Alzheimer's disease (AD) is a significant public health problem that afflicts approximately 10% of those ages 65 and over. Tremendous efforts have been dedicated toward understanding the mechanisms of cognitive decline, but few studies have focused on the early non-cognitive symptoms of AD. Several lines of evidence indicate that depressive symptoms precede the development of cognitive decline, but the underlying circuits are poorly understood. Earlier studies have found that dynorphin is overexpressed in the brains of AD patients, which may induce deficits in dopamine signaling that can lead to anhedonia. We have previously found that stimulating dynorphin neurons in the nucleus accumbens induces depressive-like behaviors in mice, so we asked whether dynorphin signaling in the NAcc was enhanced in mice expressing human tau pathology (htau mice). We also have data suggesting that NAcc dynorphin neurons inhibit local dopamine release, which we expect to be potentiated in htau mice. Recent studies also suggest that heavy alcohol use may worsen tau pathology associated with AD. Our lab has also shown that chronic alcohol use heightens activity in NAcc dynorphin neurons, raising the possibility that alcohol may act in synergy with tau to promote depressive-like behaviors. We will determine whether chronic ethanol exacerbates tau pathology in NAcc dynorphin neurons and whether enhanced neural activity in these neurons plays a role in this process. Together, these experiments will reveal neural mechanisms underpinning the early non-cognitive symptoms of AD and the role of chronic alcohol in facilitating the progression of AD.
This project will help to elucidate the role of chronic ethanol in the progression of Alzheimer's disease. The goal of these studies is to determine whether tau pathology in NAcc dynorphin neurons can lead to altered dopaminergic transmission and depressive-like behaviors and whether chronic alcohol can accelerate the formation of tau tangles in these neurons. Ultimately, this investigation may identify new potential targets for the treatment of both alcohol dependence and Alzheimer's disease.
