Modulation of NAc-DA Signaling by Learning Motivational State and Peptides

描述(申请人提供)：肥胖和毒瘾是影响人口比例高得令人不安的疾病，治疗费用高达数十亿美元，并对我们的医疗保健系统造成越来越大的消耗。导致这些疾病发生的一个因素是寻求奖励的行为。当个人变得肥胖时，他们寻找和消费的食物远远超过卡路里的需要。当个人上瘾时，他们会寻求和消费非营养性药物。中脑边缘系统由腹侧被盖区多巴胺神经元和伏隔核组成，在正常的奖赏寻找行为和包括过度进食和吸毒在内的不适应行为中起重要作用。几十年来，人们已经知道生理状态(饥饿、饱腹感)可以调节寻求奖励的行为。然而，这种情况发生的机制仍不清楚。在这里，将通过在对营养(食物)和非营养(可卡因)的奖励寻求行为期间实时监测中脑边缘信号来解决这一知识差距。这种竞争性更新的父母授权有助于建立中边缘信号的阶段性波动，作为目标导向行为的关键。事实上，在寻求奖赏和奖赏消费后数百毫秒内出现的边缘中信号的阶段性波动，似乎对奖赏导向行为和强化特别重要。这些波动将被记录下来，使用快速扫描循环伏安法来分析多巴胺水平，电生理学来分析单个伏核神经元的放电率。这两种技术都允许将时相信号与清醒、行为正常的大鼠的离散行为事件相关联。这项建议的目的是：i)确定在对食物、可卡因或颅内自我刺激的操作反应中，营养物质的积累如何改变奖赏诱发的边缘相活动，以及碳水化合物的代谢是否对于营养反馈对边缘相信号和奖赏寻求是必需的；ii)确定中枢和腹内被盖区胰高血糖素样肽1(GLP-1)是中枢活跃的饱腹区信号，是否为边缘相信号和奖赏寻求提供负反馈；以及iii)确定中枢和腹内被盖区ghrelin是否为中央活跃的边缘相信号和奖赏寻求提供正反馈。这项工作的意义在于发现了正常和非适应性奖赏寻求背后的新机制。这将为包括肥胖和药物成瘾在内的动机障碍的治疗提供外周和中脑边缘回路的治疗靶点。

DESCRIPTION (provided by applicant): Obesity and drug addiction are diseases that affect a disturbingly large percentage of the population, cost billions of dollars to treat, and represent a increasing drain on our health care system. One factor that contributes to the onset of these diseases is reward seeking behavior. As individuals become obese, they seek and consume food well beyond caloric need. As individuals become addicted, they seek and consume non-nutritive drugs. The mesolimbic system, comprising the ventral tegmental area dopamine neurons and the nucleus accumbens, critically participates in normal reward seeking behavior as well as maladaptive behaviors including the overconsumption of food and drug taking. It has been known for decades that physiological state (hunger, satiety) can modulate reward seeking behavior. However, the mechanisms by which this occurs remain unknown. Here, this gap in knowledge will be addressed by monitoring mesolimbic signaling in real-time during reward seeking behavior towards nutritive (food) and non-nutritive (cocaine, intracranial self-stimulation rewards. The parent grant of this competitive renewal contributed to the establishment of phasic fluctuations in mesolimbic signaling as critical for goal-directed behavior. Indeed, phasic fluctuations in mesolimbic signaling, which occur within hundreds of milliseconds of reward seeking and reward consumption, appear to be especially important for reward-directed behaviors and reinforcement. These fluctuations will be recorded using fast-scan cyclic voltammetry to assay dopamine levels and electrophysiology to assay the firing rates of individual nucleus accumbens neurons. Both techniques allow phasic signals to be correlated with discrete behavioral events in awake, behaving rats. The aims of this proposal are: i) to determine how accumulation of nutrients alters reward-evoked phasic mesolimbic activity during operant responding for food, cocaine or intracranial self-stimulation, and whether metabolism of carbohydrates is necessary for nutrient feedback on phasic mesolimbic signaling and reward seeking; ii) to determine whether central and intra-ventral tegmental area glucagon-like peptide 1 (GLP-1), a centrally active satiety signal, provides negative feedback for phasic mesolimbic signaling and reward seeking; and iii) to determine whether central and intra-ventral tegmental area ghrelin, a centrally active hunger signal, provides positive feedback for phasic mesolimbic signaling and reward seeking. The significance of this work is in the discovery of novel mechanisms underlying normal and maladaptive reward seeking. This will provide therapeutic targets, in both the periphery and within mesolimbic circuitry, for treating disorders of motivatio, including obesity and drug addiction.