Project Summary / Abstract Alcohol (EtOH) is the most-commonly abused drug worldwide and chronic EtOH consumption increases the risk and progression of Alzheimer’s disease (AD). These latter findings indicate that chronic EtOH use plays a critical role in the pathogenesis of AD, the most common neurodegenerative disorder and cause of dementia. AD is a progressive disease cause by brain atrophy, including massive neuronal loss in the hippocampus and resulting cognitive and memory deficits characteristic of this disease. Alcohol use disorders (AUDs) are associated with CNS damage and the hippocampus is a central target of its neurotoxic effects. Adult neurogenesis, the phenomenon of new neuron proliferation, is a key contributor to hippocampal integrity and function. Neurodegeneration and excessive EtOH consumption decrease hippocampal neurogenesis while physical exercise increases neurogenesis. Impaired neurogenesis is a common feature of AD mouse models. Also, chronic EtOH feeding decreases neurogenesis in mice by suppressing hippocampal neural stem cell (NSC) proliferation. Decreased neurogenesis is believed to be a critical component of hippocampal degeneration and atrophy seen in AD and AUDs in humans. The parent grant for this supplement is based upon our finding that Regulator of G protein signaling 6 (RGS6) is a critical regulator of EtOH seeking, reward behavior, dependence, and withdrawal in mice due to its ability to regulate dopamine release in the mesolimbic circuit, the major circuit of drug seeking/addiction. This supplement is based upon 4 critical findings: 1) RGS6 mediates exercise-induced adult hippocampal neurogenesis leading to increases in learning and memory in mice, 2) impairment of hippocampal neurogenesis is a common feature of AD mouse models and mice fed chronically with EtOH, 3) chronic EtOH feeding significantly reduces hippocampal RGS6 expression in mice, and 4) chronic EtOH consumption exacerbates hippocampal neuropathology and cognitive and memory deficits in AD mutant mice, while exercise-induced neurogenesis attenuates these changes in these mice. Our findings lead to the innovative hypothesis that chronic EtOH consumption promotes hippocampal degeneration and cognitive deficits in AD by suppressing RGS6-mediated hippocampal neurogenesis. Aim 1 will determine the role of RGS6 in dentate gyrus (DG) neurons on chronic EtOH consumption-induced impairment of hippocampal neurogenesis, hippocampal degeneration, and cognitive function in an APP model of AD. Effects of both loss and overexpression of RGS6 in DG NCSs will determine how RGS6 regulation of neurogenesis combats hippocampal degeneration and cognitive and memory deficits in AD following chronic EtOH. Effects of voluntary wheel running, which induces RGS6-dependent neurogenesis, on these processes will be interrogated. These studies seek to illuminate an entirely novel hippocampal mechanism involving RGS6 that explains how EtOH increases the risk and progres...