Alcohol and Development of the Prefrontal Cortex

描述（由申请人提供）：发育中的大脑对包括乙醇在内的损伤特别敏感。虽然胎儿脑发育和酒精毒性已被广泛研究，但出生后早期和青少年阶段的大脑皮质脑发育尚未得到广泛研究。独特的高环境调节可塑性的“关键时期”发生在许多大脑区域，研究最多的是视觉皮层。在这些“可塑性的关键时期”，发育过程导致持续突触和其他细胞结构和细胞功能的形成。人类在青春期和青年期的酒精滥用与成年期酒精中毒的风险增加有关。因此，总的假设是，在出生后大脑发育期间滥用酒精将引起急性毒性，导致成年大脑皮层细胞的持续改变，并导致成年行为和成年大脑结构的持续变化。这项提案将调查乙醇暴露在不同时期的早期出生后的生活和青春期的细胞和突触的架构，行为和大脑结构的成年动物。 额叶皮层由于其发育较晚和对乙醇毒性的敏感性而成为目标。本项目的三个具体目标及其相关技术如下：1。用组织化学方法测定出生后第7天和第14天（PND）以及整个青春期（PND 28 -38）乙醇对处理后细胞死亡标记物（活化的半胱天冬酶3和银染）的影响;并使用GABA中间神经元和锥体细胞的神经元特异性标记物检查产前处理后的成年额叶皮质结构; 2.确定出生后早期和青春期酒精对成人行为的影响，包括工作记忆、学习和逆转学习、前脉冲抑制和焦虑的测试;使用磁共振成像（MRI）确定出生后早期和青少年时期乙醇对大脑结构的影响。人类的磁共振成像发现，大脑皮层区域在生命的第三个十年中仍在继续发育。这一时期的小鼠大脑发育尚未得到很好的研究，尽管神经化学和行为研究表明人类和小鼠的大脑发育过程相似;尽管时间明显不同。使用结构MRI，我们将测试早期出生后和青少年暴露于乙醇对成人脑区域体积的影响。人类青少年通常酗酒，青少年饮酒与酒精中毒的风险增加有关。如果确定青少年大脑具有独特的脆弱性，这可能会导致增加对青少年酗酒的预防和治疗。

DESCRIPTION (provided by applicant): The developing brain is uniquely sensitive to insults, including ethanol. Although fetal brain development and alcohol toxicity have been extensively studied, early postnatal and adolescent stages of cerebral cortical brain development have not been extensively studied. "Critical periods" of unique high environment regulated plasticity occurs for many brain regions with the most studied being visual cortex. During these "critical periods of plasticity", developmental processes result in the formation of persisting synaptic and other cytoarchitecture and cellular function. Human alcohol abuse during adolescence and young adulthood is associated with an increased risk of alcoholism in adulthood. Thus the overall hypothesis is that alcohol abuse during post-natal periods of brain development will cause acute toxicity that results in persistent alterations to adult brain cortical cells and results in persistent changes in adult behavior and adult gross brain structure. This proposal will investigate the effects of ethanol exposure during distinct periods of early postnatal life and adolescence on cellular and synaptic architecture, behavior, and gross brain structure in adult animals. The frontal cortex will be targeted due to its late development and sensitivity to ethanol toxicity. The three specific aims of this project and their associated techniques are as follows: 1. to histochemically determine the effects of ethanol on post-natal days (PND) 7 and 14 as well as through adolescence (PND28-38) on cell death markers (activated caspase 3 and silver stain) just after treatment; and to examine adult frontal cortical structure following prenatal treatment using neuron specific markers for GABA interneurons and pyramidal cells; 2. to determine the effects of early postnatal and adolescent ethanol on adult behaviors, including tests of working memory, learning and reversal learning, prepulse inhibition, and anxiety; and 3. to determine the effects of ethanol during the early postnatal and adolescent periods on gross brain structure using Magnetic Resonance Imaging (MRI). Magnetic resonance imaging in humans has found continued development of cortical regions into the 3rd decade of life. Mouse brain development during this period has not been well studied, although neurochemical and behavioral studies have suggested similar courses of brain development between humans and mice; although the timing is clearly different. Using structural MRI we will test the effects of early postnatal and adolescent exposure of ethanol on adult brain regional volumes. Human adolescents commonly binge drink, and adolescent drinking is associated with increased risk of alcoholism. If it is established that the adolescent brain has unique vulnerability this could lead to increased prevention and treatment of adolescent binge drinking.