Apathy, defined as ?lack of motivation? or a ?quantitative reduction in goal-directed behavior? is a major and prevalent (up to 72%) debilitating symptom of Alzheimer's disease and related dementias. It is also associated with poor outcome, and is the primary cause of caregiver distress. Remarkably, however, very few studies have probed for disrupted reward processing and goal-directed decision-making underlying the apathy domain using rodent models of Alzheimer's disease. Apathy may result from dysfunction of one or more of the behavioral processes necessary to achieve goal-directed behavior, including internal and external determinants that motivate behavior, selection of goals, elaboration of a plan of action, initiation, execution, evaluation of goals achieved and feedback control of the behavioral response. We will employ a battery of behavioral tasks, used routinely in our labs to probe reward and decision making deficits in rats related to normal aging and addiction, to examine such processes in a double- transgenic rat model of Alzheimer's disease (TgF344-AD). This model expresses a single `Swedish mutation' human amyloid precursor protein (APPsw) gene plus a delta exon 9 mutant human presenilin-1 (PS1deltaE9) gene and manifests age-dependent cerebral amyloidosis, including an abundance of soluble amyloid-beta, that precedes tauopathy, gliosis, apoptopic loss of neurons in the cortex and hippocampus, and cognitive deficits. We will perform in-depth microstructural analysis of licking behavior during reward consumption as a measure of experienced hedonia; instrumental incentive learning to determine how experienced reward value is used to guide reward-seeking actions; Pavlovian-to-instrumental transfer to evaluate the motivational impact of reward-paired cues; and progressive ratio instrumental testing as a catch-all motivational assay of willingness to work for rewards, to test the hypothesis that these core emotional and motivational processes are disrupted in the TgF344-AD rat. In addition to probing for an apathy phenotype at a late stage of development when neuropathology is profound (18 months), we will also probe prior to presentation of overt neuropathology (3 months) and at an early stage of progression (6 months), to test the hypothesis that such deficits precede cognitive impairments in this model and that individual variability in motivation at early stages predicts severity of cognitive deficits and neuropathology assessed later in the animals' life. Apathy is a core behavioral symptom of Alzheimer's disease. Identifying the neurobehavioral basis for apathy in an animal model of the disease will provide targets for behavioral and pharmacological therapeutic intervention. Further, demonstration that emotional and/or motivational deficits precede and predict cognitive decline and overt neuropathology in an animal model will inform the development of tools for using measures of apathy (and their neural correlates) as biobehavioral markers of disease risk and onset in humans, allowing for the implementation of interventions that can be tailored to the unique needs of individual patients.

Public Health Relevance

We propose to probe for specific deficits in decision-making underlying an hypothesized apathy phenotype in a rat model of Alzheimer's disease. Identifying the neurobehavioral basis for apathy in an animal model of the disease will provide targets for behavioral and pharmacological therapeutic intervention in humans and potentially support use of motivational measures as biobehavioral markers of disease risk/disease onset.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Roberts, Luci
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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