PROJECT SUMMARY/ABSTRACT Depression in late life is prevalent, affects nearly one fifth of older adults, and exacts an enormous burden on public health. One hallmark of late-life depression is a loss in the ability to experience pleasure and reduced motivation to seek rewarding experiences. Loss of pleasure and motivation limits engagement in activities that could improve physical and mental health, leads to social isolation, and increases risk of suicide and early mortality. These devastating impairments in reward function are also notoriously difficult to detect and treat, due in part to a limited understanding of the mechanisms that contribute to impaired reward function. Elevated inflammation, which is closely linked to depression, has been implicated as a biological mechanism of reward dysregulation in preclinical models. Translational work has shown that pro-inflammatory challenges, such as endotoxin administration, also alter reward behavior and reward neurocircuitry in healthy human adults. Our laboratory has extended this line of inquiry to older adults, and preliminary data show that endotoxin administration reduces motivational behavior in non-depressed older adults with elevated, but not low, anxiety. Anxiety is prevalent in older adults, a risk factor for depression, and increases vulnerability to inflammation- induced negative mood; moreover, aging increases exposure to inflammation (e.g., higher susceptibility to infection, chronic disease, inflammaging). As such, anxiety and inflammation are risk factors that may comprise “two hits” to impair reward behavior in older adults. Yet, no studies have tested whether such behavioral effects are driven by alterations in reward neurocircuitry to help clarify mechanistic pathways and identify intervention targets. The objective of the current study is to use multilevel analysis of reward function and an experimental design to test effects of experimentally induced inflammation on reward behavior (Aim 1) and reward neurocircuitry (Aim 2) as a function of anxiety in older adults. A double-blind, placebo-controlled, inflammatory challenge with endotoxin in older adults (60-80 y) with (n=40) and without (n=40) anxiety symptoms will evaluate whether anxious older adults are especially vulnerable to inflammation-induced deficits in reward function and should be prioritized for monitoring and intervention. Insights from multilevel analysis of reward can be used to inform the development of precision-based and personalized medicine strategies for the prevention and treatment of late-life depression. With the support of the K01 Award, I will use this study to launch an independent research program that uses experimental methods to identify mechanisms of late-life depression to improve health and well-being in older adults. To this end, I am seeking 1) advanced training in experimental clinical trial methodology using the endotoxin model to accelerate my development as an independent investigator; 2) acquisition of skills in neuroimaging techniques and data analysis to evaluate neural mechanisms that may be sensitive to inflammation and drive aberrant behavior; and 3) expertise in late- life anxiety to broaden my research program and test new conceptual models of reward deficits.

RELEVANCE TO PUBLIC HEALTH Late-life depression remains an enormous public health burden, and deficits in motivation and pleasure are particularly devastating and difficult to treat. Using an experimental inflammatory challenge, the current study will evaluate a “two-hit” model of vulnerability and evaluate whether older adults with symptoms of anxiety who are exposed to inflammatory activation are at elevated risk for loss of pleasure, reduced reward motivation, and dysregulated reward neurocircuitry. Through this integrative, multilevel assessment of biological, neural and affective mechanisms that may underlie the emergence of late-life depression, the current study will yield information that can be used to identify individuals at elevated depression risk and to develop novel preventative and treatment interventions that target specific deficits to improve mental and physical health outcomes in older adults with depression.