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

描述（由申请人提供）：肥胖和药物成瘾是影响大量人口的疾病，令人不安，花费数十亿美元用于治疗，并代表我们的医疗保健系统日益消耗。导致这些疾病发生的一个因素是寻求奖励的行为。当个体变得肥胖时，他们会寻找和消耗远远超出热量需求的食物。当人们上瘾时，他们会寻找并消费非营养性药物。由腹侧被盖区多巴胺神经元和伏隔核组成的中边缘系统，在正常的寻求奖励行为以及过度进食和吸毒等适应不良行为中发挥着重要作用。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，发生这种情况的机制仍然未知。在这里，这种知识上的差距将通过实时监测中脑边缘信号来解决对营养（食物）和非营养（可卡因，颅内自我刺激奖励）的奖励寻求行为。这种竞争性更新的母体授予有助于建立中脑边缘信号的阶段性波动，这对目标导向行为至关重要。实际上，中脑边缘信号的阶段性波动（发生在寻求奖励和消耗奖励的数百毫秒内）似乎对奖励导向行为和强化尤为重要。这些波动将用快速扫描循环伏安法记录下来，以测定多巴胺水平和电生理学来测定单个伏隔核神经元的放电率。这两种技术都可以将相位信号与清醒、行为正常的大鼠的离散行为事件联系起来。本研究的目的是：1)确定在食物、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励诱发的中脑边缘活动，以及碳水化合物的代谢是否对中脑边缘信号和奖励寻求的营养反馈是必要的；ii)确定中央和腹侧被盖区胰高血糖素样肽1 (GLP-1)，一种中枢活跃的饱腹感信号，是否为阶段性中脑边缘信号和奖励寻求提供负反馈；iii)确定中央和腹侧被盖区胃饥饿素（中枢活跃的饥饿信号）是否为阶段性中脑边缘信号和奖励寻求提供正反馈。这项工作的意义在于发现了正常和不适应奖励寻求的新机制。这将为治疗动机障碍，包括肥胖和吸毒成瘾，在外围和中脑边缘回路内提供治疗靶点。

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.