Novel Cross-Species Neurophysiological Assays of Reward and Cognitive Domains

项目摘要 奖励和认知领域的缺陷是几乎所有神经精神疾病的定义特征。 疾病，并且对功能恢复、疾病慢性化和发病率具有有害影响。发展 由于缺乏经过充分验证的靶点参与临床前措施， 在不同的物种中功能相似。利用基础和转化之间的伙伴关系， 具有良好合作记录的神经科学家，UH 2/UH 3 MH 109334的总体目标是 开发新的奖励和认知的翻译评估，其中神经生理和行为 所有物种的指标都是一样的 我们已经通过修改和验证奖励学习、认知和认知的评估来实现这一目标。 控制和认知灵活性，每一个都在疾病中被破坏。在UH 2阶段，我们有 开发（或修改），测试和优化侧翼任务（认知控制）的人类和啮齿动物版本 和概率逆向学习任务（PRL;认知灵活性），使得任务参数类似 人类和老鼠之间。此外，我们还记录了人类和大鼠的EEG数据， 完成每一项任务。在这两个物种中，使用几种技术分析EEG数据，包括时间- 频率小波分析和时域事件相关电位（ERP）分析。这些分析得出 先验EEG和行为变量（例如，θ振荡，误差相关负性，反馈相关 阴性），包括莫达非尼（第3年）和哌甲酯 (Year 4）挑战。 由于COVID-19大流行，由于工作原因，无法开始人体哌醋甲酯研究- 来自Partners HealthCare和姆克林医院的家庭订单。同样，临床前哌醋甲酯 姆克林医院的组件（目标：Flanker任务）受到严重影响，只有有限的研究 3月中旬至8月中旬允许的活动。UCSD的临床前哌醋甲酯组分 （目标：可能性抑制学习任务）也受到影响，但不太严重。当前 行政补充申请资金，以完成所有地点的4年哌醋甲酯实验。 最终，这些研究将为人类和大鼠的奖励和/或认知提供新的测量方法。 这些研究表明，在行为和神经生理学方面， 跨越物种。这些任务将有助于缩小临床前动物和 人类研究，并将促进迫切需要的奖励和认知治疗的发展 紊乱

Project Summary 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 UH2/UH3 MH109334 is to develop new translational assessments of reward and cognition in which the neurophysiological and behavioral metrics are identical across species. We have addressed 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 have developed (or modified), tested and optimized human and rodent versions of a flanker task (cognitive control) and a probabilistic reversal learning task (PRL; cognitive flexibility), such that task parameters are analogous between humans and rats. Additionally, we have recorded EEG data in both humans and rats during performance of each task. In both species, EEG data were analyzed using several techniques, including time- frequency wavelet analyses and time-domain event-related potential (ERP) analyses. These analyses yielded a priori EEG and behavioral variables (e.g., theta oscillations, error-related negativity, feedback-related negativity) that were manipulated in the UH3 phase, which included modafinil (Year 3) and methylphenidate (Year 4) challenges. Due to the COVID-19 pandemic, the human methylphenidate studies could not be started owing to work- from-home orders from Partners HealthCare and McLean Hospital. Similarly, the preclinical methylphenidate component at McLean Hospital (target: Flanker Task) was severely affected, with only limited research activities allowed between mid-March and mid-August. The preclinical methylphenidate component at UCSD (target: Probabilistic Reversal Learning Task) was also affected, although less severely. The current administrative supplement requests funding to complete the Year 4 methylphenidate experiments at all sites. 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.