Project Summary / Abstract Dementia and age-related cognitive decline is an escalating major health concern in the United States. Approximately 20% of the US population will be 65 or older by year 2030, and roughly 8 million of these individuals are expected to suffer from Alzheimer’s disease (AD). We propose to examine detailed AD-related neural circuit mechanisms that will be critical for developing new AD treatment strategies by use of two complementary AD mouse models, which share many features of human AD. Our guiding hypothesis is that AD-related neurodegeneration causes maladaptive changes of memory circuit connections and neural ensemble activities in the hippocampus. We discovered recently in the mouse that non-canonical subicular back- projections to hippocampal CA1 underlie object-place learning, a prominent impairment in AD. This circuit has been recently identified in human brain. We will test our hypothesis that significant impairments in bidirectional information processing between hippocampal CA1 and the subiculum (SUB) develop over time during AD progression. In Aim 1, we will determine the effect of AD-like neurodegeneration on local and global circuit connections to hippocampal CA1 and SUB excitatory neurons. We will map and compare circuit input connections and output projections of excitatory CA1 and SUB neurons in adult control, and AD-like mice using retrograde monosynaptic rabies tracing and anterograde monosynaptic herpes simplex virus (HSV) tracing. Further, we will perform experiments in postmortem human hippocampus of aged-matched control and AD patients to map the SUB-CA1 pathway in human brains and understand detailed changes of this brain circuit in AD patients. In Aim 2, we will test the hypothesis that neurodegeneration in AD-like mice degrades object- location memory encoded by hippocampal CA1 and SUB excitatory neurons. To map neuronal activity to behavioral performance, we will use in vivo miniature microscopic imaging to examine and compare spatial representations of CA1 excitatory neurons and SUB excitatory neurons during open-field exploration, track- based route-running and object-location memory tasks. Thus, we can longitudinally track progressive AD-like functional defects. In Aim 3, we will determine whether spatial memory can be rescued by patterned stimulation of the non-canonical SUB-CA1 back-projection in the AD model mice. Human literature and our preliminary data show high relevance of our proposed research for Alzheimer’s disease. Together, the proposed research will advance our understanding of specific neural mechanisms underlying AD etiology and help to identify new therapeutic targets in humans.