RC3 Functional Neuroimaging of Alcoholism vulnerability: gultamate, reward, and

RC3 酒精中毒脆弱性的功能神经影像：谷氨酸、奖励和

• 批准号: 8467659
• 负责人: GODFREY D PEARLSON
• 金额: $ 23.41万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8467659
• 关键词: Affect; Age; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Ally; Anterior; Behavior; Behavioral; Biological Assay; Brain; Clinical; Code; Corpus striatum structure; Cues; DNA; Data; Dependence; Disease; Double-Blind Method; Face; Family; Fathers; First Degree Relative; Functional Magnetic Resonance Imaging; Funding; Genes; Genetic; Genetic Polymorphism; Glutamates; Grant; Image; Impulsivity; Incentives; Individual; Learning; Light; Link; Longitudinal Studies; Measures; Memantine; Modification; Mothers; Motivation; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; National Institute on Alcohol Abuse and Alcoholism; Neurobiology; Nucleus Accumbens; Online Systems; Oral; Outcome; Pathway Analysis; Patient Self-Report; Pattern; Phase; Placebos; Population; Population Study; Process; Proteins; Psychological reinforcement; Punishment; Randomized; Reaction Time; Recording of previous events; Relative (related person); Research; Rewards; Risk; Risk Factors; Series; Signal Transduction; Speed; Stimulus; Study Subject; Sucrose; System; Testing; Therapeutic Intervention; Time; Training; Ventral Striatum; Visual; addiction; alcohol craving; alcohol cue; alcohol misuse; alcohol response; classical conditioning; college; cue reactivity; drinking; drinking behavior; follow-up; member; neural circuit; neuroimaging; neuromechanism; novel; prospective; reinforcer; relating to nervous system; response; reward circuitry; soft drink; translational neuroscience; university student

In CTNA-2, we showed that in a Monetary Incentive Delay (MID) task, FH+ subjects, relative to FH-individuals, had increased engagement of cortico striatal networks when the opportunity for reward presented itself (reward prospect), but reduced activation of this same network when rewards/punishments were delayed (reward anticipation) or when the reward was presented (consummatory reward phase) (see P3). Striatal abnormalities were also seen in FH+ during a Go/No-Go (GNG) task. In CTNA-3, we face the challenge of directly linking the altered cortical-striatal function in FH+ to its underlying neurobiology. Aim #1: The first aim of this project is to determine whether increased NMDA-R function contributes to alterations in cortico-striatal activity associated with FH+ status. Preliminary data (see full project) support the Aim #1's hypothesis by suggesting that memantine 40 mg. p.o. normalizes the deficits in ventral striatal (VS) activation associated with reward anticipation in FH+ individuals but has only modest effects on VS activation in FHN. Aim#2: This aim explores memantine effects on activation of VS and anterior cingulate during GNG. Aim #3: The third project aim is critical to linking the pattern of cortico-striatal functional alterations associated with FH+ to the initial step in the addiction process, Pavlovian Conditioning. To that end, FH+ individuals who complete Aim #1 also will complete alcohol cue reactivity testing during fMRI imaging. Aim #4: This exploratory aim examines a modification of the MID by inclusion of PIT-related stimuli in FH+ compared to FH- subjects. Lastly, these subjects will be college students who will enter a prospective 2-year follow-up supported by a separate NIAAA grant (the "BARCS" study). This follow-up period will enable CTNA to explore the possibility that reward-related activation (MIDT), alcohol Pavlovian conditioning (cue reactivity), and alcohol PIT (assessed via the Core Battery) predict the intensity of drinking over time. DNA will be collected on all study subjects and the impact of polymorphisms in the genes coding for the proteins in figure 6 will be explored via the Genetics Core.

在CTNA-2中，我们表明，在货币激励延迟（中）任务中，FH+相对于FH-个体个人，当获得奖励的机会（奖励前景）时，Cortico纹状体网络的参与度增加了（奖励前景），但在奖励延迟时（奖励预期）（当前的奖励）（奖励的奖励）（奖励3个阶段）（提出了奖励的奖励）（奖励3阶段）（奖励3个阶段）（出现）（奖励3个阶段）（出现）（奖励3阶段）。在GO/No-GO（GNG）任务中，FH+中也发现了纹状体异常。在CTNA-3中，我们面临的挑战是将FH+中的皮质纹状体功能与其潜在的神经生物学联系起来。 AIM＃1：该项目的第一个目的是确定增加的NMDA-R功能是否有助于与FH+状态相关的皮质 - 纹状体活动的改变。初步数据（请参阅完整项目）通过暗示纪念40 mg来支持目标＃1的假设。 P.O.将与FH+个体的奖励预期相关的腹侧纹状体（VS）激活的缺陷归一化，但对FHN中的VS激活只有适度的影响。 AIM＃2：此目标探讨了美容对GNG期间VS激活和前扣带回的影响。 AIM＃3：第三个项目目标对于将与FH+相关的皮质 - 纹状体功能变化的模式与成瘾过程Pavlovian条件的第一步联系起来至关重要。为此，完成AIM＃1的FH+个体还将在fMRI成像期间完成酒精提示反应性测试。 AIM＃4：与FH-受试者相比，该探索性目标通过在FH+中包含与PIT相关的刺激来检查中MID的修饰。 最后，这些学科将是大学生，他们将参加由单独的NIAAA赠款（“ BARCS”研究）支持的前期2年随访。此随访期将使CTNA能够探索与奖励相关的激活（MIDT），酒精帕夫洛维亚调节（提示反应性）和酒精坑（通过核心电池进行评估）预测饮酒强度随时间的可能性。将通过遗传学核心探索DNA对所有研究主题的DNA，并在图6中编码的蛋白质编码的基因中的影响。