Prelimbic somatostatin peptide signaling in binge ethanol consumption

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ABSTRACT Alcohol use is a major risk factor for Alzheimer’s Disease and Related Dementias (ADRD), but the biological mechanisms by which alcohol consumption leads to this increased risk are poorly understood. The aims of the parent award are to understand binge drinking-induced reductions in somatostatin peptide signaling within the prelimbic cortex – a key nexus for executive functioning, memory, and other cognitive-related behavior. In this supplement, we will extend this work to understand whether this alcohol-induced reduction in somatostatin is a mechanism of increase amyloid beta plaques. We will build upon existing literature suggesting that somatostatin is a key regulator of the enzyme neprilysin, known to prevent the initial formation of plaques, and that binge drinking breaks down this preventative pathway. We will explore 1) how binge drinking leads to reductions in SST peptide expression and transmission, and how this relates to reductions in neprilysin and amyloid beta buildup; 2) the ability for somatostatin agonists to reduce both cognitive decline and alcohol-induced cognitive decline, including in memory and exploration-related tasks. By complementing experiments in the parent award, we will collect new data on this innovative hypothesis for alcohol-induced ADRD risk. Public Health Statement: This administrative supplement will expand our understanding of the basic mechanisms by which binge alcohol drinking contributes to the cognitive decline seen in Alzheimer’s Disease and Related Dementias. A better mechanistic understanding of this mediator of decline is necessary for targeting both treatments and preventative efforts.