Uncovering Neural Substrates of Diminished Temporal Binding Capacity in Aging

Temporal binding capacity, which enables the relational association of discontiguous stimuli and events, diminishes with normal aging and aging-associated neuropsychiatric disorders. Decline in this key mental function is a major limiting factor underlying aging-associated cognitive and affective impairment. The global economic burden of such aging-associated impairment is estimated at over $1 trillion and is growing at an alarming pace. An improved understanding of changes in neural functions with aging that contribute to degraded temporal binding capacity could greatly facilitate the long-term objective of alleviating cognitive and affective impairments in normative aging and aging-associated neuropsychiatric disorders. Yet, the changes in circuit and network functioning contributing to diminished temporal binding capacity with aging remain unknown. The Principal Investigator's recent NIH-funded work using trace fear learning paradigms has identified critical neural activity dynamics in the CA1 output region of the hippocampus (HPC) supporting the encoding and representation of emotionally salient associations during temporal binding in young adult subjects. This framework will now be extended to uncovering altered processes in aged subjects. The current project utilizes a novel, conceptually innovative model for temporal binding based upon previously uncharacterized functioning of a known CA1 radial sublayer-biased microcircuit motif and proposes that alterations in subpopulation activity and network dynamics may underlie age-related impairment of temporal binding capacity. Based on prior data the model predicts that, in early adulthood, deep CA1 pyramidal cells (CA1PCs) output stimulus representations across discontiguous gaps for temporal binding, while learning-related increases in sharp-wave ripple (SWR) event incidence facilitate consolidation of relational associations outside of the behavioral episode. Aging-related alterations in sublayer-biased signaling during temporal binding and/or SWR dynamics during consolidation of relational associations may thus underlie diminished temporal binding capacity in aging. In future work, any alterations uncovered here will then be used to inform novel strategies for improving temporal binding capacity with aging and alleviating impaired relational organization and affective associations in memory. To uncover aging-related alterations in neural dynamics supporting temporal binding capacity, the project combines state- of-the-art techniques including 2-photon imaging of subcircuit activity, electrophysiology, and optogenetic triggering of network activity events in awake, behaving mice. In Aim 1, aging-related changes in the CA1 radial sublayer outputs mediating temporal binding for trace fear memory acquisition will be identified. In Aim 2, aging-related alterations in SWR activity for consolidation of relational fear associations will be uncovered. The proposed studies are aligned with NIH objectives and will advance the understanding of the neural processes underlying the decline in temporal binding capacity with aging, which is essential to improving therapeutics for cognitive and affective impairments across the normal lifespan as well as in aging-associated disorders.