ADHD and the influence of adolescent alcohol drinking on cognition and behavior

项目Summary_________________________________________________________________________ 注意缺陷多动障碍(ADHD)是一种高度遗传性的神经发育疾病，其特征是 由于注意力不集中、多动症和冲动。患有ADHD的人患上瘾的风险更高 青春期的行为，包括过度饮酒，更有可能发展为 酒精使用障碍(AUD)。流行病学和遗传学研究表明，ADHD和AUD的发病率很高 并共享几个风险相关基因，从而推断出共同的潜在内表型。 ADHD患者的神经成像研究显示大脑成熟延迟，特别是在额叶 大脑皮层。青春期大量饮酒也会扰乱额叶皮质的发育，导致加速 灰质丢失。因此，青春期大量饮酒很可能会加剧ADHD， 在成年后延续ADHD和AUD症状。尽管ADHD患者的高患病率 患有ADHD，我们对ADHD的易感性和青少年酒精的影响知之甚少 暴露于额叶皮质功能。为了更好地了解ADHD的潜在神经生物学以及 认知功能障碍与青少年饮酒之间的关系，我们将评估 ADHD显著遗传模型Lphn3的认知控制和酒精自我给药 基因敲除老鼠。拉特罗西林3(LPHN3)是一种突触细胞黏附G蛋白偶联受体 参与谷氨酸能突触的形成和维持。LPHN3中功能变异的丢失有很强的 基因与ADHD有关，并已被证明是发展为AUD的一个重要风险因素。我们 提出一个两次打击模型，在该模型中，青少年酗酒和酗酒会加剧ADHD症状的严重性 促进成年后大量饮酒。通过关注已知的额叶皮质丘脑(CT)电路 为了调节注意力、工作记忆和冲动，我们可以评估特定的神经机制 受青少年酒精和Lphn3丢失的影响。在本提案的目标1中，我们将检验以下假设 额叶皮质Lphn3基因缺失会导致谷氨酸神经传递减少， 在青春期大量饮酒加剧了这种影响，使用体外电生理学和 额叶皮质内特定亚群的脊柱密度测量。在目标2中，我们将测试 假设Lphn3和青少年饮酒对认知控制有负面影响 额叶皮质中特定的神经回路调节这些缺陷。在目标3中，我们将检验假设 Lphn3缺失和青少年饮酒增强了Lphn3的增强和激励特性 酒精以额部CT巡回方式。这些研究的结果将提供关于 酒精与ADHD的相互作用可能揭示ADHD中有问题的饮酒的新干预措施 个人。

Project Summary_________________________________________________________________________ Attention deficit hyperactivity disorder (ADHD) a highly heritable neurodevelopmental condition characterized by inattentiveness, hyperactivity, and impulsivity. Individuals with ADHD are at a higher risk for addictive behavior during adolescence including excessive alcohol consumption and are more likely to developing an alcohol use disorder (AUD). Epidemiological and genetic studies indicate that ADHD and AUD have high rates of comorbidity and share several risk-associated genes, inferring a common underlying endophenotype. Neuroimaging studies of individuals with ADHD demonstrate delayed brain maturation particularly in the frontal cortex. Heavy drinking during adolescence also disrupts frontal cortex development, leading to accelerated loss of grey matter. Thus, it is likely that ADHD is likely exacerbated by heavy alcohol use during adolescence, perpetuating ADHD and AUD symptoms in adulthood. Despite the high prevalence of ADHD individuals that suffer from comorbid AUD, we know very little about ADHD predisposition and the impact of adolescent alcohol exposure on frontal cortex function. To better understand the underlying neurobiology of ADHD as well as the relationship between cognitive dysfunction and adolescent alcohol consumption, we will evaluate measures of cognitive control and alcohol self-administration in a prominent mouse genetic model of ADHD, the Lphn3 knockout mouse. Latrophillin 3 (LPHN3) is a synaptic cell adhesion G-protein coupled receptor (GPCR) involved in forming and maintaining glutamatergic synapses. Loss of function variants in LPHN3 have a strong genetic association with ADHD and have been shown to be a significant risk factor for developing an AUD. We propose a two hit model, where ADHD symptom severity can be worsened by adolescent binge drinking and promote heavy alcohol consumption in adulthood. By focusing on frontal corticothalamic (CT) circuitry known to mediate attention, working memory and impulsivity, we can evaluate the specific neural mechanisms affected by adolescent alcohol and loss of Lphn3. In Aim 1 of this proposal, we will test the hypothesis that genetic deletion of Lphn3 in the frontal cortex causes reductions in glutamate neurotransmission and that binge-like alcohol consumption during adolescence exacerbates this effect using ex vivo electrophysiology and spine density measurements of specific subpopulations within frontal cortex. In Aim 2, we will test the hypothesis that Lphn3 and adolescent alcohol consumption negatively affects cognitive control and that specific neural circuits in the frontal cortex regulate these deficits. In Aim 3, we will test the hypothesis that Lphn3 deletion and adolescent alcohol consumption potentiate the reinforcing and motivational properties of alcohol in a frontal CT circuit manner. Results from these studies will provide valuable information on the interactions of alcohol with ADHD and potentially reveal novel interventions for problematic drinking in ADHD individuals.