Local circuitry mechanisms regulating adult hippocampal neurogenesis

描述（由申请人提供）：在成人大脑中，一种引人注目的可塑性形式是在几乎所有哺乳动物（包括人类）的离散大脑区域中正在进行的神经发生过程。在成人海马体中，由常驻神经干细胞产生的新神经元在许多适应性行为中发挥重要作用，包括学习、记忆、稳态应激反应和情绪调节。越来越多的证据还表明，成人神经发生参与或改变了许多病理状况，如癫痫、发育性精神障碍和退行性神经疾病。因此，了解成人神经发生的基本机制可能为这些精神障碍的病因和病理以及潜在的新疗法提供线索。虽然该领域在过去几十年里取得了巨大的进步，但在我们能够利用成人大脑的内源性可塑性和再生能力来增强或修复损伤或疾病后的功能之前，我们对成人神经发生的理解还存在重大差距，需要充分解决。干细胞生物学中的一个基本问题是生态位信号是否以及如何根据局部组织需求校准功能后代的数量。由于成年海马神经发生在一个动态的神经网络中，局部回路的活动可以作为当前组织需求的有效读数，并为微调神经发生过程提供信号。我们的中心假设是，神经递质GABA是一个动态的生态位因子，它将局部回路的激活耦合到成人海马神经发生的不同阶段的调节中。先前的研究已经确定去极化GABA信号在调节成年神经发生过程中有丝分裂后新生神经元的发育中起关键作用，GABA最近被证明影响特定群体的静止神经干细胞的激活。然而，GABA是否调节不同类型的静止神经干细胞和增殖性神经后代在很大程度上是未知的，并且在成人神经发生过程中抑制性GABA信号的功能的数据很少。借助单个静态神经干细胞克隆分析和特定中间神经元亚型光遗传学操作的新技术，我们将在体内研究GABA的生态位来源和局部神经元中间回路在调节年轻成年小鼠海马神经发生的三个关键步骤中的作用，包括不同静态神经干细胞的激活和谱系选择、增殖后代的存活、以及新生神经元成熟时谷氨酸能突触输入的发育。我们提出的研究将解决成人神经干细胞生物学和神经发生的基本问题。从这些研究中获得的基本原理可能会影响干细胞和发育生物学、神经可塑性和再生医学等领域。

DESCRIPTION (provided by applicant): One striking form of plasticity in the adult brain is the ongoing process of neurogenesis in discrete brain regions of almost all mammals examined to date, including humans. In the adult hippocampus, new neurons arising from resident neural stem cells play important roles in many adaptive behaviors, including learning, memory, homeostatic stress responses and mood regulation. Accumulating evidence also suggests that adult neurogenesis is involved or altered in many pathological conditions, such as epilepsy, developmental psychiatric disorders and degenerative neurological diseases. Therefore, understanding the basic mechanisms of adult neurogenesis may provide clues regarding the etiology and pathology of these mental disorders, and potential novel therapies. While the field has made tremendous progress during past decades, there are major gaps in our understanding of adult neurogenesis that need to be fully addressed before we can harness the endogenous plasticity and regenerative capacity of the adult brain for functional enhancement or repair after injury or diseases. One fundamental question in stem cell biology is whether and how niche signals calibrate the number of functional progeny based on local tissue demands. As adult hippocampal neurogenesis occurs within a dynamic neuronal network, local circuit activity could serve as an effective readout of current tissue demands and provide a signal to fine tune the neurogenesis process. Our central hypothesis is that the neurotransmitter GABA is a dynamic niche factor that couples activation of the local circuitry to regulation of distinct stes of adult hippocampal neurogenesis. Previous studies have established a critical role for depolarizing GABA signaling in regulating development of post-mitotic newborn neurons during adult neurogenesis and GABA has recently been shown to affect activation of a specific population of quiescent neural stem cells. However, whether GABA regulates different types of quiescent neural stem cells and proliferative neural progeny is largely unknown and there are little data on the function of inhibitory GABA signaling during adult neurogenesis. Aided by new technologies for clonal analysis of individual quiescent neural stem cells and optogenetic manipulation of specific interneuron subtypes, we will investigate the niche source(s) of GABA and roles of local interneuron circuitry in regulating three critical steps of young adult mouse hippocampal neurogenesis in vivo, including activation and lineage choice of different quiescent neural stem cells, survival of proliferating progeny, and development of glutamatergic synaptic inputs as newborn neurons mature. Our proposed studies will address fundamental questions in adult neural stem cell biology and neurogenesis. Basic principles learned from these studies may impact the fields of stem cell and developmental biology, neural plasticity and regenerative medicine.