PROJECT SUMMARY/ABSTRACT
Alzheimer’s disease is devastating for individuals and society. Impaired learning and memory, particularly in the
context of spatial navigation, is one of its early and major symptoms. Similarly, rodents recapitulating aspects of
Alzheimer’s disease also exhibit early impairments in spatial navigation. A preponderance of evidence suggests
abnormal cortical-hippocampal communication in humans with Alzheimer’s disease. Hippocampal-cortical
interactions during sleep are thought to be critical for consolidation of newly acquired memories. However, no studies
have assessed these brain dynamics during sleep in rodents modeling Tau and amyloid beta (Aß) aggregation aspects
of Alzheimer’s disease. Thus, the proposed research will explore the functionality of brain dynamics during sleep
in the hippocampal-PC network in animal models of Tau and Aß aggregation (TAßA). To do this, we will use a
triple transgenic mouse where three major genes associated with familial Alzheimer’s disease are expressed
leading to TAßA. This mouse model mimics plaque and tangle pathological hallmarks of the disease, with a
distribution pattern similar to human patients, including synaptic changes in the limbic system. In addition, all
findings will be confirmed in a transgenic rat with Aß accumulation, plaque formation, tau accumulation, cell loss,
and spatial memory impairments. Specifically, we will: 1) assess the relationship between spatial learning and
memory, as well as brain dynamics during sleep, both within and across the hippocampus and cortex; 2) use a
novel targeted optogenetic approach to functionally dissect the relative contributions of TAßA in the
hippocampus to impaired hippocampal-cortical coupling during sleep and impaired spatial learning. 3) test the
efficacy of a non-invasive visual stimulation approach, known for clearing cortical TAßA, to relieve impaired
hippocampal-cortical coupling during sleep and impaired spatial learning. This project will provide insight into
the normal function of a circuit that is dysfunctional in Alzheimer’s disease and allow us to probe dysfunction in
this circuit that emerges in very early stages of disease progression in rodents modeling TAßA aspects of
Alzheimer’s disease. This research will allow us to begin understanding changes in this network which may
underlie the emergence of cognitive impairments observed in Alzheimer’s disease and begin testing the efficacy
of a non-invasive treatment for reversing the functional brain abnormalities and impaired cognition.