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

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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.