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

项目摘要 特定类型神经元的丧失是许多神经退行性疾病的标志。弥补这些损失或 通过基于干细胞的疗法恢复受损神经元的正常脑功能长期以来一直是一个主要的 与神经退行性疾病作斗争的目标。然而，我们对为什么某些 神经元群体选择性地易受细胞死亡的影响，或者干细胞衍生的功能整合如何影响神经元的功能。 可以促进神经元的生长。哺乳动物大脑中很少有区域保留了产生新神经元的能力， 成年了解内源性干细胞衍生的神经元如何成功整合 而不破坏现有的回路可能为成功的治疗提供重要的机制见解， 干细胞衍生的神经元的用途。小鼠嗅球（OB）中的多巴胺（DA）能神经元是一种高度依赖性的神经元。 活动依赖性群体，其中一个亚群在感觉输入被阻断时经历细胞死亡。DA神经元 在整个生命过程中也从脑室下区的祖细胞连续产生。这两 这些特性使OB DA神经元成为研究选择性和非选择性神经元的决定因素的理想模型系统。 脆弱性和新生神经元整合。为此，我将采用一个实验系统， 感觉输入被消除，然后逐渐恢复。我提出这项建议有两个目的。首先我会确定 在感觉输入丧失期间对细胞死亡脆弱或有弹性的OB DA神经元的大小， 一旦感觉输入恢复，新生神经元的位置就会整合。第二，我会确定气味 当去除气味输入时，脆弱的、有弹性的和新生的OB DA神经元的反应特性， 恢复.基于以前的研究，我预测，一个小的，出生后产生的DA神经元的亚型将是 特别容易受到细胞死亡的影响，但当感觉到神经再生时， 输入已恢复。我将使用慢性体内双光子结构和功能成像来跟踪存活率， 单个神经元在长时间（10周）内的整合。通过追踪它们的大小和气味反应 DA神经元的特性，我将能够评估这些重要的特性是否不同的脆弱 和弹性神经元，并确定新生神经元是否可以在功能上取代失去的神经元。 OB电路。这些数据将促进我们对选择性神经元凋亡机制的理解。 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.