PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that is characterized by the accumulation of toxic proteins, aberrant neural activity, and deficits in spatial learning and memory. The hippocampus, an area of the brain crucial for spatial learning and memory, is affected early in the course of AD. Previously, the PI and collaborators have shown that acute exposure to gamma frequency (40 Hz) auditory and light flicker stimulation drives gamma frequency neural activity in the hippocampus. Furthermore, extending gamma stimulation exposure from acute presentations to multiple days of stimulation periods rescues cognitive deficits in a mouse model of AD. However, it is unknown how these improvements in behavior arise, and if they are due to the rescue of established neural activity deficits. Understanding the neural circuit mechanism through which the prolonged manipulation of hippocampal activity acts to affect cognitive deficits is crucial for the development of this technique as a therapeutic for neurodegenerative disease. Thus, the goal of this proposal is to study the functional effects of gamma frequency sensory stimulation on deficits in neural connections and neural codes essential for learning and memory in the hippocampus of a mouse model of AD. Aim 1 will establish how prolonged gamma stimulation affects deficient inhibition of excitatory pyramidal cells in the hippocampus. Aim 2 will examine the effects of prolonged gamma stimulation on deficits in patterns of hippocampal activity that are important for learning and memory. To achieve these aims, local field potentials and spiking activity will be recorded from many single neurons in head-fixed mice as they navigate through a virtual reality (VR) environment. This innovative approach will allow neural activity to be recorded from awake, behaving mice, the primary animal model of disease, with the high temporal resolution and large number of cells needed to study precise neural activity in the hippocampus. The proposed work has the potential to result in a non-invasive method to rescue neural activity deficits, carrying promising translational applications to Alzheimer’s disease, as well as other neurological diseases with altered oscillatory neural activity. The training proposed in this application will take place in the Coulter Department of Biomedical Engineering, a joint department between Georgia Institute of Technology and Emory University School of Medicine. Training will be overseen by the applicant’s sponsor, Dr. Annabelle Singer, and co-sponsor, Dr. Garrett Stanley. The applicant will receive significant training to develop new skills necessary to complete the proposed research. She will pursue a variety of professional development activities to support her long-term career goal to conduct basic and translational research in neurodegenerative disease as an independent scientist at a research institution.