Nucleus accumbens circuits for regulating cue-motivated behavior

伏隔核回路调节提示诱发的行为

基本信息

批准号：
10552619
负责人：
Sean Bjorn Ostlund
金额：
$ 57.18万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
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/10552619
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 Genetic 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 Shapes Signal Transduction Source Structure Substance Use Disorder System Testing Thalamic structure Time Work addiction 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 neural circuit neurochemistry neuropsychiatric disorder optogenetics prevent response

项目摘要

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.

项目概要表明奖励可用性的情境线索可以对奖励寻求产生强大的激励影响然而，这种寻求奖励的冲动并不总是适应性的。动机性奖励寻求受到稳态和认知控制过程的调节。有证据表明，这些过程在一系列神经精神疾病中失调，包括物质使用障碍、强迫性暴饮暴食和抑郁，导致健康奖励寻求下降活动（例如，冷漠和快感缺乏）和/或适应不良的奖励寻求（例如，强烈的药物尽管它们对健康和疾病都很重要，但对神经的了解仍然很多。该项目旨在填补这一知识空白。根据最近的研究和我们强有力的初步发现，我们认为多巴胺的释放是通过胆碱能活动在伏隔核 (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对此过程的影响，以确保适应性奖励寻求。我们将使用多方面来严格测试这一点。结合了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，以及翻译相关的线索驱动行为的巴甫洛夫-仪器转移分析目标 1 将研究胆碱能如何。 NAc 多巴胺释放的调节有助于稳态和对提示激励奖励的认知控制我们将具体确定线索引发的 NAc 多巴胺是否编码需求状态和变化。奖励概率，这与中脑多巴胺神经元活动有何关系，以及多巴胺是否具有激励作用信息由作用于含 β2 烟碱乙酰胆碱受体的胆碱能中间神经元局部塑造目标 2 将研究从 PVT 到 NAc 的投射是否促进了提示动机行为。符合当前的需求，以及是否通过调节 NAc 胆碱能和/或多巴胺能活性来实现这一点。 3 将确定 ACC 对 NAc 的预测是否在提示信号时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/或我们的发现将导致特定神经回路和多巴胺知识的重大进步。负责调节线索激发行为的神经化学机制，并将指导未来的研究关于这些机制的功能障碍如何导致成瘾和相关的不良适应奖励寻求疾病状态。