Hippocampal neurogenesis continues throughout life in mammals. These adult-generated dentate granule cells (DGCs) are generally believed to contribute to hippocampal memory processing and are generated at varying rates in response to neuronal network activity. Deep brain stimulation (DBS) allows clinicians to influence brain activity for therapeutic purposes and raises the possibility of targeted modulation of adult hippocampal neurogenesis. It has recently been shown that DBS may ameliorate cognitive decline associated with Alzheimer’s disease (AD), and while underlying mechanisms are unknown, one possibility is activity-dependent regulation of hippocampal neurogenesis. To this end, whether or not adult-generated DGCs can assume functional roles of developmentally-generated neurons, and stimulation-induced enhanced neurogenesis can benefit memory function in the normal and diseased brain, warrant study. First, we examined separate cohorts of developmentally- and adult-generated DGCs in intact mice and demonstrated similar rates of activation during hippocampus-dependent spatial memory processing, suggesting functional equivalence. Second, we examined the neurogenic and cognitive effects of targeted entorhinal cortex (EC) stimulation in mice using parameters analogous to clinical high frequency DBS. Stimulation increased the generation of DGCs. Moreover, stimulation-induced neurons were functionally recruited by hippocampal spatial memory processing in a cell age-dependent fashion that is consistent with DGC maturation. Importantly, stimulation facilitated spatial memory in the same maturation-dependent manner, and not when stimulation-induced promotion of adult neurogenesis was blocked, suggesting a causal relationship. Finally, we are in the process of testing whether similar stimulation facilitates spatial memory in a transgenic (Tg) disease model of AD that exhibits amyloid neuropathology and cognitive impairment. Preliminary results suggest stimulation promotes neurogenesis and rescues impaired spatial memory in Tg animals. When considered in the context of promising clinical results, this body of work suggests stimulation-induced neurogenesis could provide a novel therapeutic modality in settings where functional hippocampal regenerative therapy is desirable.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/32906 |
| Date | 31 August 2012 |
| Creators | Stone, Scellig S. D. |
| Contributors | Lozano, Andres M. |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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