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

ADHD 以及青少年饮酒对认知和行为的影响

基本信息

  • 批准号:
    10812071
  • 负责人:
  • 金额:
    $ 33.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-20 至 2028-06-30
  • 项目状态:
    未结题

项目摘要

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.
项目概要_ 注意缺陷多动障碍(ADHD)是一种高度遗传的神经发育疾病, 注意力不集中、过度活跃和冲动。患有ADHD的人有更高的成瘾风险 青少年时期的行为,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 共患病的风险,并共享几个风险相关的基因,推断一个共同的潜在内表型。 对ADHD患者的神经影像学研究表明,大脑成熟延迟,特别是在额叶 皮层青少年时期大量饮酒也会扰乱额叶皮层的发育, 失去灰质。因此,ADHD很可能因青春期大量饮酒而加剧, 在成年期持续存在ADHD和AUD症状。尽管ADHD的患病率很高, 患有共病的AUD,我们对ADHD易感性和青少年酒精的影响知之甚少 对额叶皮层功能的影响为了更好地了解ADHD的神经生物学基础, 认知功能障碍与青少年饮酒之间的关系,我们将评估 认知控制和酒精自我管理在一个突出的小鼠遗传模型的多动症,Lphn3 敲除小鼠。Latrophillin 3(LPHN 3)是一种突触细胞粘附G蛋白偶联受体(GPCR), 参与形成和维持突触。LPHN3中的功能丧失变体具有强烈的 与ADHD的遗传关联,并已被证明是发展AUD的重要风险因素。我们 提出了一个两次打击模型,其中ADHD症状的严重程度可能会因青少年酗酒而恶化, 促进成年后大量饮酒。通过关注已知的额叶皮质丘脑(CT)回路, 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损失的影响。在本提案的目标1中,我们将检验以下假设: 额叶皮层Lphn3基因缺失导致谷氨酸神经传递减少, 使用离体电生理学,青春期的酗酒会加剧这种效应, 额叶皮质内特定亚群的棘密度测量。在目标2中,我们将测试 假设Lphn 3和青少年饮酒会对认知控制产生负面影响,并且 额叶皮层中的特定神经回路调节这些缺陷。在目标3中,我们将检验以下假设: LPHN3缺失和青少年饮酒增强了 酒精在正面CT电路的方式。这些研究的结果将提供有关 酒精与ADHD的相互作用,并可能揭示ADHD问题饮酒的新干预措施 个体

项目成果

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Michael Charles Salling其他文献

Michael Charles Salling的其他文献

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{{ truncateString('Michael Charles Salling', 18)}}的其他基金

Prefrontal Pathways Engaged in Excessive Alcohol Consumption
前额叶通路参与过量饮酒
  • 批准号:
    10363686
  • 财政年份:
    2020
  • 资助金额:
    $ 33.75万
  • 项目类别:
Prefrontal Pathways Engaged in Excessive Alcohol Consumption
前额叶通路参与过量饮酒
  • 批准号:
    10038568
  • 财政年份:
    2018
  • 资助金额:
    $ 33.75万
  • 项目类别:
Prefrontal Pathways Engaged in Excessive Alcohol Consumption
前额叶通路参与过量饮酒
  • 批准号:
    9180506
  • 财政年份:
    2018
  • 资助金额:
    $ 33.75万
  • 项目类别:
Alcohol and inhibition in the prefrontal cortex
酒精和前额皮质的抑制
  • 批准号:
    8457850
  • 财政年份:
    2012
  • 资助金额:
    $ 33.75万
  • 项目类别:
Alcohol and inhibition in the prefrontal cortex
酒精和前额皮质的抑制
  • 批准号:
    8549688
  • 财政年份:
    2012
  • 资助金额:
    $ 33.75万
  • 项目类别:
Role of CAMKII in ethanol self-administration
CAMKII 在乙醇自我给药中的作用
  • 批准号:
    7810438
  • 财政年份:
    2009
  • 资助金额:
    $ 33.75万
  • 项目类别:

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食欲素和瘦素对 VTA 中进食和成瘾行为的调节
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CBP 乙酰转移酶在成瘾行为中的作用
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CBP Acetyltransferase Function in Addictive Behavior
CBP 乙酰转移酶在成瘾行为中的作用
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