Recovery of parkinsonian deficits through stimulation-mediated neurogenesis

2014  -  Toronto, ON, CA

Organizations

University of Toronto

Supervising Advisor: Dr. Andres Lozano

Final summary:

The motor symptoms that occur in the wake of Parkinson’s disease undeniably cause human suffering and have been extensively studied, but there is another facet of this disease few have investigated which also causes great suffering – that being memory impairment. In fact dementia (decline in mental ability) is one of the most debilitating symptoms Parkinson’s disease patients experience, with up to 80% of patients eventually developing dementia. Despite its prevalence and the negative impact on patient quality of life, memory symptoms have remained minimally addressed.

The idea that neurogenesis (birth of new neurons) supports new memory formation was proposed more than 40 years ago, and has become a cornerstone in the field of learning and memory. Numerous studies have shown in people with Parkinson’s disease the rate of neurogenesis is greatly reduced. Given the importance of neurogenesis in memory, it is logical a decrease in neurogenesis could underlie the memory impairments seen in Parkinson’s disease. The most convincing explanation for why this occurs relates to the dramatic decrease in the brains ability to produce dopamine, which is known to be a key regulator of neurogenesis.

Our strategy for normalizing neurogenesis and improving memory function in Parkinson’s disease employs a technique called deep brain stimulation.  This technique involves the implantation of electrodes that deliver electrical impulses to enhance the activity in discrete brain regions. We selected a deep nuclei in the brain called the ventral tegmental area, because of its exclusive characteristics that could be levered to reverse the cognitive symptoms of Parkinson’s disease. The uniqueness of this nuclei is two fold; first it is nuclei is one of the few dopamine producing nuclei that is spared in Parkinson’s disease, and second it has projections to all the neurogenic niches of the brain. We expect this approach will enabled us to boost delivery of dopamine to neurogenic regions to compensate for diminished release and reinstate normal levels of neurogenesis in Parkinson’s disease.

Our research has shown stimulation of the ventral tegmental area promotes proliferation of new neurons in the dentate gyrus an area that plays an essential role in memory formation. To test if these new neurons become incorporated into functional circuits that can facilitate spatial learning we tested the animals on a memory test called the morris water maze 6-weeks after stimulation. We found animals that had received stimulation could create more robust memories for the target location compared to animals that had not been stimulated. Our comprehensive series of DBS-studies, have provided compelling evidence that we can elicit neurogenesis, and improve memory and learning, providing proof of concept to proceed with our technique in a model of Parkinson’s disease.