UC Irvine

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a growingmajor health impact, particularly in countries with aging populations. Traditional therapeutic approaches have been taken towards treating AD by focusing on neurochemical and neuropathological mechanisms. The examination of neural circuit mechanisms in AD mouse models is a recent focus for identifying new AD treatment strategies. Accumulating evidence shows that there are neural circuit-level maladaptive alterations in AD brains. New viral-genetic technologies facilitate quantitative mapping of cell-type-specific neural circuit connections in AD mouse models. Monosynaptic rabies virus mapping reveals age-progressive changes in both long-range and local hippocampal neural circuit connections that occur in AD mouse models – and provides neural circuit-based explanations for human AD behavioral defects. The recent developments in concepts and technology present new opportunities for studying AD pathogenesis at the neural circuit level. In Chapter 1, I provide a literature overview of new technical advancements in neural circuit mapping, describe both conventional neural tracers and state-of-the-art virus-based tracers, and discuss relevant applications using the novel viral- genetic tracers. In Chapter 2, I report our investigation of neural circuit connectivity alterations of hippocampal CA1 excitatory neurons in AD model mice. I focus on the hippocampus as it is one of the most affected brain regions in AD. I applied genetically targeted monosynaptic rabies viral xii tracing to map the neural circuit connectivity of CA1 excitatory neurons in age-matched APP-KI model mice versus wild-type (WT) control mice. Our quantitative analysis of neural circuit connections reveals that compared to WT mice, APP-KI mice show age-progressive and sex- dependent hippocampal CA1 connectivity alterations. Unexpectedly, AD mice exhibit CA1 excitatory neuron input shift with hippocampal CA3 in AD mice. Moreover, aged female AD mice show significantly reduced subiculum to CA1 projections. This study is the first to characterize hippocampal CA1 neural circuit changes in AD model mice using monosynaptic rabies viral tracing. In Chapter 3, I report our study of using monosynaptic rabies virus to map the neural circuit connectivity of the subiculum excitatory neurons in age-matched, gender-balanced control and 5xFAD mice. The subiculum is a critical brain region for relaying and integrating hippocampal and cortical information, and is among the most vulnerable brain regions in AD. My study shows that the neural connectivity of the subiculum exhibits a significant sex- and age-dependent differential pattern in the 5xFAD mice. I find an unexpected increase in visual cortex input connectivity to the subiculum in aged 5xFAD mice. Our new findings are supported by human AD literature and can help to identify potential new therapeutic circuit targets for AD treatments. Overall, the studies presented in this dissertation provide new insights into neural circuit mechanisms underlying AD pathogenesis and support the notion that neural circuit disruptions are a prominent feature of AD.