Mapping Global Brain Connectivity Mediated by DISC1 Gene in Adult-born Neurons

绘制成年神经元中 DISC1 基因介导的全球大脑连接图

• 批准号: 8969401
• 负责人: Wei Gao
• 金额: $ 19万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-18 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8969401
• 关键词: Address; Adult; Affect; Affective; Animal Model; Animals; Autistic Disorder; Axon; Behavioral; Bipolar Disorder; Brain; Brain Diseases; Brain region; Cells; Chromosomal translocation; Chronic; Clinical; Cognition; Cognitive; Cytoplasmic Granules; Data; Data Analyses; Date of birth; Degenerative Disorder; Development; Disease; Embryo; Epilepsy; Equilibrium; Exhibits; Family; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Genes; Genetic; Goals; Hippocampus (Brain); Imaging Techniques; Impairment; Label; Lead; Learning; Life; Link; Major Depressive Disorder; Maps; Measures; Mediating; Memory; Mental disorders; Modification; Molecular; Molecular Profiling; Morphogenesis; Nature; Neurodegenerative Disorders; Neurons; Neurosciences; Newborn Infant; Patients; Physiological; Play; Population; Positioning Attribute; Predisposition; Process; Property; Quality of life; Recurrence; Retroviridae; Role; Scaffolding Protein; Schizophrenia; Social Functioning; Susceptibility Gene; Testing; adult neurogenesis; base; biological adaptation to stress; dentate gyrus; effective therapy; experience; genetic risk factor; granule cell; in vivo; mood regulation; nerve supply; network dysfunction; neurogenesis; neuroimaging; neuron development; newborn neuron; novel therapeutics; optogenetics; public health relevance; relating to nervous system; synaptogenesis

 DESCRIPTION (provided by applicant): Mental disorders are chronic and disabling disorders in need of effective treatments. They affect a large portion of the world's population, with significant impairment in their social function and have devastating consequence on the quality of life. Significant progress has been made in recent years to identify genetic disruptions that increase susceptibility to mental disorders, but we have little understanding of the circuitry mechanisms linking these genetic risk factors to the widespread cognitive and affective deficits associated with these disorders. Accumulating evidence suggests that brain connectivity alteration plays an important role in the pathophysiology of mental disorders. More recently, functional imaging data garnered from patients with mental disorders and animal models of schizophrenia and autism have collectively pointed to the aberrant hippocampal activity as a central feature of pathophysiology. Together, these data suggest that aberrant hippocampal activity may be a critical factor that contributes to brain network abnormalities in mental disorders. Within the hippocampus, dentate gyrus continuously generates new neurons throughout life, therefore making significant modifications to the hippocampal circuitry activity. Cumulative evidence suggests that these adult- born neurons are involved in cognition, stress response and mood regulation; and aberrant adult neurogenesis contributes to brain disorders, such as epilepsy and mental disorders. The current project is built upon our recent discoveries, including (i) identification of critical roles of DISC1 in regulating morphogenesis, cell positionig, axon/dendritic development and synapse formation of newborn granule cells in the adult hippocampus; and (ii) DISC1 deficiency in adult-born dentate granule neurons causes cognitive and affective behavioral deficits. However, how dysregulation of adult-born neurons by genetic risk factor DISC1 leads to these behavioral deficits at the circuitry level is largely unknown. Th overall goal of this proposed project is to investigate whether aberrant adult neurogenesis mediated by DISC1 deficiency serves as a critical neural substrate for brain connectivity abnormalities associated with mental disorders. To test this hypothesis, we propose to utilize in vivo multi-channel recording to examine local hippocampal activity (Aim 1) and functional magnetic resonance imaging (fMRI) to measure global brain connectivity (Aim 2) with or without DISC1 deficiency in adult-born neurons at the baseline and upon activity stimulation of those neurons. Our proposed studies will address fundamental questions on how genetic risk factors lead to the clinical manifestation of many severe psychological disorders by focusing on adult neurogenesis as a promising but ill-defined substrate in mediating global brain connectivity. Adult neurogenesis correlates with many physiological and pathological states, such as learning and memory, epilepsy, neurodegenerative diseases and mental disorders. Therefore, targeting adult neurogenesis process could constitute a novel therapeutic strategy for treating these disorders.

 描述（由申请人提供）：精神障碍是需要有效治疗的慢性和致残性疾病。它们影响到世界人口的很大一部分，严重损害了他们的社会功能，并对生活质量造成破坏性后果。近年来，在识别增加精神障碍易感性的遗传破坏方面取得了重大进展，但我们对将这些遗传风险因素与这些疾病相关的广泛认知和情感缺陷联系起来的电路机制知之甚少。越来越多的证据表明，脑连接改变在精神障碍的病理生理学中起着重要作用。最近，从精神障碍患者和精神分裂症和自闭症动物模型中获得的功能成像数据共同指出异常海马活动是病理生理学的中心特征。总之，这些数据表明，海马活动异常可能是导致精神障碍患者脑网络异常的关键因素。在海马内，齿状回在整个生命过程中不断产生新的神经元，因此对海马电路活动进行了重大修改。累积的证据表明，这些成人出生的神经元参与认知、应激反应和情绪调节;并且异常的成人神经发生有助于大脑疾病，例如癫痫和精神障碍。目前的项目是建立在我们最近的发现，包括（i）DISC 1在调节成年海马新生颗粒细胞的形态发生，细胞定位，轴突/树突发育和突触形成中的关键作用的鉴定;和（ii）成年出生的齿状颗粒神经元中DISC 1缺陷导致认知和情感行为缺陷。然而，遗传风险因子DISC 1对成年出生的神经元的调节异常如何导致回路水平的这些行为缺陷在很大程度上是未知的。 本项目的总体目标是研究DISC 1缺陷介导的异常成人神经发生是否是与精神障碍相关的脑连接异常的关键神经基质。为了验证这一假设，我们建议利用体内多通道记录来检查局部海马活动（目标1）和功能磁共振成像（fMRI）来测量全球大脑连接（目标2）与或不与DISC 1缺陷的成人出生的神经元在基线和活动刺激这些神经元。我们提出的研究将解决遗传风险因素如何导致许多严重心理障碍的临床表现的基本问题，重点是成人神经发生作为一个有前途的，但不明确的基板在调解全球大脑连接。成人神经发生与学习记忆、癫痫、神经退行性疾病、精神障碍等多种生理和病理状态密切相关。因此，靶向成人神经发生过程可能构成治疗这些疾病的新的治疗策略。