Mechanisms underlying the functional connectivity deficit in the 22q11 microdelet

22q11 微缺失功能连接缺陷的潜在机制

• 批准号: 8881316
• 负责人: JOSEPH A GOGOS
• 金额: $ 39.87万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-02 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8881316
• 关键词: 22q11; Address; Anatomy; Behavioral; Brain; Cell Nucleus; Cell physiology; Chromosomes, Human, Pair 22; Cognitive; Copy Number Polymorphism; Development; Disease; Employee Strikes; Engineering; Functional disorder; Generations; Genes; Genetic; Goals; Hippocampus (Brain); Human; Individual; Knowledge; Lead; Lesion; Measures; Medial; Medial Dorsal Nucleus; Mediating; Medical; Memory impairment; Mental disorders; Modeling; Molecular; Mus; Mutation; Nature; Neurobiology; Neurons; Pathogenesis; Patients; Pattern; Pharmacogenetics; Phenotype; Physiological; Play; Predisposition; Prefrontal Cortex; Public Health; Rodent; Role; Schizophrenia; Science; Short-Term Memory; Staging; Structure; Susceptibility Gene; Symptoms; System; Techniques; Testing; Thalamic structure; Work; base; brain behavior; cognitive function; cognitive task; disability; executive function; improved; knockout gene; microdeletion; mortality; mouse model; mutant; neurobiological mechanism; neurophysiology; novel; novel strategies; relating to nervous system; research study; risk variant

DESCRIPTION (provided by applicant): Patients with schizophrenia typically suffer from severe and disabling cognitive function, including disturbances in executive function and working memory. To clarify the neurobiology underlying these disturbances, we have studied cognitive function in mouse lines engineered to model a microdeletion on chromosome 22, an etiologically relevant mutation unequivocally associated with susceptibility to schizophrenia. Patients with schizophrenia, as well as subjects with these mutations, have pronounced disturbances in cognitive tasks that depend on the hippocampus and prefrontal cortex. Mice carrying the microdeletion perform poorly in tests of spatial working memory. We have recently shown that deficits in functional connectivity between the hippocampus and prefrontal cortex contribute to this spatial working memory dysfunction in these mice. Building on these findings, we propose to (1) examine the molecular basis of these effects by studying working memory and hippocampal-prefrontal connectivity in mice carrying mutations of single genes within the microdeletion region; (2) study the role of the ventral hippocampus in the behavioral and physiological phenotypes in the mutants, and (3) study the role of the thalamus in these phenotypes. The proposed experiments serve both basic and translational goals. Understanding of the neurobiological mechanisms of working memory in the mouse is an important step in determining the relevance of such models to cognitive tasks studied in humans. Exploring these mechanisms in mice carrying schizophrenia-predisposing mutations uses this understanding to identify the behaviorally relevant neural consequences of these mutations. The end goal of this work is to develop an integrative model of schizophrenia pathogenesis and pathophysiology that demonstrates how these genetic lesions alter neural cells, circuits and systems to disrupt cognitive function.

描述（由申请人提供）：精神分裂症患者通常患有严重的认知功能障碍，包括执行功能和工作记忆障碍。为了阐明这些紊乱背后的神经生物学，我们研究了小鼠品系的认知功能，这些小鼠品系被设计为模拟 22 号染色体上的微缺失，这是一种与精神分裂症易感性明确相关的病因相关突变。精神分裂症患者以及携带这些突变的受试者在依赖海马体和前额皮质的认知任务中存在明显的障碍。携带微缺失的小鼠在空间工作记忆测试中表现不佳。我们最近发现，海马体和前额皮质之间的功能连接缺陷导致了这些小鼠的空间工作记忆功能障碍。基于这些发现，我们建议（1）通过研究携带微缺失区域内单基因突变的小鼠的工作记忆和海马-前额叶连接来检查这些效应的分子基础； （2）研究腹侧海马在突变体行为和生理表型中的作用，以及（3）研究丘脑在这些表型中的作用。所提出的实验既服务于基本目标又服务于转化目标。了解小鼠工作记忆的神经生物学机制是确定此类模型与人类研究的认知任务的相关性的重要一步。在携带精神分裂症诱发突变的小鼠中探索这些机制，利用这种理解来识别这些突变的行为相关神经后果。这项工作的最终目标是开发一种精神分裂症发病机制和病理生理学的综合模型，展示这些遗传病变如何改变神经细胞、回路和系统，从而破坏认知功能。