Prelimbic somatostatin peptide signaling in binge ethanol consumption

摘要 酒精使用是阿尔茨海默病和相关痴呆症（ADRD）的主要危险因素，但生物学因素 酒精消费导致这种风险增加的机制知之甚少。的目标 父母奖是为了了解酗酒引起的生长抑素肽信号转导的减少， 前边缘皮层--执行功能、记忆和其他认知相关行为的关键联系。在这 补充，我们将扩大这项工作，以了解这种酒精诱导的生长抑素减少是否是一个 增加淀粉样蛋白β斑块的机制。我们将建立在现有的文献表明，生长抑素， 是脑啡肽酶的关键调节因子，已知脑啡肽酶可以防止斑块的初始形成， 饮酒会破坏这种预防途径。我们将探讨1）酗酒如何导致减少 SST肽的表达和传递及其与脑啡肽酶和淀粉样蛋白β减少的关系 2）生长抑素激动剂降低认知能力下降和酒精诱导的认知能力 下降，包括记忆和探索相关的任务。通过补充父母奖的实验， 我们将收集关于酒精诱导ADRD风险的创新假设的新数据。公共卫生 声明：这份行政补充材料将扩大我们对基本机制的理解， 酗酒会导致阿尔茨海默病和相关痴呆症的认知能力下降。 更好地理解这种下降介质的机制对于靶向治疗和 预防的努力。

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.