Physiological markers of forebrain circuit engagement regulating effort-based decision making.

前脑回路参与的生理标志调节基于努力的决策。

• 批准号: 10006869
• 负责人: JOHN D SALAMONE
• 金额: $ 40.25万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-05 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006869
• 关键词: Activities of Daily Living; Amygdaloid structure; Animal Model; Animals; Behavioral; Brain; Bupropion; Catecholamines; Characteristics; Choice Behavior; Chronic; Clinical; Clinical Research; Computer Models; Cost-Benefit Analysis; Data; Data Analyses; Decision Making; Depressed mood; Development; Disease; Dopamine; Electrodes; Exertion; Family; Fatigue; Functional disorder; Globus Pallidus; Goals; Human; Individual; Laboratories; Lassitude; Lead; Left; Maintenance; Major Depressive Disorder; Measures; Mental disorders; Methods; Modafinil; Motivation; Multiple Sclerosis; Neurons; Neurosciences; Neurosciences Research; Nucleus Accumbens; Organism; Output; Paper; Pattern; Performance; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Prefrontal Cortex; Procedures; Prosencephalon; Psychopathology; Rattus; Regulation; Research; Resistance; Rewards; Ritalin; Rodent; Schizophrenia; Speed; Symptoms; Testing; Tetrabenazine; Therapeutic Effect; Translating; Ventral Striatum; Work; animal data; base; behavioral pharmacology; biomarker development; complex data; dopaminergic neuron; dysphoria; experimental study; frontal lobe; human data; implantation; monoamine; motivated behavior; neural circuit; pre-clinical; receptor; reward anticipation; spelling; transport inhibitor; uptake

PROJECT SUMMARY: The initiation and maintenance of motivated behaviors often are characterized by a high degree of vigor, speed, persistence and work output, and organisms frequently make effort-related decisions based upon cost/benefit analyses. Clinical neuroscience research has characterized effort-related symptoms (anergia, psychomotor slowing, fatigue, lassitude) in psychopathology. These motivational symptoms interfere with activities of daily living, and can be highly resistant to treatment. Tests of effort-related choice allow animals to choose between high-effort alternatives that lead to more highly valued rewards vs. low-effort alternatives that lead to less valued reward (i.e., less preferred or lower in magnitude). The ability to exert effort and select high-effort options is dependent upon neural circuits that involve mesolimbic dopamine (DA), ventral striatum, ventral pallidum, amygdala, and prefrontal cortex. Our laboratory has developed formal animal models that involve assessment of brain mechanisms regulating effort-related choice behavior. For example, rats treated with vesicular monoamine transport inhibitor tetrabenazine (TBZ), which induces or exacerbates symptoms such as fatigue in humans, can alter effort-related choice, reducing selection of the high effort alternative. These effects can be reversed by co- administration of bupropion (Wellbutrin), which inhibits catecholamine uptake, and several dopamine transport (DAT) inhibitors. This pattern of effects is consistent with data from human clinical neuroscience on effort-related motivational dysfunctions in psychopathology, and the effects of drugs that act on dopamine (DA). However, what is missing from this picture is the development of a physiological marker in the animal studies that can be easily translatable to human clinical research. Recent studies have demonstrated that there are electroencephalographic (EEG) markers of frontal cortex activity that are characteristic of engagement in motivated behavior and anticipation of reward, and that these markers are reduced in depressed people. Moreover, these effects are significantly correlated with dysphoria and lassitude in depressed individuals. Therefore, the proposed studies will focus on the development of frontal cortex EEG and local field potential (LFP) activity in behaving rats that are performing effort-based decision-making tasks. These rats will be tested under baseline conditions, and also after pharmacological challenges that produce effort-related motivational effects, including challenges to relevant forebrain circuits using chemogenetic methods. This research could lead to a greater understanding of the circuit mechanisms that underlie the regulation of effort-based aspects of motivation, and may provide valuable preclinical animal data that would contribute to the development of biomarkers for the therapeutic effects of agents that act upon motivational symptoms in psychopathology. This combination of physiological, behavioral, pharmacological and chemogenetic methods meets the ultimate goal of this RFA, in the sense that it may provide preclinical procedures and circuit level findings that ultimately can be translatable to methods that are applicable to human clinical neuroscience.

项目概要： 激发性行为的启动和维持通常具有高度的活力、速度， 持久性和工作产出，生物体经常根据成本/收益做出与努力相关的决定 分析。临床神经科学研究已经描述了与努力相关的症状（运动障碍，精神错乱 缓慢、疲劳、倦怠）。这些动机症状干扰日常活动 而且对治疗有很强的抵抗力。与努力相关的选择测试允许动物在 高努力的替代品，导致更高的价值回报与低努力的替代品，导致价值较低 奖励（即，较不优选或在数量级上较低）。付出努力和选择高努力选项的能力是 依赖于涉及中脑边缘多巴胺（DA），腹侧纹状体，腹侧苍白球， 杏仁核和前额叶皮层我们的实验室已经开发了正式的动物模型，包括评估 调节与努力相关的选择行为的大脑机制。例如，用囊泡单胺治疗的大鼠 转运抑制剂丁苯那嗪（TBZ），可诱导或加重人体疲劳等症状， 改变与努力相关的选择，减少对高努力选择的选择。这些影响可以通过联合逆转- 安非他酮（Wellbutrin）的给药，可抑制儿茶酚胺的摄取和几种多巴胺的转运 (DAT)抑制剂的这种效应模式与人类临床神经科学关于努力相关的数据一致。 精神病理学中的动机功能障碍，以及作用于多巴胺（DA）的药物的影响。不过 在动物研究中缺少的是一种生理标记的发展， 可用于人类临床研究。最近的研究表明，有脑电图 (EEG)额叶皮层活动的标志物，这些标志物是参与动机行为的特征， 奖励的预期，而这些标记在抑郁的人中减少。此外，这些影响是 与抑郁症患者的烦躁和倦怠显著相关。因此，拟议的研究将 专注于额叶皮层脑电图和局部场电位（LFP）活动的发展，在行为大鼠， 执行基于努力的决策任务。这些大鼠将在基线条件下进行测试， 产生与努力相关的激励效应的药理学挑战，包括对相关 用化学遗传学方法研究前脑回路。这项研究可能会导致更好地了解电路 这些机制是基于努力的动机调节的基础，并可能提供有价值的 有助于开发药物治疗效果生物标志物的临床前动物数据 在精神病理学中对动机症状起作用。这种生理的、行为的、 药理学和化学遗传学方法符合RFA的最终目标，在这个意义上，它可以 提供临床前程序和回路水平的发现，最终可以转化为 适用于人类临床神经科学。