Mechanisms underlying the functional connectivity deficit in the 22q11 microdelet

描述（由申请人提供）：精神分裂症患者通常患有严重和致残的认知功能，包括执行功能和工作记忆障碍。为了阐明这些紊乱的神经生物学基础，我们研究了小鼠系的认知功能，以模拟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有明显的障碍。携带微缺失基因的小鼠在空间工作记忆测试中表现不佳。我们最近的研究表明，海马体和前额叶皮层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)通过研究微缺失区携带单基因突变的小鼠的工作记忆和海马体-前额叶连通性来研究这些影响的分子基础；(2)研究腹侧海马在突变体行为和生理表型中的作用；(3)研究丘脑在这些表型中的作用。提出的实验服务于基本和转化的目标。了解小鼠工作记忆的神经生物学机制是确定这些模型与人类认知任务研究的相关性的重要一步。在携带精神分裂症易感突变的小鼠中探索这些机制，利用这种理解来确定这些突变的行为相关神经后果。这项工作的最终目标是建立一个精神分裂症发病机制和病理生理学的综合模型，证明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。

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.