Impact of Adolescent Alcohol on Development of the Prefrontal Cortex

青少年酒精对前额皮质发育的影响

• 批准号: 9441965
• 负责人: Mary Jane Skelly
• 金额: $ 5.43万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-13 至 2019-03-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9441965
• 关键词: Impact; Adolescent; Alcohol; Development; Prefrontal

Project Summary Alcohol use disorder is a chronic relapsing disorder that is a significant burden to afflicted individuals and society as a whole. Many adult alcoholics began to drink excessively during adolescence, and this early exposure may result in increased vulnerability to developing a lifelong addiction. The brain continues to mature throughout adolescence, and exposure to alcohol during this critical period may disrupt brain development, thereby predisposing the development of alcohol use disorder. For example, it has been suggested that the development of the medial prefrontal cortex (mPFC), a region critical to the regulation of motivated behaviors, can be adversely affected by cycles of alcohol intoxication and withdrawal during adolescence, and disrupted mPFC output is thought to contribute to the behavioral sequelae characteristic of alcohol use disorder. An understanding of how alcohol disrupts the maturation of the mPFC may therefore prove useful in preventing the transition to alcohol dependence. Toward this goal, the studies proposed in this application will make use of a mouse model of binge-like adolescent ethanol self-administration to identify the time course and behavioral consequences of chronic ethanol intake during this critical developmental period. Our lab has previously shown that adolescent binge-like alcohol intake disrupts the excitability of pyramidal neurons in the prelimbic area that form projections from the mPFC, and that perturbation of currents through hyperpolarization-activated cation channels (HCN channels) may underlie altered mPFC afferent output. Specific Aim 1 will use electrophysiological and immunohistochemical methods to determine the time course of ethanol-related disruption of mPFC HCN channels. Specific Aim 2 will determine whether the hyperpolarization of mPFC projections that arises from this ethanol-related disruption of HCN channels is responsible for the increased ethanol self-administration seen in adult animals with a history of binge-like adolescent intake. The results of these experiments could assist in the identification of novel therapeutic targets for alcohol addiction.

项目概要 酒精使用障碍是一种慢性复发性疾病，对受影响的个人和患者来说是一个重大负担 整个社会。许多成年酗酒者在青春期就开始酗酒，而且很早就开始酗酒。 接触可能会导致更容易患上终生成瘾。大脑继续成熟 整个青春期，在这个关键时期接触酒精可能会扰乱大脑发育， 从而诱发酒精使用障碍的发展。例如，有人建议 内侧前额皮质（mPFC）的发育，该区域对于调节动机行为至关重要， 可能会受到青春期酒精中毒和戒断周期的不利影响，并被破坏 mPFC 输出被认为是造成酒精使用障碍行为后遗症的原因之一。一个 因此，了解酒精如何破坏 mPFC 的成熟可能有助于预防 向酒精依赖的转变。为了实现这一目标，本申请中提出的研究将利用 小鼠模型的暴饮暴食青少年自我注射乙醇以确定时间过程和 在这个关键的发育时期长期摄入乙醇的行为后果。我们实验室有 先前表明，青少年暴饮暴食会破坏大脑中锥体神经元的兴奋性 形成 mPFC 投影的前边缘区域，以及通过的电流扰动 超极化激活的阳离子通道（HCN 通道）可能是改变 mPFC 传入输出的基础。 具体目标 1 将使用电生理学和免疫组织化学方法来确定 乙醇相关的 mPFC HCN 通道破坏。具体目标2将决定是否超极化 由这种与乙醇相关的 HCN 通道中断引起的 mPFC 预测是造成 在有青少年暴饮暴食史的成年动物中观察到乙醇自我给药增加。这 这些实验的结果可以帮助确定酒精成瘾的新治疗靶点。