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

描述(申请人提供)：奖赏、情感和行为控制的成熟与青春期和成年过渡期间额叶和边缘脑区的形态变化相吻合。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退行性变和海马神经发生的抑制更加敏感。我们还在成年小鼠身上观察到，青少年酒精暴露减少了前脑和MRI确定的其他几个区域的体积。除了MRI体积的减少，组织学测量还显示前脑面积相应减少，胆碱能神经元密度降低。这些病理改变与反转学习的功能缺陷有关。NADIA联盟的这一研究组成部分-7将扩展这些研究，以确定青少年酒精暴露的长期后果。Nadia Research Component-7假设青少年间歇性酒精(AIE)治疗将改变成人大脑区域细胞结构、神经发生、小胶质细胞、星形胶质细胞表型和髓鞘，以及大脑区域MRI体积和组织学区域。其他假设是，更高的酒精剂量、更年轻的个体和更长的滥用时间将导致更多的病理，并将反映在对压力和酒精挑战的弥漫神经回路反应中。进一步的假设是，AIE将改变应激和酒精对成人神经元激活标志物的诱导。以下4个AIMS将检验假说：AIM 1将检验AIE改变成人脑神经发生和神经前体干细胞(NPC)的假说。目标2将检验AIE改变成人脑白质的假设。目标3将确定AIE是否会改变成人大脑小胶质细胞和星形胶质细胞。目标4将确定AIE是否会改变成人脑神经元对压力或酒精的反应。建议的研究将使用不同的AIE方案进行，不同的酒精暴露年龄，例如青少年-青少年-青年成人(P25-55)，以及剂量；即暴饮暴食、重度和中度自我给药。在AIE之后，对成人进行认知(Barnes迷宫、学习和反向学习)、情感焦虑行为(高空加迷宫)、开放领域测试(中心时间焦虑-整体运动)和社交(焦虑)的评估。成人脑细胞结构和成分的组织化学将与MRI区域体积、DTI结构和行为相关。此外，研究将挑战成年大鼠酒精或应激，以通过IHC研究神经回路以寻找神经元激活标记物(例如FOS、Zif268、pERK1/2、pDARPP)。随着AIE治疗年龄的增加，成人脑细胞结构发生较大的变化，预计AIE将具有脑区特异性效应。这些研究将确定未成年饮酒模型是否会导致持续的结构、细胞和神经元激活反应，从而影响成年人的大脑网络和行为。

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.