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

肥胖和药物成瘾是影响令人不安的大比例人口的疾病，治疗费用高达数十亿美元，并代表着我们的医疗保健系统的日益枯竭。导致这些疾病发作的一个因素是寻求奖励的行为。当个体变得肥胖时，他们寻求和消耗的食物远远超过热量需求。当人们上瘾时，他们会寻求和消费非营养性药物。中脑边缘系统，包括腹侧被盖区多巴胺神经元和丘脑核，关键地参与正常的奖励寻求行为以及适应不良行为，包括过度消费食物和药物服用。几十年来，人们已经知道生理状态（饥饿，饱腹感）可以调节奖励寻求行为。然而，这种情况发生的机制仍然未知。在这里，将通过在对营养（食物）和非营养（可卡因、颅内自我刺激奖励）的奖励寻求行为期间实时监测中脑边缘信号来解决这种知识差距。这种竞争性更新的父母补助金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，中脑边缘信号的阶段性波动，发生在奖励寻求和奖励消费的数百毫秒内，似乎对奖励导向行为和强化特别重要。将使用快速扫描循环伏安法记录这些波动，以测定多巴胺水平，并使用电生理学测定单个丘脑核神经元的放电率。这两种技术都允许相位信号与清醒的行为大鼠中的离散行为事件相关。该建议的目的是：i）确定在对食物、可卡因或颅内自我刺激的操作性反应期间，营养物质的积累如何改变奖励诱发的阶段性中脑边缘活动，以及碳水化合物的代谢对于阶段性中脑边缘信号传导和奖励寻求的营养反馈是否是必要的; ii）确定中枢和腹侧被盖区胰高血糖素样肽1（GLP-1）（一种中枢活性饱腹感信号）是否为阶段性中脑边缘信号传导和奖赏寻求提供负反馈;和iii）确定中枢和腹侧被盖区ghrelin（一种中枢活性饥饿信号）是否为阶段性中脑边缘信号传导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适应不良的奖励寻求的新机制。这将在外周和中脑边缘回路中提供治疗靶点，用于治疗动力障碍，包括肥胖和药物成瘾。

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.