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: 10199956
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10199956
• 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.

项目总结： 激励行为的启动和维持通常具有高度的活力，速度， 持久性和工作量，生物体经常根据成本/收益做出与努力相关的决定 分析。临床神经科学研究的特点是努力相关的症状(神经痛、精神运动 减速、疲倦、疲倦)。这些动机症状干扰了日常的活动 活着，并且可能对治疗具有高度抗药性。与努力相关的选择测试允许动物在 带来更高回报的高努力替代方案与导致价值较低的低努力替代方案 奖励(即，不太受欢迎或数额较低)。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、 杏仁核和前额叶皮质。我们的实验室已经开发出正式的动物模型，包括评估 大脑调节努力相关选择行为的机制。例如，用泡腾单胺治疗的大鼠 转运抑制剂四苯肼(TBZ)会导致或加剧人类的疲劳等症状，它可以 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 安非他酮(Wellbutrin)抑制儿茶酚胺摄取和几种多巴胺转运 (DAT)抑制剂。这种效应模式与人类临床神经科学关于努力相关的数据是一致的 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。然而，什么？ 这幅图中缺少的是动物研究中一种生理标记的发展，这种标记很容易 可翻译为人类临床研究。最近的研究表明，有脑电 (EEG)额叶皮质活动的标志物，其特征是参与动机行为和 对奖励的预期，这些标记物在抑郁症患者中降低。此外，这些影响是 抑郁个体的焦虑症和疲倦感显著相关。因此，拟议的研究将 重点研究以下行为大鼠的额叶皮质脑电和局部场电位(LFP)活动的发展 执行基于努力的决策任务。这些老鼠将在基线条件下进行测试，也将在 产生与努力相关的激励效应的药理学挑战，包括对相关 使用化学发生方法的前脑回路。这项研究可能会对电路有更好的理解 以努力为基础的激励方面的监管机制，并可能提供有价值的 有助于开发药物治疗效果生物标记物的临床前动物数据 根据精神病理学中的激励症状而起作用。这种生理、行为、 药理学和化学遗传学方法符合这种RFA的最终目标，从某种意义上说，它可以 提供临床前程序和电路级别的结果，最终可以转换为 适用于人类临床神经科学。

项目成果

Effects of the dopamine depleting agent tetrabenazine in tests evaluating different components of depressive-like behavior in mice: sex-dependent response to antidepressant drugs with SERT and DAT blocker profiles.

• DOI: 10.1007/s00213-023-06412-9
• 发表时间: 2023-08
• 期刊: PSYCHOPHARMACOLOGY
• 影响因子: 3.4
• 作者: Carratala-Ros, Carla;Martinez-Verdu, Andrea;Olivares-Garcia, Regulo;Salamone, John D.;Correa, Merce
• 通讯作者: Correa, Merce

Effects of the dopamine depleting agent tetrabenazine on detailed temporal parameters of effort-related choice responding.

• DOI: 10.1002/jeab.754
• 发表时间: 2022-05
• 期刊: JOURNAL OF THE EXPERIMENTAL ANALYSIS OF BEHAVIOR
• 影响因子: 2.7
• 作者: Ren, Naxin;Carratala-Ros, Carla;Ecevitoglu, Alev;Rotolo, Renee A.;Edelstein, Gayle A.;Presby, Rose E.;Stevenson, Ian H.;Chrobak, James J.;Salamone, John D.
• 通讯作者: Salamone, John D.

Critical review of RDoC approaches to the study of motivation with animal models: effort valuation/willingness to work.

对动物模型动机研究 RDoC 方法的批判性审查：努力评估/工作意愿。

• DOI: 10.1042/etls20220008
• 发表时间: 2022
• 期刊: Emerging topics in life sciences
• 影响因子: 3.8
• 作者: Salamone,JohnD;Correa,Merce
• 通讯作者: Correa,Merce

Behavioral and dopamine transporter binding properties of the modafinil analog (S, S)-CE-158: reversal of the motivational effects of tetrabenazine and enhancement of progressive ratio responding.

• DOI: 10.1007/s00213-020-05625-6
• 发表时间: 2020-11
• 期刊: Psychopharmacology
• 影响因子: 3.4
• 作者: Rotolo RA;Kalaba P;Dragacevic V;Presby RE;Neri J;Robertson E;Yang JH;Correa M;Bakulev V;Volkova NN;Pifl C;Lubec G;Salamone JD
• 通讯作者: Salamone JD