Preclinical neurophysiological and behavioral assays of motivation and effort

项目总结 缺乏动力和努力(即，自暴自弃)是几种精神疾病和 神经功能障碍；对功能恢复、疾病慢性化和发病率有不利影响；以及缺乏 有效的治疗方法。心脏撕裂的新疗法的研究和开发一直受到 缺乏经过充分验证的目标参与度功能衡量标准，这些衡量标准在人类和非人类中都是相似的 模式物种，可能是由于在实验室动物和人类中使用了不同的方法，缺乏 翻译。重要的是，神经生理记录可以直接观察同步的神经活动。 具有高(Ms)的时间分辨率，并被认为在跨物种比较中具有更高的有效性 与细胞或分子测量相比，药物对行为的影响。在这方面，并与RFA一致-- MH-19-235和NIMH RDoC计划，当前的应用程序建议优化、评估和 机械地测试身体和认知努力的神经生理和行为分析 将使临床前管道能够为临床人群的血液流失开发新的有效的治疗方法 在目标1中，我们将优化啮齿动物对体力和认知努力的行为评估 体力努力任务(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定的神经基础 制作。在目标2中，我们将使用药理学挑战(莫达非尼和托卡彭)来验证这些模型 增强努力决策的行为和神经生理学相关性。最后，在目标3中，我们 将研究药物诱导的强效应激增强的纹状体和中皮质机制 在基因定义的神经元中使用光遗传操作的组合进行决策， 电生理记录和行为药理学。总的来说，此应用程序将描述 中脑边缘和大脑皮层多巴胺环路在调节不同形式的 努力的行为，识别可以针对的神经底物，以改善动机方面的损害 它们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.