Circuitry mechanisms underlying normal and aberrant adult hippocampal neurogenesis

描述（由申请人提供）：成体神经发生概括了成熟中枢神经系统中神经元发育的整个过程，从成体神经祖细胞的增殖和命运特化、形态发生、迁移、轴突/树突发育，最后是突触形成，最终使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脑功能和异常的成人神经发生可能有助于大脑疾病。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实验模型系统，以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神经元发育中精神障碍风险基因的新功能。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，DISC 1（精神分裂症1型破坏）最初在一个苏格兰大家族中与精神分裂症共分离的平衡（1;11）（q42;q14）易位的断点处鉴定。最近的研究进一步表明DISC 1不仅是精神分裂症的一般风险因素，也是双相情感障碍和重度抑郁症的一般风险因素。在功能上，DISC 1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期间调节神经元发育。目前的项目是建立在我的实验室在过去11年中的发现，无论是在细胞水平上对成年神经发生期间新神经元发育的连续阶段，还是DISC 1在调节成年海马中新生颗粒细胞发育的多个阶段中的关键作用，以及在系统水平上对DISC 1在海马新生神经元中特异性功能的需求，依赖性认知和情感行为缺陷。DISC 1的遗传失调如何导致异常的成人神经发生和广泛的神经回路水平的精神障碍尚不清楚。本项目的总体目标是阐明成人海马神经发生和异常发育过程中由于DISC 1缺陷导致的正常神经元发育的局部interneuron电路机制。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元回路活动相互作用，以表现出发育缺陷。我们具有独特的优势，可以使用我们开发的遗传学、光遗传学、跨突触追踪和成像工具来解决这一基本问题。我们提出的研究不仅可能提供新的机制的见解正常和异常的神经元的发展，但也导致更好地了解某些精神疾病。一个例子是我们的假设驱动识别DISC 1和FEZ 1之间的上位相互作用，DISC 1和NKCC 1之间的上位相互作用影响人类精神分裂症的风险和脑功能，所有这些都基于我们使用成年神经发生作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.