Determinants of selective vulnerability and functional replacement of olfactory bulb dopaminergic neurons

项目总结 特定类型的神经元丢失是许多神经退行性疾病的标志。替换这些丢失的或 长期以来，通过基于干细胞的治疗来恢复正常大脑功能的受损神经元一直是一个主要的 与神经退行性疾病作斗争的目标。然而，我们对其中任何一个原因都知之甚少 神经元群体选择性地容易受到细胞死亡的影响，或者说干细胞的功能整合是如何产生的 神经元可以被提升。哺乳动物大脑中很少有区域保留在大脑中产生新神经元的能力 成人期。了解内源性干细胞来源的神经元如何成功整合 在不破坏现有电路的情况下，可能为成功的治疗提供重要的机械洞察 干细胞来源的神经元的使用。小鼠嗅球(OB)中的多巴胺(DA)能神经元是一种高度的 依赖活动的群体，当感觉输入被阻断时，亚群经历细胞死亡。DA神经元 在整个生命过程中，脑室下区的祖细胞也会不断产生。这两个 OB DA神经元的特性使其成为研究两者选择性决定因素的理想模型系统 脆弱性和新生神经元整合。要做到这一点，我将采用一个实验系统，该系统能够 感觉输入被消除，然后逐渐恢复。我在这项提议中有两个目的。首先，我会确定 OB DA神经元的大小，这些神经元在感觉输入丧失和 一旦感觉输入恢复，新生神经元整合的位置。第二，我会确定气味 易损性、恢复性和新生OB-DA神经元在气味输入去除后的反应特性 恢复了。根据以前的研究，我预测出生后产生的一种小的DA神经元亚型将是 特别容易受到细胞死亡的影响，但当感觉时，可以被正在进行的神经再生功能所取代 输入已恢复。我将使用体内慢性双光子结构和功能成像来跟踪存活和 长时间(10周)内单个神经元的整合。通过跟踪大小和气味反应 DA神经元的属性，我将能够评估这些重要属性在脆弱的 和弹性神经元，并确定新生神经元是否可以在功能上取代丢失的神经元 OB电路。这些数据将促进我们对选择性神经元潜在机制的理解。 新生神经元的脆弱性和功能整合。

PROJECT SUMMARY Loss of specific types of neurons is a hallmark of many neurodegenerative diseases. Replacing these lost or damaged neurons to restore normal brain function through stem cell-based therapies has long been a major goal in the fight against neurodegenerative diseases. However, we know little about either why certain populations of neurons are selectively vulnerable to cell death, or how functional integration of stem cell-derived neurons can be promoted. Few areas of the mammalian brain retain the capacity to generate new neurons in adulthood. Understanding how endogenously generated stem cell-derived neurons can successfully integrate without disrupting existing circuits may provide important mechanistic insights into the successful therapeutic use of stem cell-derived neurons. Dopaminergic (DA) neurons in the mouse olfactory bulb (OB) are a highly activity dependent population, with a subset undergoing cell death when sensory input is blocked. DA neurons are also generated continuously throughout life from progenitor cells in the subventricular zone. These two properties make OB DA neurons an ideal model system in which to investigate the determinants of both selective vulnerability and newborn neuron integration. To do so, I will employ an experimental system that enables sensory input to be eliminated and then gradually restored. I have two aims in this proposal. First, I will determine the size of OB DA neurons that are vulnerable or resilient to cell death during loss of sensory input and the location of newborn neurons that integrate once sensory input is restored. Second, I will determine the odor response properties of vulnerable, resilient and newborn OB DA neurons when odor input is removed and then restored. Based on previous studies, I predict that a subtype of small, postnatally-generated DA neurons will be particularly susceptible to cell death but can be functionally replaced by ongoing neurogenesis when sensory input is restored. I will use chronic in vivo 2-photon structural and functional imaging to track the survival and integration of individual neurons over long periods of time (10 weeks). By tracking the size and odor response properties of DA neurons, I will be able to assess whether these important properties differ between vulnerable and resilient neurons, and also to determine whether newborn neurons can functionally replace lost neurons in OB circuits. These data will advance our understanding of the mechanisms underlying selective neuronal vulnerability and functional integration of newborn neurons.