Neural Mechanisms of Adaptive Reward Seeking and Salt Appetite

适应性奖励寻求和盐食欲的神经机制

• 批准号: 9244066
• 负责人: Stephen Chang
• 金额: $ 5.92万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9244066
• 关键词: Affect; Attenuated; Behavior; Behavioral; Behavioral Paradigm; Brain; Clinical; Compulsive Behavior; Cues; Decision Making; Desire for food; Development; Disease; Dopamine; Employee Strikes; Exposure to; Food; Foundations; Functional disorder; Globus Pallidus; Goals; Human; Intervention; Knowledge; Lead; Learning; Measures; Memory; Mental Depression; Modeling; Motivation; Neuronal Dysfunction; Neurons; Nucleus Accumbens; Obesity; Pathway interactions; Pattern; Pharmaceutical Preparations; Process; Property; Psychological reinforcement; Rattus; Reaction; Research; Rewards; Rodent; Role; Sodium; Sodium Chloride; Stress; Sucrose; System; Taste Perception; Techniques; Testing; Therapeutic Intervention; Time; Transgenic Organisms; Update; Ventral Tegmental Area; Viral Vector; Work; addiction; cue reactivity; deprivation; dopaminergic neuron; drinking; experience; hedonic; indexing; insight; motivational processes; neural circuit; neuromechanism; new technology; novel; optogenetics; orofacial; preference; public health relevance; relating to nervous system; response; reward circuitry; sugar; tool

 DESCRIPTION (provided by applicant): Environmental cues associated with rewards like food can acquire motivational value themselves, resulting in the initiation of reward-seeking behaviors upon subsequent cue presentations. These goal-directed behaviors are not acquired through incremental trial-and-error learning, but arise from an interaction between current states and learned associations. A key example is "salt appetite". Rats that have learned to associate a cue with an aversively concentrated salt taste will respond to the cue and seek out salt if they are sodium-depleted, even before salt has ever been experienced as positive. Little is known about how cues and goals can acquire value in such a drastic manner before a prediction error can occur (i.e., when salt is first tasted in a sodium-deprived state). The proposed research will investigate the neural circuitry of adaptive salt-seeking behavior using this striking phenomenon as a model. Previous work has shown that neurons of the ventral pallidum (VP), which is bidirectionally connected to other reward circuit regions including the nucleus accumbens (NAc) and ventral tegmental area (VTA), activate to salt-paired cues and salt itself following sodium deprivation in a similar manner to sucrose-paired cues and sucrose. Although these VP neural dynamics correlate with the behaviorally-relevant shifts in the value of cues and rewards, it is unknown whether VP dynamics are necessary for salt-seeking behavior, nor how NAc and dopamine inputs to VP regulate its activity and the valuation of cues. The proposed studies will use optogenetic tools, new viral vectors, and transgenic TH-Cre rats to investigate the effects of temporarily inhibiting VP (Aim 1), the NAc-VP pathway (Aim 2), and dopaminergic VTA inputs to NAc or VP (Aim 3) on adaptive salt-seeking behavior and salt reward following sodium deprivation. In addition, Aims 2 and 3 include simultaneous tetrode recordings of VP (Aim 2) and NAc or VP (Aim 3) to uncover how patterns of activity related to goal seeking arise. The proposed studies will provide fresh insight into the neural mechanisms of adaptive goal-seeking behaviors, and could substantially update our understanding of disorders of reward dysfunction including depression, obesity, and compulsive behaviors. These disorders are characterized by hypo- or hyper-reactivity to cues and motivational problems, and are thought to involve VTA-NAc-VP dysfunction. Moreover, such problems often arise as immediate changes in motivation due to a change in state, such as stress or drug priming, a feature not easily explained by current incremental learning and prediction-error models. By applying new techniques and behavioral paradigms to study mechanisms of how such immediate changes in goal-seeking occur in the brain, the work carries great potential for updating our understanding of how disorders of the reward system arise.

 描述(由申请者提供)：与食物等奖励相关的环境线索本身可以获得激励价值，导致在随后的线索呈现时启动奖励寻求行为。这些以目标为导向的行为不是通过渐进式的试错学习获得的，而是来自当前状态和习得的联想之间的相互作用。一个关键的例子是“食盐量”。已经学会将线索与反常浓缩的盐味联系在一起的老鼠会对线索做出反应，如果钠耗尽，就会寻找盐，甚至在盐被认为是积极的之前。关于线索和目标如何在预测误差发生之前(即盐在缺钠状态下第一次品尝时)以如此剧烈的方式获得价值，我们知之甚少。这项拟议的研究将以这一惊人的现象为模型，研究适应性求盐行为的神经回路。先前的工作表明，腹侧苍白球(VP)神经元与伏核(NAC)和腹侧被盖区(VTA)等其他奖赏环路区域双向连接，在缺钠后激活盐对线索和盐本身，与蔗糖对线索和蔗糖类似。虽然这些VP神经动力学与线索和奖赏价值的行为相关变化相关，但尚不清楚VP动力学是否对寻找盐分行为是必要的，也不知道NAC和多巴胺输入VP如何调节其活动和线索的价值。本研究将利用光遗传工具、新型病毒载体和转基因TH-CRE大鼠来研究暂时抑制VP(Aim 1)、NAC-VP途径(Aim 2)和多巴胺能VTA向NAC或Vp的输入(Aim 3)对缺钠后适应性求盐行为和盐奖励的影响。此外，目标2和目标3包括同时记录VP(目标2)和NAC或VP(目标3)，以揭示与目标寻求相关的活动模式是如何产生的。这项研究将为适应性目标寻求行为的神经机制提供新的见解，并将极大地更新我们对包括抑郁、肥胖和强迫行为在内的奖赏功能障碍的理解。这些障碍的特点是对线索和动机问题的低或高反应，并被认为涉及VTA-NAC-VP功能障碍。此外，这类问题经常会出现，如由于状态变化而导致动机的立即变化，如压力或药物启动，这一特征不容易被当前的增量学习和预测错误模型解释。通过应用新的技术和行为范式来研究目标寻求的这种即时变化如何在大脑中发生的机制，这项工作具有巨大的潜力，可以更新我们对奖励系统障碍如何产生的理解。