Co-engineering Hebbian and Homeostatic Plasticity Mechanisms to Induce Targeted Functional Neural Connectivity Changes

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Project Summary: Our memories and behaviors are encoded by the plastic changes in connectivity between the trillions of synapses connecting the neurons in our brains. Neurological disorders such as schizophrenia, epilepsy, and stroke often result in aberrant neural connectivity that causes debilitating deficits in cognition and behavior. One approach to treating these disorders is to harness the brain’s natural plasticity mechanisms to restore lost function following injury through neural stimulation. These plastic connectivity changes occur through two main identified mechanisms: Hebbian and homeostatic plasticity. In accordance with Hebbian plasticity mechanisms, connections are strengthened or weakened when activity between neurons is correlated or uncorrelated, respectively. Stimulation-based approaches attempt to utilize this mechanism for inducing plastic changes with limited efficacy to strengthen connectivity (long-term potentiation, LTP), while neglecting the effects of homeostatic plasticity mechanisms. Homeostatic plasticity mechanisms alter connectivity to maintain consistent neuronal activity levels by modifying synaptic strengths, levels of inhibition, and the threshold for LTP induction based on previous activity levels. Here, I hypothesize that homeostatic plasticity plays a significant role in determining Hebbian-informed stimulation-induced plasticity outcomes and that both mechanisms of plasticity can be engineered to improve these outcomes towards strengthening corticocortical connectivity. In aim 1, I assess the impact of reducing neuronal activity on Hebbian-informed stimulation-induced functional connectivity changes in healthy and diseased states. In the diseased state, I will measure the impact of this strategy on promoting functional recovery following targeted cortical lesioning. In aim 2, I explore the suppression of homeostatic plasticity mechanisms that oppose Hebbian-informed stimulation-induced functional connectivity changes. The outlined research strategy will allow me to build experimental and professional skills that will propel my career as I transition into a postdoctoral position. By incorporating homeostatic plasticity mechanisms in the design of Hebbian-based stimulation protocols for targeted neural connectivity change, the findings of the proposed study can transform the efficacy of future stimulation-based therapies for neurological disorders.