Local circuitry mechanisms regulating adult hippocampal neurogenesis

调节成人海马神经发生的局部电路机制

• 批准号: 8657489
• 负责人: HONGJUN SONG
• 金额: $ 40.1万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8657489
• 关键词: Adaptive Behaviors; Address; Adult; Affect; Biology; Brain; Brain Injuries; Brain region; Cell Survival; Couples; Data; Development; Developmental Biology; Disease; Employee Strikes; Epilepsy; Etiology; Funding; Genetic; Glutamates; Goals; Growth; Heterogeneity; Hippocampus (Brain); Human; Individual; Injury; Interneurons; Laboratories; Learning; Maintenance; Mammals; Memory; Mental disorders; Methodology; Mitotic; Molecular; Mus; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Neurotransmitters; PTEN gene; Pathology; Phase; Play; Population; Process; Production; Proliferating; Property; Proto-Oncogene Proteins c-akt; Radial; Regenerative Medicine; Regulation; Rodent; Role; Signal Transduction; Source; Staging; Stem cells; Synapses; Technology; Tissues; Transplantation; Work; adult neurogenesis; aspartate racemase; base; biological adaptation to stress; dentate gyrus; gamma-Aminobutyric Acid; human FRAP1 protein; improved; in vivo; migration; mood regulation; nerve stem cell; nestin protein; neurogenesis; neuronal circuitry; neurotransmitter release; new technology; newborn neuron; novel; novel therapeutics; optogenetics; progenitor; public health relevance; regenerative; relating to nervous system; repaired; research study; stem cell biology; synaptogenesis; young adult

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.

描述（由申请人提供）：成人大脑中可塑性的一种引人注目的形式是迄今为止几乎所有检查的哺乳动物的离散大脑区域中的神经发生过程，包括人类。在成年海马中，由常驻神经干细胞引起的新神经元在许多适应性行为中起着重要作用，包括学习，记忆，稳态压力反应和情绪调节。积累的证据还表明，在许多病理状况中涉及或改变了成年神经发生，例如癫痫，发育精神疾病和退化性神经系统疾病。因此，了解成人神经发生的基本机制可能会提供有关这些精神疾病的病因和病理学以及潜在的新型疗法的线索。尽管该领域在过去几十年中取得了巨大的进步，但我们对成人神经发生的理解存在很大的差距，在我们可以利用成人大脑的内源性可塑性和再生能力之前，需要完全解决，以便在受伤或疾病后进行功能增强或修复。干细胞生物学中的一个基本问题是，利基市场是否以及如何根据局部组织需求来校准功能后代的数量。由于成年海马神经发生发生在动态神经元网络中，因此局部电路活性可以作为当前组织需求的有效读数，并提供信号以微调神经发生过程。我们的中心假设是，神经递质GABA是一个动态的生态位，它伴随着局部电路的激活，以调节成人海马神经发生的不同STE。先前的研究已经在成年神经发生过程中在调节有丝分裂后新生儿神经元的发展中的去极化的GABA信号传导中确定了关键作用，并且最近已证明会影响特定静态神经干细胞的激活。然而，GABA是否调节不同类型的静态神经干细胞和增殖性神经后代，在很大程度上是未知的，在成人神经发生过程中，关于抑制性GABA信号传导功能的数据很少。 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后代和谷氨酸能突触输入的发展，作为新生儿神经元成熟。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。从这些研究中学到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领域。