UNC-CH NADIA Underage Drinking and Adult Brain Morphology in Rats

描述（由申请人提供）：奖励，情感和行为控制的成熟与青春期和向成年过渡期间额叶和边缘脑区域的形态变化相吻合。我们实验室以前的研究表明，青春期大鼠对乙醇诱导的前脑神经变性和海马神经发生的抑制更为敏感。我们还在成年小鼠中观察到，青少年乙醇暴露减少了前脑和其他几个区域的体积，这是通过MRI确定的。除了MRI体积减少外，组织学测量还表明前脑面积相应减少，胆碱能神经元密度降低。这些病理变化与逆转学习的功能缺陷有关。NADIA联盟的第7项研究将扩展这些研究，以确定青少年酒精暴露的长期后果。本NADIA研究组件-7假设青少年间歇性乙醇（AIE）治疗将改变成人脑区域细胞结构，神经发生，小胶质细胞，星形胶质细胞表型和髓鞘，以及脑区域MRI体积和组织学区域。其他假设是，较高的酒精剂量，年轻人和较长时间的滥用将导致更多的病理，并将反映在弥漫性神经回路反应的压力和乙醇的挑战。进一步假设AIE将改变成年人中神经元活化标志物的应激和酒精诱导。以下4个目的检验假设：目的1将检验AIE改变成人脑神经发生和神经祖细胞干细胞（NPC）的假设。目的2将检验AIE改变成人脑白色物质的假设。目的3将确定AIE是否改变成人脑小胶质细胞和星形胶质细胞。目的4将确定AIE是否改变成人脑神经元对应激或乙醇的反应。拟定研究将使用不同的AIE方案进行，这些方案改变了乙醇暴露的年龄，例如青年-青少年-年轻成人（P25-55）和剂量;即暴饮暴食、重度和中度自我给药。评估AIE后的成年人的认知（巴恩斯迷宫、学习和逆转学习）、情感焦虑行为（高架十字迷宫）、旷场测试（中心时间焦虑-整体运动）和社会互动（焦虑）。组织化学对成人脑细胞结构和组成的研究将与MRI区域体积、DTI结构和行为有关。此外，研究将用乙醇或应激激发成年大鼠，以通过IHC研究神经元活化标志物（例如fos、zif 268、pERK 1/2、pDARPP）的神经回路。预期AIE将具有脑区域特异性效应，AIE治疗的年龄越小，成人脑细胞结构的变化越大。这些研究将确定未成年人饮酒模型是否会导致影响成年人大脑网络和行为的持续结构，细胞和神经元激活反应。

DESCRIPTION (provided by applicant): Maturation of reward, affect and behavioral control coincides with morphological changes in frontal and limbic brain regions during adolescence and the transition to adulthood. Previous studies from our lab have shown that adolescent rats are far more sensitive to ethanol-induced forebrain neurodegeneration and to inhibition of hippocampal neurogenesis. We have also observed in adult mice that adolescent ethanol exposure reduced the volume of the forebrain and several other regions as determined by MRI. In addition to a reduction in MRI volume, histological measurements indicated corresponding reduction of forebrain area and decreased cholinergic neuron density. These pathological changes were associated with functional deficits in reversal learning. This Research Component-7 of the NADIA consortium will extend these studies to determine the long-term consequences of adolescent alcohol exposure. This NADIA Research Component- 7 hypothesizes that adolescent intermittent ethanol (AIE) treatment will alter adult brain regional cellular structure, neurogenesis, microglia, astrocyte phenotypes and myelin, as well as brain regional MRI volumes and histologic areas. Additional hypotheses are that higher alcohol doses, younger individuals and longer periods of abuse will cause more pathology and will be reflected in diffuse neurocircuitry responses to stress and ethanol challenges. It is further hypothesized that AIE will alter stress and alcohol induction of neuronal activation markers in adults. The following 4 Aims test hypotheses: Aim 1 will test the hypothesis that AIE alters adult brain neurogenesis and neuroprogenitor-stem cells (NPC). Aim 2 will test the hypothesis that AIE alters adult brain white matter. Aim 3 will determine if AIE alters adult brain microglia and astrocytes. Aim 4 will determine if AIE alters adult brain neuronal responses to stress or ethanol. The proposed studies will be conducted using different AIE protocols that vary age of ethanol exposure, e.g. youth-adolescent-young adult (P25-55), and dose; i.e. binge, heavy and moderate self-administration. Adults following AIE, are assessed for cognition (Barnes maze, learning and reversal learning), affect-anxiety behaviors (elevated plus maze), open field test (center time anxiety-overall locomotor) and social interaction (anxiety). Histochemistry on adult brain cellular structure and composition will be related to MRI regional volumes, DTI structure and behavior. In addition, studies will challenge adult rats with ethanol or stress to investigate neurocircuitry through IHC for neuronal activation markers (e.g. fos, zif268, pERK1/2, pDARPP). It is expected that AIE will have brain region specific effects with younger ages of AIE treatment inducing larger changes in adult brain cell structure. These studies will determine if models of underage drinking result in persistent structural, cellular, and neuronal activation responses that impact adult brain networks and behavior.