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

 描述(申请人提供)：精神障碍是一种需要有效治疗的慢性致残障碍。它们影响了世界上很大一部分人口，严重损害了它们的社会功能，并对生活质量造成了毁灭性的后果。近年来，在识别增加精神障碍易感性的基因中断方面取得了重大进展，但我们对将这些遗传风险因素与与这些疾病相关的广泛认知和情感缺陷联系在一起的电路机制知之甚少。越来越多的证据表明，脑连通性改变在精神障碍的病理生理学中起着重要作用。最近，从精神障碍患者以及精神分裂症和自闭症动物模型获得的功能成像数据共同表明，海马区活动异常是病理生理学的核心特征。综上所述，这些数据表明，异常的海马体活动可能是导致精神障碍患者大脑网络异常的关键因素。在海马区，齿状回在一生中不断地产生新的神经元，因此对海马区的电路活动进行了重大的修改。累积的证据表明，这些成年出生的神经元参与认知、应激反应和情绪调节；而异常的成人神经发生导致大脑障碍，如癫痫和精神障碍。目前的项目是建立在我们最近的发现基础上的，包括：(I)确定DISC1在调节成年海马区新生颗粒细胞的形态发生、细胞位置、轴突/树突发育和突触形成中的关键作用；以及(Ii)DISC1在成年出生的齿状颗粒神经元中的缺陷导致认知和情感行为障碍。然而，遗传风险因子DISC1对成年出生的神经元的失调如何导致电路水平上的这些行为缺陷，在很大程度上是未知的。这个拟议项目的总体目标是调查DISC1缺乏所介导的异常的成人神经发生是否作为与精神障碍相关的脑连接异常的关键神经底物。为了验证这一假设，我们建议利用在体多通道记录来检测局部海马区活动(AIM 1)和功能磁共振成像(FMRI)来测量在基线和在这些神经元的活动刺激下有或没有DISC1缺陷的成年出生神经元的全局脑连通性(AIM 2)。我们提出的研究将解决关于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，重点放在成人神经发生作为一种有希望但定义不明确的底物来调节全球大脑连接。成人神经发生与许多生理和病理状态有关，如学习记忆、癫痫、神经退行性疾病和精神障碍。因此，针对成人神经发生过程可能构成治疗这些疾病的一种新的治疗策略。

 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.