Impact of Adolescent Alcohol on Development of the Prefrontal Cortex

项目摘要 酒精使用障碍是一种慢性复发性障碍，对患有酒精的人和 社会作为一个整体。许多成年酗酒者在青春期就开始过度饮酒，而且这么早 暴露可能会增加患上终身成瘾的风险。大脑继续成熟 在整个青春期，在这一关键时期接触酒精可能会扰乱大脑发育， 从而易患上酒精使用障碍。例如，有人建议， 内侧前额叶皮质(MPFC)的发育，这是调节动机行为的关键区域， 在青春期会受到酒精中毒和戒断的循环的不利影响，并被扰乱 MPFC的输出被认为是酒精使用障碍的行为后遗症的原因之一。一个 因此，了解酒精如何扰乱mPFC的成熟可能被证明有助于预防 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 建立酗酒样青少年酒精自我给药的小鼠模型，以确定时间进程和 在这一关键的发育期，长期摄入酒精的行为后果。我们的实验室有 先前研究表明，青少年酗酒扰乱了锥体神经元的兴奋性。 从mPFC形成投影的初步区域，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。 特定目标1将使用电生理和免疫组织化学方法来确定时间进程 酒精相关的mPFC HCN通道中断。具体目标2将决定超极化是否 这种与酒精有关的HCN通道中断引起的mPFC预测是导致 在有青少年暴饮史的成年动物中，乙醇自我给药增加。这个 这些实验的结果可能有助于确定酒精成瘾的新治疗靶点。

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.