UC Irvine

Alzheimer’s disease (AD) is the most common neurodegenerative disease, often culminating in life-altering behavioral and cognitive changes. As current pharmacotherapies for the disease are limited, novel approaches to understanding the alterations in neuronal circuits prior to symptom onset are crucial for effective therapeutic intervention. Despite the critical need, the brain circuitry underlying AD pathophysiology is yet to be fully understood. Recent shifts towards early intervention strategies highlight the importance of understanding the preclinical stage of AD. By taking a circuit mapping approach, this body of work aimed to identify and probe the neuronal populations within entorhinal cortex circuitry that underlie these early stages of AD (Chapter 1). Here we used a cutting-edge viral-genetic method, rabies virus (RABV) tracing, which delineates the input connections of targeted starter cell populations. By implementing rabies virus tracing at different time points, we captured how these circuits look before the emergence of any overt behavioral or pathological deficits and during the later stages of the disease when both cognitive and pathological impairments are present. Our findings identified a critical circuit between the retrosplenial cortex (RSC) and entorhinal cortex (EC) that is disrupted related to the early development and progression of AD (Chapter 2). These results lay the groundwork for creating targeted therapies to mitigate or halt the development of AD.Parallel studies into the central mechanisms driving learning, memory, and cognitive decline are essential for advancing our understanding of AD progression. Long-term potentiation (LTP) is a fundamental cellular mechanism that underlies learning and memory processes, yet the dynamics of LTP stabilization or disruption over time remain to be fully understood. In this study, we assessed the effects of the small molecule macropinocytosis inhibitor amiloride on LTP stabilization and memory in the 5xFAD mouse model of Alzheimer’s disease (Chapter 3). Our findings indicated that amiloride administration into the basal lateral amygdala can enhance memory retention in these mice during the early stages of AD, as evidenced by increased freezing behaviors in an auditory fear conditioning task. These findings suggest that macropinocytosis inhibitors like amiloride may be a potential therapeutic agent for the treatment of AD-related memory deficits. Our final study shifted focus to the broader implications of brain changes in addiction-like behaviors in rodents, particularly examining the anterior cingulate cortex’s (ACC) role in the context of the opioid crisis—a pressing public health issue with no clear solution for opioid use disorders (Chapter 4). By exploring the biological differences between individuals susceptible to opioid addiction and those who are not, we employed an unbiased whole-brain activity method approach to investigate crucial networks and circuits related to opioid withdrawal behavior. The TRAP2 technique was used to permanently mark neurons activated by an initial opioid exposure, establishing a link between these activity patterns and subsequent opioid-induced behaviors. Utilizing network control theory to pinpoint critical brain areas contributing to resilience, we found a significant correlation between ACC activity and the development of resilience against addiction-like withdrawal behaviors. This dataset offers a promising platform for further explorations into the ACC's connection to morphine addiction, opening avenues for novel therapeutic interventions.