Neurogenesis and neurodegeneration in adolescent binge alcohol exposure

描述（由申请人提供）：青春期是许多人开始尝试酒精的时候。酒精滥用和酒精依赖，统称为酒精使用障碍，约6%的青少年被诊断出，并导致显着的神经心理和/或认知缺陷。目前，多达一半的高中生可能饮酒，其中高达70%的学生是酗酒者。考虑到酗酒是预测酒精脑损伤的因素之一，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，青少年酒精使用障碍的海马体积减少。这一发现证实了动物模型中的行为和神经生理学研究，即青少年海马体是酒精的目标。然而，没有人研究过酒精是否直接导致青春期大鼠的神经退行性变或细胞或神经元减少的基本机制。最近发现神经干细胞参与神经发生和海马结构的形成，提示了酒精诱导的神经退行性变的一种新的潜在机制 神经变性因此，本申请将测试总体假设，即青春期大鼠的酗酒暴露会改变神经干细胞和神经发生，从而产生神经变性。三个具体目标将通过以下方式在青少年酒精使用障碍的体内大鼠模型中解决该假设：（1）研究青少年酗酒给药对神经发生组分的影响，（2）确定酒精中毒抑制神经干细胞增殖的机制和（3）评估神经发生的变化是否与神经变性有关（细胞净减少）。在每一个目标，重要的问题，关于酒精剂量或持续时间的贡献，改变神经发生的组成部分和细胞死亡的贡献将进行调查。了解酒精对神经干细胞和齿状回颗粒细胞损失的影响机制，为研究青少年大脑对酒精影响的不同敏感性以及细胞死亡和细胞出生机制在神经变性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.