Alcohol drinking behavior and prefrontal cortex neuron loss during adolescence

描述（由申请人提供）：人类的青春期是一个经常开始使用酒精的时期。不幸的是，这也是一些人发展长期酗酒和酗酒模式的时候。人类和动物研究表明，在青春期，大脑区域，如前额叶皮层（PFC）正在经历突触连接的显着，但正常的变化。突触组织的这些变化在青少年和成人PFC中具有重要意义。2007），我们证明了与成年大鼠相比，青少年内侧PFC（mPFC）中神经元数量的区域和性别特异性减少。酒精可能会改变mPFC从成年到成年的正常变化模式，从而产生一个特别敏感的神经系统。此外，青春期激素可能与酒精在mPFC中的作用相互作用，这可能导致饮酒行为的性别差异。在这里提出的研究中，我们将使用动物模型来探索青春期酒精暴露对mPFC和成年后酒精的操作性自我管理的影响。这将通过以下方式实现：（1）研究青春期的酒精暴露是否会改变大鼠mPFC中神经元数量的减少，以及性腺激素是否有助于酒精的影响;（2）研究青春期的酒精暴露是否会改变成年后的饮酒行为，以及性别和激素状态是否会产生影响。根据性别（雄性或雌性）、激素状态（完整或青春期前性腺切除术）和青少年酒精暴露（生理盐水或3.0 g/kg乙醇），将大鼠分为8个不同的组（n = 10/组）。成年后（PND 90），将对大鼠实施安乐死，以切除脑组织并随后对mPFC中的神经元数量进行体视学分析（目标1），或者将对大鼠进行开始酒精操作性自我给药训练（目标2）。最终，这些研究中获得的信息将帮助我们了解酒精引起的大脑变化是否是开始饮酒的人酗酒率高的一个因素。

DESCRIPTION (provided by applicant): Adolescence in humans is a period of life when alcohol use is often initiated. Unfortunately, it is also a time when some individuals develop long-lasting patterns of alcohol abuse and alcoholism. Human and animal studies have revealed that during adolescence, brain areas such as the prefrontal cortex (PFC) are undergoing significant, yet normal, changes in synaptic connectivity. These changes in synaptic organization have important implications in the adolescent and adult PFC. For example, in a recent report (Markam et al., 2007), we demonstrated region- and sex-specific decreases in the number of neurons in the medial PFC (mPFC) of adolescent compared to adult rats. It is possible that alcohol alters these normal patterns of adolescent-to adult changes in mPFC and thereby produces a particularly susceptible nervous system. Furthermore, pubertal hormones may interact with alcohol's effects in the mPFC, and this might contribute to sex differences in drinking behavior. In the research proposed here, we will use animal models to explore the effects of alcohol exposure during adolescence on the mPFC and on the operant self-administration of alcohol in adulthood. This will be accomplished by: (1) examining whether alcohol exposure during adolescence alters decreases in neuron number in the rat mPFC and if gonadal hormones contribute to alcohol's effects; and (2) investigate whether alcohol exposure during adolescence alters alcohol drinking behavior in adulthood and if there is an influence of sex and hormonal status. Rats will be divided into eight different groups (n = 10/group) based on sex (male or female), hormone status (intact or pre-pubertal gonadectomy), and adolescent exposure to alcohol (saline or 3.0 g/kg ethanol). As adults (PND 90), rats will be either euthanized for brain removal and subsequent stereological analysis of the number of neurons in the mPFC (Aim 1) or they will begin training for operant self-administration of alcohol (Aim 2). Ultimately, the information learned in these studies will help us understand if alcohol-induced brain changes are a contributing factor to the high rates of alcoholism in individuals who begin drinking at an early age.