Seminars

ABSTRACT:

There is a surprising lack of direct evidence on if and how changes in neural activity play a causative role in Alzheimer’s Disease and cognitive decline, let alone the mechanisms. I have used 2-photon Ca²⁺ imaging and high density silicon probes to study single-neuron resolution activity during a learning and memory behavior in Alzheimer’s Disease-related model mice, and identified brain regions with either healthy or dysfunctional neural circuit operation and latent task-specific neural substrates of learning that were predictive of performance and progressively impaired over aging. Using highly sensitive optogenetic tools, I developed a strategy for spatiotemporally precise modulation of neural dynamics that fully rescued learning deficits which had been completely lost in aged Alzheimer’s disease-related model mice–with memory persisting long after cessation of treatment. This work demonstrates that even after a complete loss of a learning ability, the brain still maintains remarkable potential to be restored. Discovering fundamental mechanisms of neural circuit dysfunction could enable more precise and rationally targeted approaches to repair neural circuits, and could transform how we treat aging and neurodegenerative diseases.

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