Alcohol and Development of the Prefrontal Cortex

描述(申请人提供)：发育中的大脑对包括酒精在内的侮辱特别敏感。虽然胎儿大脑发育和酒精中毒已被广泛研究，但出生后和青春期大脑皮质发育的早期阶段尚未被广泛研究。许多大脑区域都会出现独特的高度环境调节可塑性的“关键期”，其中研究最多的是视皮层。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。人类在青春期和青春期滥用酒精与成年后酗酒的风险增加有关。因此，总体假设是，在出生后大脑发育时期滥用酒精将导致急性毒性，导致成人大脑皮层细胞持续变化，并导致成人行为和成人大脑皮层结构持续变化。这项建议将研究在出生后早期和青春期的不同时期酒精暴露对成年动物的细胞和突触结构、行为和大脑组织结构的影响。 额叶皮质将成为目标，因为它发育较晚，对乙醇毒性敏感。本项目及其相关技术的三个具体目标是：1.用组织化学方法确定酒精在出生后7天和14天以及青春期(PND28-38)对细胞死亡标志物(激活的caspase 3和银染)的影响；以及使用GABA中间神经元和锥体细胞的神经元特异性标志物检测产前治疗后成人额叶皮质结构；2.确定出生后早期和青少年酒精对成人行为的影响，包括工作记忆、学习和反向学习、脉冲前抑制和焦虑测试；3.用磁共振成像(MRI)研究出生后早期和青春期酒精对大脑皮层结构的影响。人类的核磁共振成像发现，大脑皮层区域持续发育到生命的第三十年。尽管神经化学和行为学研究表明，人类和小鼠的大脑发育过程相似，但这一时期的小鼠大脑发育还没有得到很好的研究，尽管时间明显不同。利用结构磁共振成像，我们将测试出生后早期和青春期酒精暴露对成人大脑区域体积的影响。人类青少年通常酗酒，青少年饮酒与酗酒风险增加有关。如果确定青少年大脑具有独特的脆弱性，这可能导致加强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.