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Preclinical neurophysiological and behavioral assays of motivation and effort

动机和努力的临床前神经生理学和行为分析

基本信息

批准号：
10439637
负责人：
ANDRE DER-AVAKIAN
金额：
$ 39.17万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-05 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10439637
关键词：
Address Adverse effects Animals Anterior Attenuated Automobile Driving Behavior Behavior assessment Behavioral Behavioral Assay Behavioral trial Biological Assay Characteristics Chemosensitization Chronic Clinical Clinical assessments Cognitive Corpus striatum structure Cost Analysis Data Decision Making Disease Dopamine Dorsal Drug usage Electroencephalography Electrophysiology (science)Ensure Evaluation Exertion Feedback Frequencies Goals Human Impairment Laboratory Animals Measures Mediation Mental disorders Modafinil Modeling Molecular Morbidity - disease rate Motivation National Institute of Mental Health Neurobiology Neurons Nucleus Accumbens Outcome Pharmaceutical Preparations Pharmacology Physical Efforts Physical assessment Play Population Rattus Recovery of Function Research Research Domain Criteria Rewards Rodent Role Specificity Task Performances Testing Translating Translations Tyrosine 3-Monooxygenase Ventral Tegmental Area Work base behavior measurement behavioral pharmacology cingulate cortex cost drug discovery effective therapy efficacious treatment in vivo interdisciplinary approach motivated behavior nervous system disorder neural circuit neurobiological mechanism neurophysiology novel optogenetics pre-clinical relating to nervous system research and development response targeted treatment temporal measurement therapy development tolcapone

项目摘要

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.

项目总结