Alzheimer?s Disease (AD) is the most common human dementia, which extracts substantial emotional and economic costs on AD patients and their caregivers. Thus, there is considerable interest in mechanisms which reflect treatment targets, including for cognitive and emotional disruptions. Part of the Parent R01 for this Supplement focuses on the central importance of Locus Coeruleus (LC) and norepinephrine (NEPI) receptors in compulsion-like alcohol drinking, where intake continues despite known negative consequences. The LC/NEPI system is a key regulator of cognition and emotion, especially under challenge or stress, and one long-term goal is to develop sufficient mechanistic understanding of the LC/NEPI to provide pharmacotherapies that disrupt compulsion-like and anxiety-driven aspects of addiction. Considerable evidence suggests that AD patients have a disrupted LC/NEPI system. There is partial loss of LC NEPI cells and some compensatory upregulation of NEPI release, and many AD LC/NEPI changes correlating with dementia severity. Also, aggression, a common AD symptom, is reduced by inhibiting several NEPI receptors (alpha1 or beta). Our R01 work finds that alpha1 or beta inhibition is particularly effective against compulsion-like drinking, with others showing similar results for excessive drinking with dependence, suggesting important LC/NEPI mechanistic similarities between AD cognitive/emotional dysregulation and uncontrolled addictive drives. However, there is also evidence for hypoactivity of some aspects of the LC/NEPI system. To better understand the LC/NEPI impact during AD, it is critically important to understand the actually activity level of LC NEPI neurons. We hypothesize that AD-related disruptions of LC neurons can produce hyperactivity or hypoactivity, which could vary across AD development (possibly switching from hyper early to hype later) and across individuals. To address this central question of actual LC cell activity, we seed dbh-Cre mouse LC with human AD-tau brain material (or non-AD control) and, after 2.5-3 or 5-6 months, examine LC cell activity using the cutting-edge fiber photometry. Since LC cells fire tonically, we will inhibit LC cells with clonidine and local infusion of a strong inhibitor (lidocaine), where drop in activity gives strong indication of basal LC activity. We also examine LC cells and NEPI/metabolite levels to better understand LC disruption across AD-like development. These studies will allow us to initiate a complementary line of research for the lab, including an R01 submission (based from Supplement studies) to examine how altered activity of LC cells (or LC terminals) in a given individual, and at different times of AD development, relates to cognitive and affective behavioral disruptions. Our association with the Indiana University Alzheimer?s Center and Stark Model-AD (in the same building as my lab) will allow us to be immediate contributors to the AD research field and will greatly increase the potential for long-term success.
The results of these experiments in animal models will provide critical new information about the brain regions and molecules that drive compulsive alcohol intake, where intake continues despite aversive consequences. Since compulsive intake is a major clinical hurdle in the treatment of alcoholism, our experiments investigating the molecular bases of aversion-resistant, compulsive alcohol intake will help identify novel therapeutic targets for the treatment of human alcoholism and other human diseases involving compulsion.
