Brain Circuit Mechanisms for Reward Cue Attraction

奖励提示吸引的脑回路机制

• 批准号: 10223253
• 负责人: Kyle S Smith
• 金额: $ 48.14万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223253
• 关键词: Acetylcholine; Addictive Behavior; Address; Animals; Area; Attention; Behavior; Biological Assay; Brain; Cells; Clozapine; Complement; Consumption; Contralateral; Cues; Desire for food; Drug Addiction; Drug usage; Eating Behavior; Equilibrium; Food; Gene Expression Profiling; Globus Pallidus; Goals; Immediate-Early Genes; Lateral; Lead; Ligands; Maps; Measures; Medial; Methods; Modeling; Motivation; Neurons; Nucleus Accumbens; Outcome; Oxides; Pathologic; Pathway interactions; Pattern; Pharmaceutical Preparations; Physiological; Population; Procedures; Process; Rattus; Reaction; Research; Rewards; Role; Saline; Stimulus; Symptoms; Technology; Testing; Transgenic Organisms; Viral; Work; addiction; base; cholinergic; cholinergic neuron; designer receptors exclusively activated by designer drugs; expectation; experimental study; feeding; incentive salience; motivated behavior; motivational processes; neural circuit; neural model; receptor; recruit; reduced food intake; relating to nervous system; remote control

Drug addiction involves an excessive motivation to pursue and consume drugs. Part of this motivation is thought to involve the attribution of value to drug-paired cues. Cues for rewards, including drugs and food, can become motivational targets and attract attention and behavior. In the brain, a basic sketch of areas responsible for this process is known and includes the nucleus accumbens (NAc) and ventral pallidum (VP). Although these areas are bidirectionally connected as a circuit, little is known about how motivation arises out of their circuit dynamics. To address this, the proposed research will incorporate a method called chemogenetics for relatively non-invasive “remote control” perturbation of brain activity. Combining this method with transgenic delivery strategies, we will both increase and decrease activity in pathways connecting the NAc and VP to evaluate their role in the motivational attraction to reward cues. This motivational process is exemplified by sign-tracking behavior, in which animals appetitively engage with a cue predicting reward. In the proposed research, connections between the NAc and VP will be manipulated using DREADDs to assess the role of these pathways in acquiring and expressing the sign-tracking behavior. Recordings of neural activity and gene expression assays will complement these experiments in order to establish neural activation patterns that change in register with changes in motivated behavior. We will similarly test the role of neurons in the VP expressing acetylcholine, which receive NAc input and are hypothesized to guide attention towards reward cues. Results showing how NA-VP circuits control motivation, and what neural activity signatures map on to increases and decreases in motivation, will provide critical reference points for an understanding of how pathway-specific changes in brain activity could contribute to excessive motivation in addictive behaviors. The relative non-invasiveness of the procedure also carries translational potential for disrupting severely excessive reactions to drug-associated stimuli.

吸毒成瘾涉及追求和消费毒品的过度动机。 这种动机被认为涉及对药物配对线索的价值归因。 奖励，包括药物和食物，可以成为激励目标并吸引注意力和 在大脑中，负责这一过程的区域的基本草图是已知的。 包括伏隔核 (NAc) 和腹侧苍白球 (VP)，尽管这些区域是。 作为一个电路双向连接，人们对动机如何产生的知之甚少。 为了解决这个问题，拟议的研究将采用一种称为电路动力学的方法。 化学遗传学对大脑活动进行相对非侵入性的“远程控制”扰动。 将此方法与转基因递送策略相结合，我们将同时增加和减少 连接 NAc 和 VP 的通路中的活动，以评估它们在动机中的作用 对奖励线索的吸引力。 这种动机过程可以通过信号追踪行为来体现，其中动物 在拟议的研究中，有兴趣地参与预测奖励的线索。 NAc 和 VP 之间将使用 DREADD 进行操纵，以评估这些角色的作用 获取和表达神经活动记录的途径。 基因表达测定将补充这些实验，以便建立神经 激活模式的变化会随着动机行为的变化而变化。 测试表达乙酰胆碱的 VP 中神经元的作用，这些神经元接收 NAc 输入并且 结果显示 NA-VP 是如何循环的。 控制动机，以及神经活动特征映射到什么增加和减少 动机，将为理解路径特异性如何提供关键参考点 大脑活动的变化可能会导致成瘾行为的过度动机。 该程序的相对非侵入性也具有破坏性的转化潜力 对药物相关刺激的严重过度反应。