Re-engineering excitation-inhibition connectivity to rejuvenate memory circuits in aging

Massachusetts General Hospital, Boston MA

Investigators

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Abstract

? DESCRIPTION (provided by applicant): Impairments in episodic memory are a hallmark of aging and early stages of Alzheimer's disease. Episodic memory formation requires a balance of two distinct mnemonic processes, pattern separation and pattern completion in the dentate gyrus (DG)-CA3 circuit of the hippocampus. Whereas, pattern separation in DG is essential to distinguish between similar experiences by minimizing interference, pattern completion in CA3 facilitates the retrieval of memories based on partial cues. Studies in rodents and humans have suggested that pattern separation-completion balance is disrupted in aging and in individuals with mild cognitive impairment. Although structural and functional alterations have been identified within the medial temporal lobe during aging, the neurobiological mechanisms underlying pattern separation-completion imbalance are poorly understood. The proposed research aims to causally link changes in connectivity underlying feed-forward excitation-inhibition (E-I) balance in the DG-CA3 circuit with encoding and memory deficits seen in aging and determine whether molecular restoration of feed-forward E-I balance in DG-CA3 circuitry is sufficient to reverse age-related impairments. Critical to testing these hypotheses is our identification of a novel molecular regulator of connectivity underlying feed-forward E-I balance that does not affect input specificity of mature dentate granule neurons. Using newly developed viral systems to bi-directionally regulate levels of this molecular agency in dentate granule neurons, we will re-engineer connectivity underlying feed-forward excitation and inhibition with unprecedented spatial precision and interrogate its impact on network level pattern separation mechanisms and encoding and memory precision in adulthood and in aging. These studies may generate insights into fundamental mechanisms underlying encoding and memory precision in DG-CA3 circuit in aging and how they may be targeted for reversing age-related cognitive impairments.