Neurogenesis and neurodegeneration in adolescent binge alcohol exposure

描述(申请人提供)：青春期是许多人开始尝试饮酒的时期。酒精滥用和酒精依赖，统称为酒精使用障碍，在约6%的青少年中被诊断出，并导致严重的神经心理和/或认知缺陷。目前，多达一半的高中生可能会饮酒，其中高达70%的学生是酗酒者。考虑到酗酒是预测酒精对大脑损伤的因素之一，了解酗酒对青少年大脑结构的影响是一个重要的公共卫生问题。青少年饮酒的神经解剖学后果没有得到很好的描述，尽管两项研究表明，患有酒精使用障碍的青少年海马体体积减少。这一发现证实了动物模型中的行为和神经生理学工作，即青少年的海马体是酒精的靶子。然而，还没有人研究酒精是否直接导致青春期大鼠的神经退化，或者细胞或神经元减少的基本机制。最近发现，神经干细胞对正在进行的神经发生和海马体结构有贡献，这表明了酒精诱导神经变性的一种新的潜在机制。 神经退行性变。因此，这项应用将检验总体假设，即在青春期大鼠中酗酒会改变神经干细胞和神经发生，从而产生神经退化。在青少年酒精使用障碍的活体大鼠模型中，有三个具体目标将解决这一假说：(1)调查青少年酗酒对神经发生组成部分的影响，(2)确定酒精中毒抑制神经干细胞增殖的机制，以及(3)评估神经发生的变化是否与海马齿状回的神经退化(细胞净减少)有关。在每个目标中，关于改变神经发生成分所需的酒精剂量或持续时间的贡献以及细胞死亡的贡献的重要问题将被调查。了解酒精诱导的神经干细胞和齿状回颗粒细胞丢失的机制为研究青少年大脑对酒精效应的差异敏感性以及细胞死亡和细胞出生机制在神经退行性变中的动态作用奠定了坚实的基础。

DESCRIPTION (provided by applicant): Adolescence is a time when many individuals begin to experiment with alcohol. Alcohol abuse and alcohol dependence, collectively termed alcohol use disorders, are diagnosed in ~6% of adolescents and result in significant neuropsychological and/or cognitive deficits. As many as half of all high school students may currently drink alcohol and up to 70% of those students are binge drinkers. Considering that binge drinking is one of the factors that predicts brain damage from alcohol, understanding the impact of binge drinking on adolescent brain structure is an important public health concern. The neuroanatomical consequences of adolescent drinking are not well described, though two studies have shown hippocampal volume reductions in adolescents with alcohol use disorders. This finding confirmed behavioral and neurophysiological work in animal models that the adolescent hippocampus is targeted by alcohol. However, no one has examined whether alcohol directly produces neurodegeneration in the adolescent rat or the basic mechanism of cell or neuron reduction. The recent discovery that neural stem cells contribute to ongoing neurogenesis and to hippocampal structure suggests a novel potential mechanism of neurodegeneration alcohol-induced neurodegeneration. Thus, this application will test the overall hypothesis that binge alcohol exposure in the adolescent rat alters neural stem cells and neurogenesis to produce neurodegeneration. Three specific aims will address this hypothesis in an in vivo rat model of an adolescent alcohol use disorder by (1) investigating the effects of adolescent binge alcohol administration on the components of neurogenesis, (2) determining the mechanism by which alcohol intoxication inhibits neural stem cell proliferation and (3) evaluating whether changes in neurogenesis are associated with neurodegeneration (net reduction of cells) in the hippocampal dentate gyrus. Within each aim, important questions regarding the contribution of alcohol dose or duration necessary to alter the components of neurogenesis and the contribution of cell death will be investigated. Understanding the mechanism of alcohol-induced effects on neural stem cells and dentate gyrus granule cell loss forms a solid foundation to investigate the differential sensitivity of the adolescent brain to alcohol effects and the dynamic role of both cell death and cell birth mechanisms in neurodegeneration.