PROJECT SUMMARY Alzheimer’s disease is characterized by accumulation of insoluble forms of amyloid- (A) in the extracellular space and within vessel walls, aggregation of the microtubule protein tau in intracellular neurofibrillary tangles and neuroinflammation - contributing to neuronal damage and clinical dementia. A critical barrier in treating Alzheimer’s disease is the years to decades-long lag between initiation of disease and clinical diagnosis, when reversal of brain pathology and recovery of neurons may at best, slow cognitive decline. Thus, it is essential to identify the pathological processes in early disease to characterize biomarkers for diagnosis and find interventional targets that will halt disease prior to symptoms and signs of dementia. An early phenotype of Alzheimer’s is smell loss. Because sniff-induced gamma oscillations generated in the olfactory bulb (OB) are directionally coupled to the hippocampus, smell loss would result in decreased hippocampal gamma oscillations that has been postulated to lead to neurodegeneration and cognitive decline. Interestingly, research has shown that entrainment of gamma oscillations in the hippocampus through activation of visual or auditory cortex recruits both neuronal and glial responses to attenuate Alzheimer’s-disease-associated pathology. Taken together these studies raise the question whether activation of gamma oscillations in the OB- hippocampus axis attenuates Alzheimer’s-disease-associated pathology. We hypothesize that that gamma frequency optogenetic stimulation of olfactory bulb input will alleviate the deficit in learning and memory and loss of smell in 5xFAD mice, an animal model of familial Alzheimer’s disease. To test this hypothesis, we will determine whether optogenetic entrainment of the input to the olfactory bulb results in decreased neuroinflammation and improved cognitive function: (Aim 1): Test whether optogenetic stimulation of olfactory input to the olfactory bulb results in improved learning and memory in the go-no go odorant discrimination task in 5xFAD-hChR2V mice. (Aim 2): Test whether optogenetic stimulation of olfactory input to the olfactory bulb in 5xFAD-hChR2V mice elicits decreased microglial activation, phosphorylated tau and amyloid plaque deposition in the olfactory bulb/hippocampal circuit. The experiments proposed here are within the scope of the parent grant DC000566 that investigates through combined behavioral, two photon imaging and electrophysiological recording olfactory function in mice and are significant since they will identify pathogenic mechanisms that occur in early AD prior to the onset of clinical dementia that can provide early therapeutic targets to slow or halt progression of AD.