Marsland Paige, Vore Andrew S, Lutzke Ashley, Gano Anny, Fischer Abigail, Trapp Sarah, Savage Lisa M, Deak Terrence
Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY 13902-6000, United States.
Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY 13902-6000, United States.
Brain Behav Immun. 2025 Aug;128:192-207. doi: 10.1016/j.bbi.2025.03.034. Epub 2025 Apr 3.
Alcohol consumption across the lifespan contributes to mood fluctuations and cognitive dysfunction, two neurobehavioral features also associated with Alzheimer's Disease and Related Dementias (ADRD). Yet, few studies have used rodent models to determine how a history of ethanol consumption across the lifespan might contribute to neurobehavioral and neuropathological features of ADRD. We exposed Wild Type (WT) and transgenic Fischer 344 CE rats (TgF344-AD) that have been genetically modified to express the human Amyloid Precursor Protein (APP) and presenilin-1 genes with mutations, to ethanol using a chronic, intermittent ethanol consumption model. Beginning at P28, rats were given a single bottle 10 % ethanol solution for 2 consecutive days, followed by 2 days of tap water. This pattern (2 days on, days off) was repeated for a total of 12 cycles until rats reached the age of ∼ 3 months, and repeated at 6 (Exp 1 and Exp 2) and 9 months of age (Exp 2). In experiment 1, ethanol consumption decreased alternations in a spontaneous alternation task in females, only at the 3-month time point, whereas TgF344-AD females showed increased contextual fear conditioning in the test of retention and reinstatement tests at 6 months of age. In experiment 2, a battery of anxiety-like behaviors (Elevated Plus Maze, Marble Burying, and Novelty Induced Hypophagia) were assessed following a 2-week abstinence period at 3, 6, and 9 months of age in ethanol-consuming rats. Data from the EPM and marble burying tasks revealed evidence of heightened anxiety-like behavior in Tg-F344-AD rats that varied by sex and age, with no significant effects of ethanol. In the novelty-induced hypophagia task, males with a history of ethanol consumption had a lower latency to approach a familiar, salient reward at 3 months old, but effects of ethanol were overall minimal. Examination of dorsal hippocampal gene expression at 6 months of age under basal conditions also revealed predominantly genotype and sex-specific effects on inflammation- and AD-related genes (App, Il-6, Bace1, Rage, Lrp-1). When examined at 9 months old following LPS challenge, ethanol increased inflammatory genes in males (Il-1β, Il-6) in the hippocampus, whereas ethanol decreased several inflammatory and AD-related genes (Hmgb1, Rage, Bace1, Lrp-1) in TgF344-AD females. Overall, these data provide further evidence that females are especially vulnerable to AD, and that a history of ethanol consumption had selective, rather than global, effects on AD- and inflammation-related genes following an inflammatory stimulus.
一生中饮酒会导致情绪波动和认知功能障碍，这两种神经行为特征也与阿尔茨海默病及相关痴呆症（ADRD）有关。然而，很少有研究使用啮齿动物模型来确定一生的乙醇消费史如何可能导致ADRD的神经行为和神经病理学特征。我们使用慢性间歇性乙醇消费模型，将经过基因改造以表达人类淀粉样前体蛋白（APP）和早老素-1基因且带有突变的野生型（WT）和转基因Fischer 344 CE大鼠（TgF344-AD）暴露于乙醇中。从出生后第28天开始，大鼠连续2天给予单瓶10%乙醇溶液，随后2天给予自来水。这种模式（2天饮用，2天停用）重复总共12个周期，直到大鼠达到约3个月龄，并在6个月（实验1和实验2）和9个月龄（实验2）时重复。在实验1中，仅在3个月时间点，乙醇消费降低了雌性大鼠在自发交替任务中的交替次数，而TgF344-AD雌性大鼠在6个月龄的记忆保持测试和恢复测试中表现出情境恐惧条件反射增加。在实验2中，在3、6和9个月龄的乙醇消费大鼠经过2周禁欲期后，评估了一系列类似焦虑的行为（高架十字迷宫、大理石掩埋和新奇诱导的摄食减少）。来自高架十字迷宫和大理石掩埋任务的数据显示，Tg-F344-AD大鼠存在类似焦虑行为加剧的证据，其因性别和年龄而异，乙醇无显著影响。在新奇诱导的摄食减少任务中，有乙醇消费史的雄性大鼠在3个月大时接近熟悉的显著奖励的潜伏期较短，但乙醇的总体影响最小。在基础条件下对6个月龄大鼠背侧海马基因表达的检查还显示，对炎症和AD相关基因（App、Il-6、Bace1、Rage、Lrp-1）主要存在基因型和性别特异性影响。在9个月龄经脂多糖刺激后检查时，乙醇增加了雄性大鼠海马中的炎症基因（Il-1β、Il-6），而乙醇降低了TgF344-AD雌性大鼠中的几种炎症和AD相关基因（Hmgb1、Rage、Bace1、Lrp-1）。总体而言，这些数据提供了进一步的证据，表明女性对AD特别易感性，并且乙醇消费史在炎症刺激后对AD和炎症相关基因具有选择性而非全局性影响。
