Effects of adolescent alcohol exposure on functional brain connectivity

摘要 这是一份申请导师研究科学家发展奖(K01)以支持职业生涯的申请书 发展玛格丽特·布罗德沃特博士成为独立的学术研究科学家。候选人是一位 具有较强的行为酒精药理学研究背景的早期研究人员，相对 核磁共振成像(MRI)领域的新技术。申请者的职业和研究培训将是 由一个强大的指导团队监督，并得到对候选人 职业发展。这份建议书中概述的培训将使应聘者能够培养成功的、 生产性研究实验室，将走在酒精研究的前沿，使用功能连接磁共振 (FcMRI)。在人类和啮齿动物中，功能连通性可以通过相关的磁共振成像来评估 血氧水平依赖(BOLD)信号的波动，这是神经活动的替代标志 大脑区域。拟议的研究将使用这一工具来检查青少年酒精暴露对 大脑。青春期饮酒很常见，早年就开始饮酒与此有关 随着后来酒精使用障碍的发展。青春期长期饮酒可能导致营养不良 前额叶皮质(PFC)对皮质下结构的抑制性、自上而下的控制，可能 导致强迫性和僵化的行为，通常见于成瘾。事实上，前额叶皮质 (PFC)在青春期尤其容易受到酒精的影响，青春期是大脑皮质发育的时期 成熟；然而，目前尚不清楚青少年如何影响与其他大脑区域的PFC连接 酒精暴露。这项提议的主要假设是青少年接触酒精将 改变PFC连接的成熟，导致PFC功能连接和 成年后对急性酒精挑战的反应发生变化。这些结果将为正在进行的工作提供参考 来自美国国立卫生研究院的研究计划评估了青少年饮酒对人类的影响，并最终 将有助于我们理解成瘾易感性的潜在机制，以确定目标 治疗性干预和逆转。

ABSTRACT This is an application for a Mentored Research Scientist Development Award (K01) to support the career development of Dr. Margaret Broadwater as an independent academic research scientist. The candidate is an early stage investigator with a strong background in behavioral alcohol pharmacology studies and is relatively new to the field of magnetic resonance imaging (MRI). The applicant's career and research training will be overseen by a strong mentoring team and supported by strong institutional commitment to the candidate's career development. The training outlined in this proposal will allow the candidate to develop a successful, productive research laboratory that will be at the forefront of alcohol research using functional connectivity MRI (fcMRI) in rodents. In humans and rodents, functional connectivity can be assessed with MRI by correlating fluctuations in blood-oxygen-level-dependent (BOLD) signal, a surrogate marker of neural activity, between brain regions. The proposed studies will use this tool to examine the effects of adolescent alcohol exposure on brain. Alcohol use during adolescence is common and initiation of alcohol use at an early age is associated with development of later alcohol use disorders. Chronic alcohol use during adolescence may result in deficits of inhibitory, top-down control of the prefrontal cortex (PFC) on subcortical brain structures, possibly contributing to compulsive and inflexible behavior typically seen in addiction. Indeed, the prefrontal cortex (PFC) is particularly vulnerable to alcohol use during adolescence, the developmental period of cortical maturation; however, it is unknown how PFC connectivity to other brain regions may be affected by adolescent alcohol exposure. The overarching hypothesis of this proposal is that adolescent alcohol exposure will alter maturation of PFC connectivity, leading to persistent deficits in PFC functional connectivity and altered responding to acute alcohol challenge in adulthood. These results will be informative for ongoing research initiatives from the NIH assessing consequences of adolescent alcohol use in humans, and ultimately will aid in our understanding of potential mechanisms for addiction vulnerability to identify targets for therapeutic intervention and reversal.