Circuitry mechanisms underlying normal and aberrant adult hippocampal neurogenesis

描述(申请人提供)：成人神经发生概述了成熟中枢神经系统中神经元发育的整个过程，从成年神经前体细胞的增殖和命运指定，形态发生，迁移，轴突/树突发育，最后突触形成，最终新神经元完全整合到现有神经元中。 电路。累积的证据表明，新的神经元参与特定的大脑功能，而异常的成人神经发生可能导致大脑紊乱。在过去的11年里，我的实验室一直使用成年海马神经发生作为一个实验模型系统来阐明调控神经元发育的分子机制。此外，我们一直在使用这个系统来探索精神障碍风险基因在神经元发育中的新功能。从人类遗传学研究中已经确定了许多精神分裂症的易感基因。其中，DISC1(精神分裂症1中断)最初是在一个苏格兰大家庭中与精神分裂症共分离的平衡(1；11)(q42；q14)易位的断裂点发现的。最近的研究进一步表明DISC1不仅是精神分裂症的一般危险因素，而且也是双相情感障碍和严重抑郁症的危险因素。从功能上讲，DISC1是一种多功能支架蛋白，在胚胎、出生后早期和成年神经发生过程中调节神经元的发育。目前的项目是建立在我的实验室在过去11年中所发现的，既在细胞水平上，在成年神经发生期间新神经元发育的连续阶段，DISC1在调节成年海马区新生颗粒细胞发育的多个阶段中的关键作用，以及在系统水平上，在系统水平上，DISC1功能的需求，特别是在新生神经元中，对海马依赖的认知和情感行为缺陷的需求。DISC1的遗传失调如何在回路水平上导致成人异常神经发生和广泛的精神障碍尚不清楚。我们这个项目的总体目标是阐明成年海马神经发生和DISC1缺陷导致的异常发育过程中支持正常神经元发育的局部神经元间回路机制。我们的总体假设是，精神障碍的遗传风险因素与特定的神经细胞回路活动相互作用，表现出发育缺陷。使用我们开发的遗传学、光遗传学、跨突触追踪和成像工具，我们在解决这一根本问题方面处于独特的地位。我们提出的研究不仅可能为正常和异常神经元发育提供新的机制见解，而且还可能导致对某些精神障碍的更好理解。一个例子是我们在假设的驱动下确定了DISC1和FEZ1之间以及DISC1和NKCC1之间的上位性相互作用在影响人类精神分裂症风险和脑功能方面的作用，所有这些都基于我们以成人神经发生为模型系统的动物研究。

DESCRIPTION (provided by applicant): Adult neurogenesis recapitulates the whole process of neuronal development in a mature central nervous system, from proliferation and fate specification of adult neural progenitors, morphogenesis, migration, axon/dendritic development, and finally synapse formation, culminating in the full integration of new neurons into the existing circuitry. Cumulative evidence suggests that new neurons participate in specific brain functions and aberrant adult neurogenesis may contribute to brain disorders. During the past 11 years, my laboratory has been using adult hippocampal neurogenesis as an experimental model system to elucidate molecular mechanisms regulating the neuronal development. Furthermore, we have been using this system to explore novel functions of risk genes for mental disorders in neuronal development. A number of susceptibility genes for schizophrenia have been identified from human genetic studies. Among them, DISC1 (disrupted-in- schizophrenia 1) was initially identified at the breakpoint of a balanced (1;11)(q42;q14) translocation that co- segregates with schizophrenia in a large Scottish family. Recent studies have further implicated DISC1 as a general risk factor not only for schizophrenia, but also for bipolar disorders and major depression. Functionally, DISC1 is a multifunctional scaffold protein that regulates neuronal development during embryonic, early postnatal and adult neurogenesis. The current project is built upon discoveries made in my laboratory during the past 11 years, both at the cellular lever on sequential phases of new neuron development during adult neurogenesis and critical roles of DISC1 in regulating multiple phases of newborn granule cell development in the adult hippocampus and at the system level for the requirement of DISC1 function specifically in newborn neurons on hippocampal-dependent cognitive and affective behavioral deficits. How genetic dysregulation of DISC1 contributes to aberrant adult neurogenesis and a wide spectrum of mental disorders at the circuitry level is unknown. Our overall goal of this project is to elucidate local internneuron circuitry mechanisms underlying normal neuronal development during adult hippocampal neurogenesis and aberrant development due to DISC1-deficency. Our overall hypothesis is that genetic risk factors for mental disorders interact with specific neurona circuit activity to manifest developmental defects. We are uniquely positioned to address this fundamental questions using genetic, optogenetic, trans-synaptic tracing and imaging tools we have developed. Our proposed studies may not only provide novel mechanistic insights of normal and aberrant neuronal development, but also lead to better understanding of certain mental disorders. One example is our hypothesis-driven identification of epistatic interaction between DISC1 and FEZ1 and between DISC1 and NKCC1 in affecting schizophrenia risks and brain function in humans, all based on our studies from animals using adult neurogenesis as a model system.