Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

Abstract

Stroke is a leading cause of adult disability with no pharmacological treatments to restore lost function. Our laboratory has shown that treatment with neutralizing antibodies against the neurite growth-inhibitory protein Nogo-A improves sensorimotor and cognitive recovery after stroke in adult and aged rats. This recovery is paralleled by increased dendritic and axonal plasticity in anti-Nogo-A-treated rats. Neurogenesis, an alternate form of plasticity involving the de novo production of new neurons, may contribute to post-stroke neural repair. While previous studies have found roles for Nogo-A in adult neurogenesis, neurogenesis has not been investigated after stroke and anti-Nogo-A treatment. The goal of these studies was to examine whether anti-Nogo-A antibody treatment potentiated post-stroke neurogenesis in the brain’s two main neurogenic niches, the subventricular zone (SVZ) and dentate gyrus (DG). We first identified that immature neurons, but not stem cells, in the SVZ expressed Nogo-A. However, Nogo-A was not found at the surface of SVZ-derived neuroblasts and accordingly, the motility of SVZ-derived neuroblasts was not altered by anti-Nogo-A antibody treatment in vitro. However, these cells were still susceptible to Nogo-A signaling, as treatment with recombinant Δ20 peptide, one of the inhibitory domains of Nogo-A, led to a modest reduction in neuroblast maximum velocity. After stroke, anti-Nogo-A treatment had no effect on the number of proliferating cells in the SVZ, or on the density of doublecortin-positive neuroblasts, suggesting that anti-Nogo-A treatment does not stimulate neurogenesis in the SVZ after stroke. In the DG, Nogo-A was again found to be expressed by immature neurons, but not neural stem cells. However, as in the SVZ, anti-Nogo-A treatment did not affect the number of proliferating neural precursors or the number of new neurons produced after stroke. These results suggest that neurogenesis contributes little to the sensorimotor and cognitive recovery observed after stroke and anti-Nogo-A treatment. Due to its stagespecific expression in immature neurons, Nogo-A is likely to play a role in adult neurogenesis in both the SVZ and DG, but is not targeted by anti-Nogo-A antibody treatment.

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