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.
In this proposal, we are optimizing, validating and mechanistically testing the neural circuitry involved in physical and cognitive effort using novel rodent neurophysiological and behavioral measures that may eventually be translated to analogous clinical assessments. The overall goal of this approach is to create cross-species assessments of motivation that can be used for drug discovery purposes.