Mapping Abnormal Neurodevelopment in Schizophrenia

描述(申请人提供)：大脑结构和功能的异常是精神分裂症的关键神经生物学特征之一。在精神分裂症受试者中，组织体积的损失、神经元密度的变化和功能激活的缺陷出现在神经结构的回路中。这个精神疾病神经科学中心(CCNMD)的中心科学目标是更准确地定义这些大脑结构和功能异常的解剖模式，调查其可能的原因(即，遗传和/或环境)和发病机制，并在这些结构异常和可能构成精神病理学和残疾基础的认知功能异常(例如，工作和情景记忆)之间建立功能联系。我们的总体假设是，精神分裂症的遗传易感性可能部分通过特定大脑区域网络中神经解剖结构和功能的变化来表达，这些相同的结构可能会在发育早期受到环境侮辱的影响，最终导致目前定义这种疾病的认知和临床异常。 建议的CCNMD将1)对精神分裂症受试者、他们的非精神病兄弟姐妹、健康对照组及其兄弟姐妹的大脑结构和功能进行综合调查。2)研究胎儿环境侮辱的猕猴模型中大脑结构变化的发育进程。3)使用猕猴再次阐明工作记忆背后的神经回路的特定细胞元件。最后，我们将使用重组近交系小鼠来识别影响这些神经解剖学和行为表型的基因。 为该中心提出的各个项目都涉及几个主题。结合共享的技术和资源，最重要的假设和这些主题代表了作为一个中心资助这项研究的强大理由，而不是一系列R01项目。

DESCRIPTION (provided by applicant): Abnormalities of brain structure and function are one of the key neurobiologic characteristics of schizophrenia. In schizophrenia subjects, losses of tissue volume, changes in neuronal density, and deficits of functional activation are present within a circuit of neural structures. The central scientific goals of this Conte Center for the Neuroscience of Mental Disorders (CCNMD) are to more precisely define the anatomical pattern of these abnormalities in brain structure and function, to investigate their possible causes (i.e., genetic and/or environmental) and pathogenesis, and to establish functional links between these structural abnormalities and abnormalities of cognitive function (e.g., working and episodic memory) that may underlie psychopathology and disability. Our overarching hypothesis is that genetic liability for schizophrenia may be expressed in part by variation in neuroanatomical structure and function within a network of specific brain regions and that these same structures may be impacted by environmental insult during early development, ultimately leading to the cognitive and clinical abnormalities that currently define the disease. The proposed CCNMD will 1) carry out an integrated investigation of brain structure and function in schizophrenia subjects, their non-psychotic siblings, healthy controls and their siblings.2) Study the developmental progression of changes in brain structure in a macaque model of fetal environmental insult. and 3) elucidate the specific cellular elements of the neural circuit underlying working memory again using macaques. Finally, we will use recombinant, inbred strains of mice to identify genes that influence these neuroanatomical and behavioral phenotypes. Several themes are carried across the individual Projects proposed for the Center. Taken together with shared technologies and resources, the overarching hypothesis and these themes represent a strong rationale for the funding of this research as a Center, rather than a series of R01 projects.