Alcohol and Development of the Prefrontal Cortex

酒精与前额皮质的发育

• 批准号: 7755831
• 负责人: Leon Garland Coleman
• 金额: $ 2.95万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-09 至 2012-09-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7755831
• 关键词: Acute; Adolescence; Adolescent; Adult; Aftercare; Age; Alcohol abuse; Alcohol dependence; Alcoholism; Alcohols; Anxiety; Apoptosis; Architecture; Area; Behavior; Behavioral; Biological; Brain; Brain imaging; Brain region; Cell Death; Cell physiology; Cells; Cellular Structures; Cerebrum; Complex; Development; Developmental Process; Dysmorphology; Environment; Ethanol; Ethanol toxicity; Growth; Histocytochemistry; Hour; Human; Inflammation; Intelligence; Interneurons; Lead; Learning; Life; MK801; Magnetic Resonance Imaging; Mus; N-Methylaspartate; Neurons; Parvalbumins; Pathology; Pharmacotherapy; Prefrontal Cortex; Prevention; Public Health; Pyramidal Cells; Reversal Learning; Risk; Short-Term Memory; Silver Staining; Staging; Stress; Structure; Synapses; Techniques; Testing; Time; Toxic effect; Visual Cortex; Weight; Youth; adolescent alcohol abuse; adolescent alcohol exposure; adolescent binge drinking; alcohol effect; alcohol exposure; alcohol sensitivity; base; binge drinking; caspase-3; critical period; fetal; frontal lobe; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; mature animal; neurochemistry; neurotoxic; postnatal; prenatal; prepulse inhibition; underage drinking

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.

描述（由申请人提供）：发育中的大脑对刺激特别敏感，包括乙醇。尽管胎儿大脑发育和酒精毒性已被广泛研究，但产后早期和青少年阶段的大脑皮层大脑发育尚未得到广泛研究。许多大脑区域都存在独特的高环境调节可塑性的“关键时期”，其中研究最多的是视觉皮层。在这些“可塑性关键时期”，发育过程导致持久突触和其他细胞结构和细胞功能的形成。人类在青春期和成年早期酗酒与成年后酗酒的风险增加有关。因此，总体假设是，出生后大脑发育期间酗酒会引起急性毒性，导致成人大脑皮层细胞持续改变，并导致成人行为和成人总体大脑结构持续变化。该提案将研究在出生后早期和青春期的不同时期接触乙醇对成年动物的细胞和突触结构、行为和总体大脑结构的影响。 由于额叶皮质发育较晚且对乙醇毒性敏感，因此将成为攻击目标。该项目的三个具体目标及其相关技术如下： 1. 通过组织化学方法确定乙醇在产后第 7 天和第 14 天以及青春期 (PND28-38) 对治疗后细胞死亡标记物（激活的 caspase 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治疗后的成人额叶皮质结构； 2. 确定产后早期和青少年乙醇对成人行为的影响，包括工作记忆、学习和逆转学习、前脉冲抑制和焦虑的测试； 3. 使用磁共振成像 (MRI) 确定产后早期和青少年时期乙醇对大脑总体结构的影响。人类的磁共振成像发现，皮质区域在生命的第三个十年持续发育。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，但这一时期的小鼠大脑发育尚未得到充分研究。尽管时间明显不同。我们将使用结构 MRI 来测试产后早期和青少年接触乙醇对成人大脑区域体积的影响。人类青少年通常会酗酒，而青少年饮酒会增加酗酒的风险。如果确定青少年大脑具有独特的脆弱性，这可能会导致加强对青少年酗酒的预防和治疗。