Alzheimer's disease (AD) is most commonly diagnosed subsequent to memory deficits, but co-morbidities include a slew of cognitive and non-cognitive impairments including depression, apathy, and movement disorders. While most work on AD has thus far focused on effects in the cortex and hippocampus, the pathophysiology associated with AD is found throughout the brain, and many of the secondary symptoms suggest involvement of the midbrain dopaminergic system. A recent major study as well as preliminary data suggest that dopamine neurons of the ventral tegmental area (VTA) may be affected in mouse models of AD prior to the formation of amyloid plaques and neurofibrillary tangles, suggesting a possible role for the VTA in the prodromal phase of the disease. This field is currently limited by the lack of information on the structural and functional deficits that develop in single dopamine neurons in the early stages of AD, as well as their relationship with decrements in hedonic and reward learning behavior. The experiments in this proposal will focus on two established mouse models of AD. APP/PS1 mice express a mutated human amyloid precursor protein and a deletion of presenilin 1, while triple transgenic 3xTg-AD mice also express a transgene for a human mutant tau. The general strategy will be to measure deficits in dopamine-mediated behavior (sucrose preference, an operant learning task, and locomotor assays) in mutant mice aged 3, 6, and 10 months, and non-transgenic controls, followed by sacrifice for electrophysiology and RNA sequencing of single VTA dopamine neurons. Aim 1 will focus on both intrinsic and synaptic conductances that affect dopamine neuron firing and have been identified in preliminary studies as possibly being affected in AD. Aim 2 will test if a commonly used anti-aging intervention, dietary restriction, can mitigate some or all decrements in ion channel physiology, behavior, and neuronal morphology. As the prevalence of ADRD continues to increase, we are in desperate need of AD treatments that not merely alleviate symptoms but slow or halt the progression of the disease. These treatments do not currently exist because we lack a fundamental understanding of the decrements in cellular and circuit function that occur during the early stages of pathology. The work in this proposal will advance the field toward better treatments by establishing the involvement of dopaminergic processes in AD mouse models. Delineating the sequence of pathological events will allow for the identification of molecular targets for intervention in early AD.