Nucleus accumbens circuits for regulating cue-motivated behavior

伏隔核回路调节提示诱发的行为

• 批准号: 10382443
• 负责人: Sean Bjorn Ostlund
• 金额: $ 60.36万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-02 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10382443
• 关键词: Acetylcholine; Anhedonia; Anterior; Basic Science; Behavior; Behavioral; Binge Eating; Biological Assay; Calcium; Characteristics; Cues; Data; Depressed mood; Desire for food; Development; Disease; Dopamine; Drops; Ensure; Fiber; Functional disorder; Goals; Health; Interneurons; Knowledge; Mental Depression; Mental disorders; Methods; Midbrain structure; Monitor; Motivation; Neuromodulator; Neurons; Nicotinic Receptors; Nucleus Accumbens; Pharmaceutical Preparations; Photometry; Probability; Process; Regulation; Rewards; Risk; Role; Signal Transduction; Source; Structure; Substance Use Disorder; System; Testing; Thalamic structure; Time; Work; addiction; base; behavior test; cell type; cholinergic; cingulate cortex; cognitive control; cognitive reappraisal; cost; dopaminergic neuron; drug craving; drug seeking behavior; food craving; innovation; maladaptive behavior; motivated behavior; neural circuit; neurochemistry; neuropsychiatric disorder; optogenetics; prevent; relating to nervous system; response

PROJECT SUMMARY Situational cues that signal reward availability can exert a powerful invigorating influence over reward-seeking behavior. However, this impulse to seek out reward is not always adaptive. To conserve time and effort, cue- motivated reward seeking is regulated by homeostatic and cognitive control processes. There is growing evidence that these processes become dysregulated in a range of neuropsychiatric diseases, including substance use disorder, compulsive overeating, and depression, leading to a drop in healthy reward-seeking activity (e.g., apathy and anhedonia) and/or the development of maladaptive reward seeking (e.g., intense drug and food cravings). Despite their importance to both health and disease, much remains unknown of the neural circuits that regulate adaptive cue-motivated behavior. This project aims to fill this critical gap in knowledge. Based on the recent studies and our strong preliminary findings, we hypothesize that dopamine release is transformed into a motivational message at nucleus accumbens (NAc) terminals by cholinergic activity, and that inputs from the paraventricular thalamus (PVT) and anterior cingulate cortex (ACC) exert opposing regulatory influences over this process to ensure adaptive reward seeking. We will rigorously test this using a multifaceted approach that combines projection- and cell type-specific activity monitoring, neurochemical recordings, projection- and cell type-specific chemogenetic and optogenetic manipulations, and a translationally relevant Pavlovian-to-instrumental transfer assay of cue-motivated behavior. Aim 1 will investigate how cholinergic modulation of NAc dopamine release contributes to homeostatic and cognitive control over cue-motivated reward seeking. We will specifically determine whether cue-elicited NAc dopamine encodes changes in need state and reward probability, how this relates to midbrain dopamine neuron activity, and whether dopamine’s motivational message is locally shaped by cholinergic interneurons acting at β2-containing nicotinic acetylcholine receptors on dopamine terminals. Aim 2 will investigate if projections from PVT to NAc facilitate cue-motivated behavior in line with current needs, and whether it does so by regulating NAc cholinergic and/or dopaminergic activity. Aim 3 will determine if ACC projections to NAc adaptively suppress active reward-seeking behavior when cues signal that an alternative response would be advantageous, and whether this depends on NAc acetylcholine and/or dopamine. Our findings will lead to major advances in knowledge of the specific neural circuits and neurochemical mechanisms responsible for regulating cue-motivated behavior, and will guide future research on how dysfunction in these mechanisms contributes to maladaptive reward seeking in addiction and related disease states.

项目摘要 暗示奖励可获得性的情境线索可以对奖励寻求产生强大的激励影响 行为然而，这种寻求奖励的冲动并不总是适应性的。为了节省时间和精力，提示- 有动机的奖赏寻求受自我平衡和认知控制过程的调节。人们越来越 有证据表明，这些过程在一系列神经精神疾病中变得失调，包括 物质使用障碍，强迫性暴饮暴食和抑郁症，导致健康的回报寻求下降 活动（例如，冷漠和快感缺乏）和/或不适应性奖赏寻求的发展（例如，强效药 食物的诱惑）。尽管它们对健康和疾病都很重要，但神经系统的许多方面仍然未知。 调节适应性线索动机行为的电路。该项目旨在填补这一关键的知识空白。 基于最近的研究和我们强有力的初步发现，我们假设多巴胺的释放是 通过胆碱能活动在丘脑核（NAc）末端转化为激励信息， 来自室旁丘脑（PVT）和前扣带皮层（ACC）的输入发挥相反的调节作用。 影响这一过程，以确保适应性奖励寻求。我们将严格测试这一点使用多方面的 结合投射和细胞类型特异性活动监测，神经化学记录， 投射和细胞类型特异性的化学遗传学和光遗传学操作，以及一种与免疫相关的 线索动机行为的巴甫洛夫-仪器转移分析。目的1将研究胆碱能 调节NAc多巴胺释放有助于对线索激励奖励的稳态和认知控制 寻找我们将特别确定线索诱导的NAc多巴胺是否编码需要状态的变化， 奖励概率，这与中脑多巴胺神经元活动的关系，以及多巴胺是否是动机性的， 胆碱能中间神经元作用于含β2的烟碱乙酰胆碱受体， 多巴胺终端目的2将研究从PVT到NAc的投射是否促进线索动机行为， 符合当前的需要，以及是否通过调节NAc胆碱能和/或多巴胺能活性来实现。目的 3将确定当线索信号发出时，ACC对NAc的投射是否自适应地抑制主动寻求奖励的行为 替代反应将是有利的，以及这是否取决于NAc乙酰胆碱和/或 多巴胺我们的发现将导致对特定神经回路的认识的重大进展， 神经化学机制负责调节线索动机的行为，并将指导未来的研究 这些机制的功能障碍如何导致成瘾和相关的适应不良的奖励寻求 疾病状态。