PROJECT SUMMARY/ABSTRACT Aging in the brain involves interactions between multiple brain regions over years yet originates from electrophysiological changes in millisecond-scale firing events from micron-sized individual neurons. The spatiotemporal scales relevant to aging span many orders of magnitude and thus make it extremely challenging to study aging in the brain of live subjects. Our understanding of brain aging comes mainly from longitudinal studies with low spatiotemporal resolution (e.g., fMRI on human patients and primates over years), and cross-sectional studies comparing different subject populations due to chronic instability (e.g., single- neuron electrophysiology with invasive brain electrodes). Neither approach can span the spatial-temporal scales necessary to resolve single-neuron activities, unravel long-range functional connections of neurons across multiple brain regions, and track the evolution of neural activity during aging-related cognitive decline over extended time periods. Recently our group has demonstrated syringe-injectable mesh-like electronics as a powerful tool for stable long-term chronic tracking of the same single neurons in rodent and primate brains for ?8 months. These capabilities, which are not possible with other brain interrogation techniques, are due to the unique mechanical and structural design of the mesh-like electronics. This design encompasses a flexibility comparable to brain tissue, feature sizes on the order of axons/somata, and macroporous structure that allows interpenetration of neurons through the electronics produce minimal glial scarring that would otherwise insulate neurons from the probe and eliminate motion of probe relative to neurons during chronic experiments. I propose to carry out in-vivo longitudinal studies of natural and pathological aging in mice with stable single- neuron-level resolution. In the mentored phase of this award, I will focus on developing and using syringe- injectable mesh electronics with high multiplexity and appropriate distribution of recording electrodes to chronically track the electrophysiological evolution of individual neurons and corresponding neural circuitry from multiple key brain regions simultaneously, with a focus on alterations in neural connectivity and plasticity associated with memory retention deficit and learning impairment. In the independent phase of this award, I will focus on further development of this technology through incorporation of simultaneous electrical stimulation and recording of neural activity, to explore potential strategies for ameliorating deleterious changes in brain circuitry associated with memory and learning due to aging. The proposed research projects will demonstrate mesh electronics as a transformative tool for addressing the real-world medical challenges of aging, and enable me to acquire the needed knowledge and skills beyond my training in the physical sciences for successful transition to an independent and highly multidisciplinary research career.