障碍以及 mPFC 神经生理学的相关变化，这我们预计这会对各个国家的代表进程产生负面影响。我们期望观察到不同基因操作的异质性损伤，反映了存在的异质性患者群体（项目 3 和 4），并为计算模型和因果关系提供素材发现分析。在我们中心，这些实验提供了一个独特的机会来精确地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皮质微电路，同时通过计算将结果转化为跨物种分析。