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

项目概要/摘要 结合起来，肥胖和吸毒成瘾等可预防的疾病影响了大量的人， 生理需要（例如口渴，饥饿），其激素信号和相关的中央回路， 调节对营养和药物刺激的寻求和消费，因此可能作为 暴饮暴食和毒瘾复发中脑被盖区（VTA）多巴胺神经元和多巴胺释放 伏隔核在强化中发挥着关键作用。这个中脑边缘系统也整合了生理功能， 国家与主要奖励和环境线索，以调整方法和消费。其实，父母 这种竞争性更新的授予确定了自稳态的偏离增强了相性中脑边缘系统， 由预测恢复性刺激的线索诱发的信号传导。它还确定了肠道激素信号 从稳态的偏离集中作用于调节食物和环境中的阶段性中脑边缘信号传导。 毒品奖励外周信号作用于中枢“一级”下丘脑部位（例如穹窿下核 (SFO)弓状核（ARC）），其具有可渗透的血脑屏障。离散种群的调制 的SFO或ARC足以诱导负面影响和调节消费行为，以恢复 以与负强化一致的方式刺激。下丘脑一级神经元 与中脑边缘系统沟通，以加强和偏向接近和完成行为 不明我们假设口渴和饥饿的平行回路通过外侧下丘脑进入腹侧被盖区 区（LHA）食欲素神经元。由于LHA食欲素神经元在吗啡戒断和食欲素释放期间被募集， 受体阻滞剂减少了与吗啡戒断相关的负面影响，我们还假设， 在吗啡戒断期间，一阶口渴和饥饿回路的异常活动是 治疗负面情绪，打破成瘾的循环。虽然下丘脑清楚地发出信号 调节寻求和服用精神兴奋剂的方面，它们在调节对其他类别的 毒品-主要是类阿片-很少受到注意。鉴于肥胖和阿片类药物流行及其共同作用， 发病率，这些都是关键的知识差距，将在这里解决。我们会测量腹侧被盖区多巴胺 在行为大鼠中使用在体纤维光度法测定细胞体活性或延髓核多巴胺释放， 选择性地调节第一和第二级下丘脑神经元。建议的目的是：1） 确定一阶口渴神经元（SFO）调节相性中脑边缘信号传导的机制， 预测水和驱动方法的线索; 2）确定一阶饥饿/饱腹感的机制 神经元（ARC）调节相性中脑边缘信号以预测食物和驱动接近的线索;以及3） 在一级干渴和饥饿神经元水平进行干预，以调节异常的多巴胺信号， 会导致吗啡戒断的负面情绪结果将确定新的治疗方法 治疗动机障碍的目标，包括肥胖和阿片类药物依赖。

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.