Adult neurobiology following adolescent drinking

描述(申请人提供)：奖赏、情感和行为控制的成熟与从青春期到成年期的额叶皮质和边缘脑区的形态变化相吻合。青春期饮酒非常普遍，但其对成熟期的影响目前尚不清楚。我们实验室以前的研究表明，青春期大鼠比成年大鼠对乙醇诱导的神经退行性变和海马神经发生抑制更敏感。青春期狂饮酒精暴露的小鼠被证明减少了前脑体积和基底核中的胆碱能细胞数量，这与Morris水迷宫上的反向学习障碍有关。尽管酗酒在青春期很常见，但目前尚不清楚酒精暴露是否会导致大脑形态的持续变化。此外，目前尚不清楚青春期酗酒是否会增加成年后患上精神病理学的可能性。这项博士后研究资助假设青少年间歇性酒精(AIE)将持续改变额叶皮质和边缘系统的细胞和形态成熟，最终导致成年人认知和情感功能的改变。AIE范式将被用于以下三个目标：目的1.检验AIE导致青春期大脑形态持续变化并持续到成年的假设。目的2.验证青春期间歇性乙醇暴露改变青春期和成人脑细胞组成和神经发生的假说。目的3.验证青春期间歇性酒精(AIE)会导致神经认知功能改变的假设，这种改变在成年后会很明显。在AIE治疗后，神经成像将用于评估青春期(P56)和成年(P80)大鼠(目标1)的大脑完整性、皮质厚度、白质束和区域体积。免疫组织化学将用于评估青少年和成人脑神经元/神经胶质细胞的组成和神经发生(目标2)。暴露于AIE的成年大鼠将接受认知(Barnes迷宫、空间和反转学习)或情绪行为组合(强迫游泳、开阔场地、社会互动、高架加码迷宫[Aim3])的评估。创新的培训方法包括神经成像(Styner和Oguz)、免疫组织化学(CROWS)和行为评估(CROWS)领域专家的指导和指导，以及出席课程和研讨会，将能够深入评估青少年酗酒对成年后大脑成熟和功能的有害影响。事实上，青春期酒精暴露后行为、形态和脑组织学的持续变化可能会改变人们对未成年人饮酒的态度，并发现成人大脑病理和精神疾病的新病因学机制。 与公共健康相关：青少年饮酒是一个主要的公共健康问题，对美国的医疗保健具有潜在的长期影响。青春期的特点是大脑发育和成熟。由于酒精对青春期大脑功能的影响与成年人不同，因此确定在酒精暴露期间 这一成熟期会带来持续的大脑变化，这种变化会一直持续到成年。

DESCRIPTION (provided by applicant): Maturation of reward, affect, and behavioral control coincides with morphological changes in the frontal cortex and limbic brain regions during the transition from adolescence to adulthood. Alcohol consumption during adolescence is highly prevalent, but its impact on maturation is currently unknown. Previous studies from our laboratory have shown that adolescent rats are far more sensitive to ethanol-induced neurodegeneration and inhibition of hippocampal neurogenesis than adults. Adolescent binge ethanol exposure in mice was demonstrated to reduce forebrain volume and cholinergic cell populations in the nucleus basalis that was associated with reversal learning impairment on the Morris Water maze. Although binge drinking is common during adolescence, it is unknown whether alcohol exposure results in persistent changes to brain morphology. Furthermore, it is unknown if binge drinking during adolescence increases the likelihood of developing psychopathology in adulthood. This Postdoctoral Fellowship grant hypothesizes that adolescent intermittent ethanol (AIE) will persistently alter both cellular and morphological maturation of th frontal cortex and limbic system, which will culminate in altered adult cognitive and emotive function. The AIE paradigm will be used in the following 3 Aims: Aim 1. Test the hypothesis that AIE induces persistent changes to adolescent brain morphology that continue into adulthood. Aim 2. Test the hypothesis that adolescent intermittent ethanol (AIE) exposure alters adolescent and adult brain cellular composition and neurogenesis. Aim 3. Test the hypothesis that adolescent intermittent ethanol (AIE) will result in alterations to neurocognitive function that wil be evident in adulthood. Following AIE treatment, neuroimaging will be used to assess brain integrity, cortical thickness, white matter tracts, and regional volumes in adolescent (P56) and adult (P80) rats (Aim 1). Immunohistochemistry will be performed to assess adolescent and adult brain neuronal/glial composition and neurogenesis (Aim 2). Adult rats exposed to AIE will be assessed on a measure of cognition (Barnes maze, spatial and reversal learning) or an emotive behavioral battery (forced swim, open-field, social interaction, elevated plus-maze [Aim3]). The innovative training approach, which involves guidance and instruction from experts in the field of neuroimaging (Styner and Oguz), immunohistochemistry (Crews), and behavioral assessment (Crews) as well as attendance of courses and seminars, will allow for an in depth assessment of the detrimental effects of adolescent alcohol abuse on brain maturation and function in adulthood. Indeed, persistent alterations in behavior, morphology, and brain histology following adolescent alcohol exposure could change attitudes regarding underage drinking and discover new etiological mechanisms of adult brain pathology and mental illness. PUBLIC HEALTH RELEVANCE: Adolescent use of alcohol represents a major public health concern with potential long-lasting impact on health care in the U.S. The adolescent period is characterized by considerable brain development and maturation. Since alcohol affects adolescent brain function differently than adults, it is imperative to determine if exposure during this maturational period confers persistent brain changes that continue into adulthood.