Novel Cross-Species Neurophysiological Assays of Reward and Cognitive Domains

项目摘要 奖赏和认知领域的缺陷定义了几乎所有神经精神病学的特征 疾病，并对功能恢复、疾病慢性化和发病率有有害影响。发展 缺乏经过良好验证的靶向参与的临床前措施，阻碍了有效治疗的实施 在不同物种之间在功能上相似。利用基础版和翻译版之间的合作伙伴关系 有着良好合作记录的神经科学家，UH2/UH3 MH109334的首要目标是 开发新的奖赏和认知的翻译评估，其中神经生理和行为 不同物种的指标是相同的。 我们已经通过修改和验证奖励学习、认知评估来解决这一目标 控制力和认知灵活性，每一项都会在疾病中被破坏。在UH2阶段，我们有 开发(或修改)、测试和优化侧翼任务的人类和啮齿动物版本(认知控制) 和概率反转学习任务(PRL；认知灵活性)，使得任务参数相似 在人类和老鼠之间。此外，我们还记录了人类和大鼠的脑电数据 每项任务的执行情况。在这两个物种中，使用了几种技术来分析脑电数据，包括时间- 频域小波分析和时域事件相关电位(ERP)分析。这些分析产生了 先验脑电和行为变量(例如，θ振荡、与错误相关的负性、与反馈相关 阴性)，在UH3阶段操作，包括莫达非尼(第3年)和哌醋甲酯 (四年级)挑战。 由于新冠肺炎大流行，由于工作的原因，人类哌醋甲酯的研究无法开始- 来自合作伙伴医疗保健和McLean医院的在家订单。同样，临床前的哌甲酸甲酯 McLean医院的组件(目标：侧翼任务)受到严重影响，只有有限的研究 允许在3月中旬至8月中旬期间进行活动。加州大学圣迭戈分校的临床前哌醋甲酯成分 (目标：概率逆转学习任务)也受到影响，尽管程度较轻。海流 行政副刊要求提供资金，以便在所有地点完成第4年的哌醋酸甲酯实验。 最终，这些研究将为人类和大鼠提供奖励和/或认知的新测量 这在行为和神经生理学上显示出明显的相似之处，可以通过假定的治疗来操纵 跨物种。这样的任务将有助于缩小临床前动物和动物之间现有的翻译差距 人类研究，并将促进开发急需的奖赏和认知治疗方法 精神错乱。

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.