Adult neurogenesis in the mammalian olfactory bulb

描述(申请人提供)：嗅球(OB)是中枢神经系统中仅有的两个出生后有大量新神经元生成的部位之一。大脑的脑室下区(SVZ)中的干细胞群体每天会产生30,000多个新的神经前体细胞。这些细胞沿着被称为吻侧迁移流(RMS)的结构迁移，最终到达OB，在那里它们分化为两个主要的抑制性中间神经元之一并定居。超过一半的这些细胞会在到达OB后的2周内死亡，这表明OB中的细胞数量有很强的动态平衡调节。这些新细胞在嗅球的功能中扮演什么角色？它们在记忆中很重要吗？它们是用于维护还是用于持续增长？我们将采用一种经典的策略来理解它们的功能：我们将摆脱它们，看看它们缺失了什么。使用选择性x射线照射这些细胞出生的脑室下区，我们将瞬间耗尽干细胞数量，并减少新细胞流入嗅球。一些解剖学和生理学的测量将被用来确定神经发生对于维持嗅球的正常功能的功能和重要性。第二个重要的问题是，这些新细胞如何将自己整合到现有的大脑回路中。它们会取代较老的细胞吗？它们只取代其他较新的细胞吗？它们是接管现有的突触，还是形成全新的突触？面对这种强大的细胞替代，嗅觉如何保持恒定？更换电池的规则是什么？这些问题将结合系统级生理学(多电极记录)和行为实验进行研究。了解神经元替换的动力学，以及更重要的是，新细胞如何整合到现有的脑组织中，将对理解出生后神经发生及其可能的治疗控制具有重要意义。与公共健康相关的神经发生，即成人身上新神经元的增殖，是一种罕见的情况。嗅球的细胞是仅有的两个发生这种情况的部位之一。了解这一过程，包括启动神经发生的因素和新细胞整合到现有脑组织的方式，将对疾病和脑损伤情况下的神经元替代具有意义。

DESCRIPTION (provided by applicant): The olfactory bulb (OB) is one of only two sites in the CNS where there is significant post natal generation of new neurons. A population of stem cells in the Subventricular Zone (SVZ) of the brain gives rise to more than 30,000 new neural progenitor cells every day. These cells migrate along a structure known as the rostral migratory stream (RMS) eventually arriving at the OB where they differentiate into one of two major populations of inhibitory interneurons and take up residence. More than half of these cells will die within 2 weeks of arriving at the OB, suggesting that there is strong homeostatic regulation of the number of cells in the OB. What role do these new cells play in the function of the olfactory bulb? Are they important in memory? Are they for maintenance or for continued growth? We will pursue a classic strategy to understand their function: we will get rid of them and see what is missing. Using selective x- ray irradiation of the subventricular zone, the region where these cells are born, we will transiently deplete the population of stem cells and reduce the flow of new cells into the olfactory bulb. Several measurements of anatomy and physiology will be employed to determine the function and importance of neurogenesis for maintaining proper functioning in the olfactory bulb. A second question of importance is how these new cells integrate themselves into existing brain circuits. Do they displace older cells? Do they only replace other newer cells? Do they take over existing synapses or form entirely new ones? How does olfactory perception remain constant in the face of this robust cell replacement? What are the rules for cell replacement? These questions will be investigated with a combination of systems level physiology (multi electrode recordings) and behavioral experiments. Understanding the dynamics of neuronal replacement and, as importantly, how new cells can integrate into existing brain tissue, will have critical implications for understanding post natal neurogenesis and its possible control for therapeutic purposes. PUBLIC HEALTH RELEVANCE Neurogenesis, the proliferation of new neurons on the adult, is a rare occurrence. The cells of the olfactory bulb are one of only two sites where this occurs. Understanding this process, including the factors that initiate neurogenesis and the way new cells are integrated into existing brain tissue, will have implications for neuronal replacement in cases of disease and brain injury.