Impact of Adolescent Alcohol Exposure on Prefrontal Cortical Function in the Adul

青少年酒精暴露对成人前额皮质功能的影响

• 批准号: 8030692
• 负责人: L Judson Chandler
• 金额: $ 39.55万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-05 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8030692
• 关键词: Adolescence; Adolescent; Adult; Alcohol consumption; Alcohols; Arts; Attention; Behavior; Behavior Control; Behavioral; Consumption; Decision Making; Development; Dopamine; Emotions; Epigenetic Process; Histone Acetylation; Interneurons; Intoxication; Legal; Medial; Methodology; Modeling; Modification; Neurons; Pattern; Pharmaceutical Preparations; Population; Prefrontal Cortex; Procedures; Process; Public Health; Rattus; Research; Risk Behaviors; Risk-Taking; Safety; Short-Term Memory; Testing; Unsafe Sex; Ventral Tegmental Area; adolescent alcohol exposure; age group; alcohol exposure; cognitive function; critical period; flexibility; innovation; multidisciplinary; neuropathology; novel; public health relevance; research study; underage drinking; young adult

DESCRIPTION (provided by applicant): The consumption of alcohol during adolescence and young adulthood is a serious public health problem. In this age group, alcohol is often consumed in large quantities in repeated binge-like episodes that result in serve levels of intoxication. In addition to legal ramifications and concerns with physical safety, these patterns of alcohol consumption appear to adversely impact continued neuromaturation during the transition from adolescence to adulthood. The prefrontal cortex (PFC) controls higher-order cognitive functions such as working-memory, behavioral flexibility, and impulse control (collectively referred to as executive cognitive function). Adolescence represents a critical period of refinement of the neurocircuitry of the PFC that supports maturation of executive cognitive functioning. Deficits in executive cognitive function are associated with loss of control over behavioral processes such as attention and emotion, and with increased engagement in risky behaviors such as unprotected sex and drug-taking. The latter includes a reduced ability to discontinue drug-taking once initiated resulting in escalation in, and loss of control over, consumption. The overarching hypothesis of this research component of the NADIA consortium is that repeated binge-like exposure to alcohol during adolescence produces a neuropathology of the PFC that manifests in the adult as deficits in executive cognitive function and behavioral control. This hypothesis will be tested by an innovative and multidisciplinary set of experiments that utilize state-of the- art methodologies and procedures in a rat model of adolescent intermittent ethanol (AIE) exposure. The overarching hypothesis will be tested by four specific aims that will: 1) Determine the effects of AIE exposure on epigenetic modifications (histone acetylation) in identified populations of excitatory pyramidal and inhibitory interneurons in the medial PFC and dopamine (DA) projection neurons in the ventral tegmental area; 2) Determine the effects of AIE exposure upon DA modulation of excitatory pyramidal and inhibitory GABAergic interneurons in the adult medial PFC; 3) Determine the effects of AIE exposure and re-exposure to alcohol during adulthood on executive cognitive function using tasks that assess working memory, behavioral flexibility, and risk-taking behavior; and 4) Assess the effects of AIE exposure and reexposure to alcohol during adulthood on cognitively modulated synchronous activity and organization of neuronal ensembles in the mPFC. Together, these studies will yield novel and exciting new finding and will significantly advance our understanding of the effect of adolescent alcohol exposure on cognitive function and behavioral control in the adult. PUBLIC HEALTH RELEVANCE: Binge-like consumption of alcohol during adolescence is common and represents a serious public health concern. Adolescence represents a critical period of development of cortical processes that underlie maturation of behavioral control and decision-making. Thus, studies examining how adolescence alcohol consumption results in deficits in these cortical processes that persist well into adulthood are highly significant.

描述（由申请人提供）：青春期和成年早期饮酒是一个严重的公共卫生问题。在这个年龄段，经常会在反复的暴饮暴食中大量饮酒，从而导致中毒程度。除了法律后果和对人身安全的担忧之外，这些饮酒模式似乎还会对从青春期到成年过渡期间的持续神经成熟产生不利影响。前额皮质 (PFC) 控制着高阶认知功能，例如工作记忆、行为灵活性和冲动控制（统称为执行认知功能）。青春期是前额皮质神经回路完善的关键时期，支持执行认知功能的成熟。执行认知功能的缺陷与注意力和情绪等行为过程的失控以及无保护性行为和吸毒等危险行为的增加有关。后者包括一旦开始吸毒就停止吸毒的能力下降，导致吸毒量增加和失去控制。 NADIA 联盟的该研究部分的总体假设是，青春期期间反复酗酒会产生 PFC 的神经病理学，在成人中表现为执行认知功能和行为控制的缺陷。这一假设将通过一组创新的多学科实验进行检验，这些实验利用最先进的方法和程序在青少年间歇性乙醇（AIE）暴露的大鼠模型中进行测试。总体假设将通过四个具体目标进行检验，这些目标将： 1) 确定 AIE 暴露对内侧 PFC 中已识别的兴奋性锥体和抑制性中间神经元群体以及多巴胺 (DA) 投射神经元中表观遗传修饰（组蛋白乙酰化）的影响。腹侧被盖区； 2) 确定 AIE 暴露对成人内侧 PFC 中兴奋性锥体和抑制性 GABA 能中间神经元的 DA 调节的影响； 3) 通过评估工作记忆、行为灵活性和冒险行为的任务，确定成年期间接触 AIE 和再次接触酒精对执行认知功能的影响； 4) 评估成年期间 AIE 暴露和再次暴露于酒精对 mPFC 中认知调节同步活动和神经元群组织的影响。总之，这些研究将产生新颖且令人兴奋的新发现，并将显着增进我们对青少年酒精暴露对成人认知功能和行为控制影响的理解。 公共卫生相关性：青春期酗酒很常见，是一个严重的公共卫生问题。青春期代表了皮质过程发展的关键时期，是行为控制和决策成熟的基础。因此，研究青春期饮酒如何导致这些皮质过程的缺陷持续到成年期是非常重要的。