Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

Abstract

Ischemic stroke is a major world-wide health problem, resulting in death and disability especially in the older population. A sex difference exists in functional recovery post-stroke, with post-menopausal women having worse functional outcome as compared to age-matched men. Although the mechanisms underlying this sex difference are not entirely clear, it is recommended that any potential therapy for stroke recovery be tested in pre-clinical models including both male and females in order to determine the efficacy of the proposed treatment on the entire population. We have reported a novel therapy to enhance brain plasticity and improve functional recovery after stroke in aged male rats by neutralizing the neurite inhibitory protein Nogo-A. We now propose to determine the efficacy of this treatment on synaptic proteins important for neural connectivity and functional recovery. We hypothesized that post-stroke sensorimotor recovery is worse in the aged female rat due to a decrease in synaptic proteins that are necessary for neuronal connectivity and this can be improved with anti-Nogo-A immunotherapy. We tested this hypothesis in the following specific aims. Specific Aim #1 determined sex differences in synaptic proteins in aged male and female rats post-stroke in the contralesional forelimb motor cortex using viral vectors to label cortical pyramidal neurons and high resolution confocal microscopy to examine synaptic proteins. Stroke was found to decrease excitatory synapse number, except in OVX females, who were already at a low number. Specific Aim #2 determined sex differences in aged male and female rats in synaptic plasticity that have been treated post-stroke with anti-Nogo-A immunotherapy and examined three weeks later for synaptic protein changes. The overall goal of this aim was to determine if anti-Nogo-A immunotherapy is useful in improving post-stroke synaptic changes in aged rats, thereby improving our understanding and therapeutic approach to this devastating condition. It was shown that anti-Nogo-A immunotherapy increased excitatory number in males and intact females, but not OVX females. Specific Aim #3 determined sex differences in aged male and female rats post-stroke using behavioral tests of skilled sensorimotor function and examined dendritic profiles of pyramidal layer V motor neurons using Golgi-Cox stain. It was shown that while males learned the forelimb reaching task slower than both female groups, they had a better post-stroke recovery. Females had the largest decrease in dendritic complexity (pre-stroke they had the highest complexity). In conclusion, it has been shown that there is a sex difference in terms of excitatory synapse number following stroke and a sex difference with regard to post-stroke recovery. Anti-Nogo-A immunotherapy was shown to have a sex steroid-dependent effect and this could have far-reaching implications for post-menopausal women receiving the therapy.

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