Investigating the effects of stimulating adult hippocampal neurogenesis in an animal model of deep brain stimulation and Alzheimer’s disease
Toronto General Hospital & Toronto Western Hospital
We propose to examine the consequences of stimulating the dentate gyrus (DG) on adult hippocampal neurogenesis and memory performance in transgenic Alzheimer’s disease model mice with mutated amyloid precursor protein.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
An increasing body of data associates dementia with impairments in specific neural elements and circuits, including those underlying cognition and memory. Deep brain stimulation (DBS) using implanted electrodes to modulate neural activity in targeted brain structures and circuits, has been successfully employed for the treatment of movement disorders, pain, and psychiatric conditions. Recent pilot human studies in Alzheimer’s patients by our group suggest that fornix/hypothalamic DBS can modulate activity in hippocampal/medial temporal lobe regions and downstream circuits, reverse regional impairments in glucose metabolism, and ultimately ameliorate cognitive decline associated with the disease. While the mechanisms underlying this clinical response and the ultimate clinical utility of DBS in AD is yet unproven, modulation of dysfunctional memory and cognitive circuits represents a novel and potentially promising approach.
- Establish baseline and stimulation-induced alterations in adult hippocampal neurogenesis, in addition to examining amyloid deposition
- Evaluate rodent performance in hippocampal-dependent memory tasks in controls and mice following stimulation
Despite the widespread and successful use of DBS in patients, the exact mechanisms of action for DBS in general and specifically for fornix stimulation on the neuronal activity of the hippocampus remain unknown. Our team has been investigating the effects of fornix DBS in rodent models of AD on neurogenesis in the hippocampus, on performance in memory‐ dependent tasks, on amyloid deposition, and on modulation of expression of several classes of proteins in the hippocampus. We have found that, fornix DBS can increase neurogenesis, improve spatial and contextual fear memory, and increase the expression of certain neuronal growth factors and of synapse proteins involved in memory processing. These findings suggest a potential molecular basis for the observed effects of DBS in the context of AD.