Alcohol use disorders (AUDs) are associated with neurodegeneration and cognitive dysfunction, but the impact of alcohol use on Alzheimer's disease and related dementias (ADRD) is unknown. Our work suggests that chronic alcohol can alter the activity of serotonin (5-HT) neurons in the DRN, which may cause disruption in sleep homeostasis in the early stages of ADRD. Both AUD and ADRD are associated with chronic insomnia, but to date no studies have linked alcohol-induced sleep disturbances to tau-based neuropathology in the brain. Sleep disruption also induces microglial activation and aging, which can promote the spread of tau pathology in the brain.
In Aim 1, we will use EEG, fiber photometry, electrophysiology and DREADD-based manipulations of neural activity in vivo in mice expressing human tau pathology (htau mice) to determine whether chronic alcohol exacerbates sleep deficits and whether enhanced neural activity in 5-HT neurons contributes to sleep disruptions.
In Aim 2, we will examine the effect of chronic alcohol on microglia and their contribution to the progression of tau pathology in the DRN.
In Aim 3, we will determine whether chronic alcohol can facilitate the spread of tau pathology from the DRN to other brain regions using an AAV-based strategy for expressing tau pathology exclusively in 5-HT neurons. 3D immunolabeling and light sheet imaging using the iDISCO technique will be used to identify areas and quantify the extent of tau spread. We will also examine whether neural activity in 5-HT neurons and microglial activation contributes to this spread. In total, the proposed research will provide mechanistic insight into the impact of chronic alcohol on early accumulation and spread of tau pathology in the brain and the later development of cognitive and memory deficits.
The goal of these studies is to determine whether alcohol enhances the progression of tau pathology in the brain by altering neuronal activity in serotonin neurons in the dorsal raphe. The resulting disruption of sleep homeostasis and neuroinflammation in the dorsal raphe may enhance propagation of tau pathology both locally and in distal regions of the brain, eventually resulting in cognitive decline. Ultimately, this investigate will establish the dorsal raphe serotonin system as an important neural substrate in the early stages of Alzheimer's disease that is impacted by alcohol use, which could play a significant role in the progression of tau pathology and the onset of cognitive and memory deficits.
