Novel Cross-Species Neurophysiological Assays of Reward and Cognitive Domains

奖励和认知领域的新型跨物种神经生理学测定

• 批准号: 9244071
• 负责人: Diego A Pizzagalli
• 金额: $ 73.18万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9244071
• 关键词: Address; Amisulpride; Animal Testing; Animals; Anterior; Area; Behavior; Behavior assessment; Behavioral; Behavioral Assay; Biological Assay; Brain; Characteristics; Chronic; Cognition; Cognition Disorders; Cognitive; Cognitive deficits; Collaborations; Computer Simulation; Coupling; Data; Development; Dimensions; Disease; Dopamine; Dorsal; Dose; Electrodes; Electroencephalography; Electrophysiology (science); Enhancers; Evaluation; Event-Related Potentials; Feedback; Foundations; Frequencies; Goals; Human; Impaired cognition; Laboratory Animals; Lateral; Learning; Link; Measures; Modafinil; Modeling; Molecular; Morbidity - disease rate; National Institute of Mental Health; Neurosciences; Nootropic Agents; Performance; Pharmaceutical Preparations; Pharmacology; Phase; Positioning Attribute; Prefrontal Cortex; Rat-1; Rattus; Reaction Time; Recovery of Function; Research; Research Domain Criteria; Reversal Learning; Rewards; Rodent; Serotonin; Solid; Task Performances; Techniques; Testing; Time; base; behavioral construct; cingulate cortex; cognitive control; effective therapy; flexibility; improved; neural circuit; neurobiological mechanism; neurophysiology; neuropsychiatric disorder; neurotransmission; novel; pre-clinical; public health relevance; receptor; relating to nervous system; research and development; response; source localization; temporal measurement; transmission process; virtual

 DESCRIPTION (provided by applicant): Deficits across the domains of reward and cognition are defining characteristics of virtually all neuropsychiatric disorders, and have deleterious effects on functional recovery, disease chronicity, and morbidity. Development of effective treatments is hindered by the lack of well-validated preclinical measures of target engagement that are functionally similar across species. Capitalizing on a partnership among basic and translational neuroscientists with a strong track record of collaborations, the overarching goal of this UH2/UH3 application is to develop new translational assessments of reward and cognition in which the neurophysiological and behavioral metrics are identical across species. We will address this objective by modifying and validating assessments of reward learning, cognitive control, and cognitive flexibility, each of which is disrupted across illnesses. During the UH2 phase, we will modify and test existing human and rodent versions of a probabilistic reward task (PRT; reward learning), a flanker task (cognitive control) [alternative task: 4-choice serial reaction time task], a probabilistic reversal learning task (PRL; cognitive flexibility), such that task parameters are analogous between humans and rats. Additionally, we will record EEG data in both humans and rats during performance of each task. In both species, EEG data will be analyzed using several techniques, including frequency-domain multi-taper power spectral analyses, time-domain event-related potential (ERP) analyses, and cross-frequency phase-amplitude coupling analyses. In humans, distributed source localization analyses will focus on a priori regions, such as the dorsal anterior cingulate cortex (dACC; reward learning and cognitive control), dorsolateral prefrontal cortex (DLPFC; cognitive control), and lateral orbitofrontal cortx (OFC; reversal learning); EEG electrodes in rats will be placed over homologous regions. We hypothesize that by increasing the congruence of task parameters, task-related behavioral and neurophysiological assays will be similar across species. The two tasks that show the highest neurophysiological (and behavioral) concordance between humans and rats will be advanced to the UH3 phase, in which the selected task(s) will be validated with pharmacological challenges. Specifically, reward learning, cognitive control, or reversal learning and their respective neurophysiological mechanisms will be probed after administration of either the dopamine D2/D3 receptor antagonist amisulpride, the serotonin neurotransmission enhancer vortioxetine, or the cognitive enhancer modafinil. Each pharmacological challenge is based on specific a priori hypotheses regarding neurobiological mechanisms underlying each behavioral construct. Ultimately, these studies will provide novel measures of reward and/or cognition in both humans and rats that show clear parallels in behavior and neurophysiology that can be manipulated with putative treatments across species. Such tasks will help narrow the existing translational gap between preclinical animal and human research and will promote the development of urgently needed treatments for reward and cognitive disorders.

 描述(由申请人提供)：奖赏和认知领域的缺陷定义了几乎所有神经精神障碍的特征，并对功能恢复、疾病慢性化和发病率产生有害影响。由于缺乏经过充分验证的跨物种功能相似的靶向参与的临床前措施，有效治疗的开发受到阻碍。利用基础和翻译神经科学家之间的合作伙伴关系，并拥有良好的合作记录，总体目标是 这个UH2/UH3应用程序是为了开发新的奖赏和认知的翻译评估，其中神经生理和行为指标在不同物种之间是相同的。我们将通过修改和验证对奖励学习、认知控制和认知灵活性的评估来解决这一目标，这些评估中的每一项都在疾病中受到干扰。在UH2阶段，我们将修改和测试概率奖励任务(PRT；奖励学习)、侧翼任务(认知控制)[替代任务：4-选择系列反应时间任务]、概率逆转学习任务(PRL；认知灵活性)的现有人类和啮齿动物版本，以便 任务参数在人和大鼠之间是相似的。此外，在每项任务的执行过程中，我们将记录人类和大鼠的脑电数据。在这两个物种中，脑电数据将使用几种技术进行分析，包括频域多锥度功率谱分析、时间域事件相关电位(ERP)分析和跨频相位-幅度耦合分析。在人类中，分布式来源定位分析将集中在先验区域，如背侧前扣带回皮质(dACC；奖励学习和认知控制)、背外侧前额叶皮质(DLPFC；认知控制)和外侧眶额叶皮质(OFC；反向学习)；大鼠的脑电电极将放置在相应区域上。我们假设，通过增加任务参数的一致性，与任务相关的行为和神经生理分析将在不同物种之间相似。显示出人和大鼠之间最高神经生理(和行为)一致性的两项任务将进入UH3阶段，在此阶段，选定的任务(S)将通过药物挑战进行验证。具体地说，在给予多巴胺D2/D3受体拮抗剂阿米舒普利、5-羟色胺神经传递增强剂伏替西汀或认知增强剂莫达非尼后，将探讨奖赏学习、认知控制或反向学习及其各自的神经生理机制。每一次药理学挑战都是基于关于每种行为结构背后的神经生物学机制的特定先验假设。最终，这些研究将在人类和大鼠身上提供奖励和/或认知的新衡量标准，显示出行为和神经生理学上的明显相似之处，这些相似之处可以通过跨物种的假定治疗来操纵。这些任务将有助于缩小临床前动物和人类研究之间现有的翻译差距，并将促进奖励和认知障碍迫切需要的治疗方法的发展。