Modulation of Nac-DA Signaling by Learning, Motivational State and Peptides

项目摘要/摘要 肥胖症和毒瘾这两种可预防的疾病加在一起，影响着大量的人和 治疗花费了数十亿美元。生理需求(如口渴、饥饿)，其荷尔蒙信号和相关的中枢回路， 调节对营养和药物刺激物的寻求和消费，因此可能成为 暴饮暴食和药物复发。大鼠中脑腹侧被盖区多巴胺神经元与多巴胺释放 伏隔核在强化中起着关键作用。这一中边缘系统还整合了生理 国家以主要的奖励和环境线索来调整方法和消费。事实上，父母 这种竞争性更新的授予决定了偏离动态平衡会增强中边缘相 由预示恢复性刺激的线索所唤起的信号。它还确定了胃肠激素信号 动态平衡的偏离在两种食物的环境中起着中心作用，以调节中间边缘信号的时相 和毒品奖励。外周信号作用于中央“一级”下丘脑部位(例如穹隆下核 (SFO)，弓状核(ARC))，具有可渗透的血脑屏障。离散总体的调制 SFO或ARC足以引发负面情绪并调节恢复性消费行为 以与负面强化一致的方式进行刺激。一阶下丘脑神经元是如何 与中边缘系统沟通以加强和偏向接近和完善行为 是未知的。我们假设口渴和饥饿的平行回路通过外侧下丘脑进入VTA 面积(LHA)食欲素神经元。在吗啡戒断和增食欲素过程中，LHA增食欲素神经元被招募 受体阻断减少了与吗啡戒断相关的负面影响，我们还假设 在吗啡戒断过程中，一级口渴和饥饿环路的异常活动是治疗 治疗负面情绪，打破成瘾循环。虽然下丘脑的信号很清楚 调节精神刺激剂寻求和获取的各个方面，它们在调节对其他类别的反应中的作用 毒品--主要是阿片类药物--几乎没有受到关注。鉴于肥胖和阿片类药物的流行及其共同 关于发病率，这些都是知识方面的严重差距，将在这里加以解决。我们将测量VTA多巴胺 用纤维分光光度法检测行为大鼠的胞体活动或伏隔核多巴胺释放 选择性地调节下丘脑一阶和二阶神经元。这项建议的目的是：1) 确定一阶口渴神经元(SFO)调制中脑边缘相信号的机制 预测水分和驱动接近的线索；2)确定一阶饥饿/饱腹感的机制 神经元(ARC)调制相位中脑边缘信号，以预测食物和驾驶方法的线索；以及3) 在一级干渴和饥饿神经元水平上进行干预，以调节异常的多巴胺信号 导致吗啡戒断的负面情绪状态。结果将确定新的治疗方法 治疗动机障碍的目标，包括肥胖和阿片依赖。

Project Summary/Abstract Combined, the preventable diseases of obesity and drug addiction impact an enormous number of people and cost billions to treat. Physiological need (e.g. thirst, hunger), its hormonal signals and related central circuits, modulate seeking for and consumption of both nutritive and drug stimuli and thus may serve as risk factors for overeating and drug relapse. Ventral tegmental area (VTA) dopamine neurons and dopamine release in the nucleus accumbens play critical roles in reinforcement. This mesolimbic system also integrates physiological state with primary reward and environmental cues to tune approach and consumption. Indeed, the parent grant of this competitive renewal determined that deviations from homeostasis potentiate phasic mesolimbic signaling evoked by cues predictive of restorative stimuli. It also determined that gut hormones signaling deviations from homeostasis act centrally to modulate phasic mesolimbic signaling in the context of both food and drug reward. Peripheral signals act on central “first order” hypothalamic sites (e.g. subfornical nucleus (SFO), arcuate nucleus (ARC)) that have a permeable blood-brain barrier. Modulation of discrete populations of the SFO or ARC is sufficient to induce negative affect and modulate consummatory behavior for restorative stimuli in a manner consistent with negative reinforcement. How first order hypothalamic neurons communicate with the mesolimbic system for reinforcement and to bias approach and consummatory behavior is unknown. We hypothesize that parallel circuits for thirst and hunger access the VTA via lateral hypothalamic area (LHA) orexin neurons. As LHA orexin neurons are recruited during morphine withdrawal and orexin receptor blockade reduces negative affect associated with morphine withdrawal, we also hypothesize that aberrant activity in first order thirst and hunger circuits during morphine withdrawal are excellent targets for the treatment of negative affect and to break the cycle of addiction. While hypothalamic signals clearly modulate aspects of psychostimulant seeking and taking, their role in modulating responses to other classes of drugs – chiefly opioids – has received little attention. In light of the obesity and opioid epidemics and their co- morbidity, these are critical gaps in knowledge which will be addressed here. We will measure VTA dopamine cell body activity or nucleus accumbens dopamine release using in vivo fiber photometry in behaving rats while selectively modulating first and second order hypothalamic neurons. The aims of the proposal are: 1) to determine the mechanism by which first order thirst neurons (SFO) modulate phasic mesolimbic signaling to cues that predict water and drive approach; 2) to determine the mechanism by which first order hunger/satiety neurons (ARC) modulate phasic mesolimbic signaling to cues that predict food and drive approach; and 3) to intervene at the level of first order thirst and hunger neurons to modulate the aberrant dopamine signaling that contributes to the negative affective state of morphine withdrawal. Results will identify novel therapeutic targets for treating disorders of motivation, including obesity and opioid dependence.