Abstract WP102: Retrograde Neurodegeneration of Substantia Nigra Projections to the Striatum Following Long Term Survival After Ischemic Stroke

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Abstract

Introduction: Stroke survivors suffer from long-term physical, cognitive and affective disabilities. These disabilities lower the quality of life, contribute to social isolation and anhedonia, and clinical disorders such as post-stroke depression (PSD), which disproportionately affects women. Preclinical studies show that lesions of the substantia nigra (pars compacta) impair both motor performance and reward seeking behavior. Neurons from the SNc project to the striatum, a region that is significantly infarcted by middle cerebral artery occlusion (MCAo).

Hypothesis: Ischemia induced by MCAo leads to retrograde degeneration of the SNc pathway projecting to the striatum.

Methods: Middle-aged Sprague-Dawley female rats (12 months old) were subjected to ischemic stroke using a silicon-coated nylon filament suture to occlude the middle cerebral artery (MCA) which was removed 75min after to allow for reperfusion. After 14 weeks of survival, rats were again anesthetized and Fluorogold (Flg) was injected into the left and right striatum. Four days later, animals were overdosed with anesthetic, perfused with saline and formaldehyde and the brain removed for cryosectioning. In three sections per animal, Flg-labeled cells in the SNc were counted on both hemispheres, using fluorescent illumination.

Results: Flg-injections into the striatum retrogradely labeled neurons in the midbrain. There was a 35% decrease (p<0.009) in the number of Flg labeled SNc cells in the ischemic hemisphere (85.5+18.2) as compared to the non-ischemic hemisphere (132.4+22.7). The reduced number of projection neurons in the ischemic hemisphere is consistent with the loss of trophic support from the striatum.

Conclusions: SNc neurons are a critical component of reward pathway and motor function, hence degeneration of these neurons could lead to long term motor deficits and depressive symptoms including anhedonia that are common after stroke.

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