Thiamine deficiency-induced neurodegeneration and neurogenesis

Abstract

Wernicke-Korsakoff syndrome (WKS) is a thiamine deficiency-induced neurodegenerative disorder that culminates in a bilateral diencephalic lesion and severe amnesia. The pyrithiamine-induced thiamine deficiency (PTD) animal paradigm models the neuropathology and behavioral impairments observed in WKS. A hallmark feature of WKS/PTD is hippocampal dysfunction in the absence of anatomical lesion. Extensive literature exists demonstrating a vital role for neurogenesis in hippocampus-based learning and memory function. Thus, a reduction of hippocampal neurogenesis may contribute to the amnestic syndrome associated with WKS and PTD. The current series of experiments sought to determine the consequences of PTD treatment on hippocampal neurogenesis. In the first experiment (Chapter 2), stage-dependent alterations of neurogenesis and gliogenesis were assessed in the hippocampal granule cell layer. Experimental thiamine deficiency increased the proliferation, but not survival, of progenitor cells. In contrast, neurogenesis was reduced and astrocytogenesis was increased during the late post-lesion stage of PTD treatment. The altered hippocampal neurogenesis was accompanied by an increase in undifferentiated cell populations during the post-lesion stages. These data demonstrate that long-term changes to neurogenesis might underlie the hippocampal dysfunction in the PTD model. The second experiment (Chapter 3) sought to determine whether voluntary exercise could ameliorate PTD-induced behavioral deficits and rescue hippocampal neurogenesis. Subjects were exposed to a running or stationary wheel for 14 days and were behaviorally tested on two spatial working memory tasks beginning either 24-hours or 2-weeks following the completion of exercise. Wheel running selectively improved PTD-induced behavioral impairments on the plus-maze spontaneous alternation task at the 2-week time point relative to the stationary PTD subjects. At this time point, exercise also increased the survival of progenitor cells, rescued the diminished neurogenesis, and facilitated cellular activation during behavioral testing. Taken together, these data demonstrate that reduced hippocampal neurogenesis (Chapter 2) might underlie some of the spatial memory impairments associated with PTD treatment and that exercise exposure restores behavioral functionality and rescues hippocampal neurogenesis (Chapter 3). Furthermore, diminished hippocampal neurogenesis may contribute to the amnestic symptoms associated with thiamine deficiency and voluntary exercise may serve as a non-invasive therapeutic approach to alleviate the observed long-term memory impairments