Preclinical neurophysiological and behavioral assays of motivation and effort

项目摘要 缺乏动力和努力（即，逃避）是几种精神病的定义特征， 神经系统疾病;对功能恢复、疾病慢性化和发病率有不良影响;缺乏 有效的治疗。研究和开发新的治疗方法已经受到阻碍， 缺乏在人类和非人类之间相似的目标参与的经过充分验证的功能性措施 模型物种，可能是由于在实验室动物和人类中使用了不同的方法， 翻译.重要的是，神经生理学记录能够直接观察同步神经活动 具有高（ms）的时间分辨率，并认为具有更高的有效性跨物种比较的 与细胞或分子测量相比，药物对行为的影响。在这方面，根据RFA- MH-19-235和NIMH RDoC倡议，目前的申请提出优化，评估， 机械地测试身体和认知努力的神经生理学和行为测定， 将使临床前管道能够开发用于临床人群的新的有效治疗方法 在目标1中，我们将使用 物理努力任务（PET）和认知努力任务（CET）。结合行为和 电生理评估将决定身体和认知努力决策的神经基础 制作。在目标2中，我们将使用药理学挑战（莫达非尼和托卡朋）验证这些模型， 增强努力决策的行为和神经生理学相关性。在目标3中，我们 将研究药物诱导的努力增强的中纹状体和中皮层机制， 在遗传定义的神经元中使用光遗传学操作的组合进行决策， 电生理记录和行为药理学。总的来说，这个应用程序将描述 中脑边缘和中皮层多巴胺回路在不同形式的 努力的行为，识别可以针对改善动机障碍的神经基质 这是几种精神和神经疾病的核心。

PROJECT SUMMARY Deficits in motivation and effort (i.e., avolition) are defining characteristics of several psychiatric and neurological disorders; have adverse effects on functional recovery, disease chronicity, and morbidity; and lack effective treatments. Research and development of novel treatments for avolition has been hindered by the lack of well-validated functional measures of target engagement that are similar across human and non-human model species, possibly due to the use of different approaches in laboratory animals and humans that lack translation. Importantly, neurophysiological recordings enable direct observation of synchronized neural activity with high (ms) temporal resolution and are argued to have higher validity for cross-species comparison of the effects of drugs on behavior compared to cellular or molecular measures. In this regard, and in line with RFA- MH-19-235 and the NIMH RDoC initiative, the current application proposes to optimize, evaluate, and mechanistically test neurophysiological and behavioral assays of physical and cognitive effort in a manner that will enable preclinical pipelines to develop novel and efficacious treatments for avolition in clinical populations In Aim 1, we will optimize rodent behavioral assessments of physical and cognitive effort using the physical effort task (PET) task and cognitive effort task (CET), respectively. Combined behavioral and electrophysiological evaluation will determine the neural substrates of physical and cognitive effortful decision making. In Aim 2, we will validate these models using pharmacological challenges (modafinil and tolcapone) to potentiate the behavioral and neurophysiological correlates of effortful decision making. Finally, in Aim 3, we will investigate the mesostriatal and mesocortical mechanisms underlying drug-induced potentiation of effortful decision making using a combination of optogenetic manipulations in genetically defined neurons, electrophysiological recording, and behavioral pharmacology. Collectively, this application will delineate the precise contributions of mesolimbic and mesocortical dopamine circuits in the mediation of different forms of effortful behavior, identifying neural substrates that can be targeted to ameliorate impairments in motivation that are core to several psychiatric and neurological disorders.