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 this UH2/UH3 application is to develop new translational assessments of reward and cognition in which the neurophysiological and behavioral metrics are identical across species. We will address 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 will modify and test existing human and rodent versions of a probabilistic reward task (PRT; reward learning), a flanker task (cognitive control) [alternative task: 4-choice serial reaction time task], a probabilistic reversal learning task (PRL; cognitive flexibility), such that task parameters are analogous between humans and rats. Additionally, we will record EEG data in both humans and rats during performance of each task. In both species, EEG data will be analyzed using several techniques, including frequency-domain multi-taper power spectral analyses, time-domain event-related potential (ERP) analyses, and cross-frequency phase-amplitude coupling analyses. In humans, distributed source localization analyses will focus on a priori regions, such as the dorsal anterior cingulate cortex (dACC; reward learning and cognitive control), dorsolateral prefrontal cortex (DLPFC; cognitive control), and lateral orbitofrontal cortx (OFC; reversal learning); EEG electrodes in rats will be placed over homologous regions. We hypothesize that by increasing the congruence of task parameters, task-related behavioral and neurophysiological assays will be similar across species. The two tasks that show the highest neurophysiological (and behavioral) concordance between humans and rats will be advanced to the UH3 phase, in which the selected task(s) will be validated with pharmacological challenges. Specifically, reward learning, cognitive control, or reversal learning and their respective neurophysiological mechanisms will be probed after administration of either the dopamine D2/D3 receptor antagonist amisulpride, the serotonin neurotransmission enhancer vortioxetine, or the cognitive enhancer modafinil. Each pharmacological challenge is based on specific a priori hypotheses regarding neurobiological mechanisms underlying each behavioral construct. 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.
Several neuropsychiatric disorders are characterized by disruption of behaviors and neural circuits underlying reward and cognition. We aim to develop, concurrently in humans and rats, novel neurophysiological and behavioral assays of reward and cognition that are expected to be identical across species. The successful development of such assessments is expected to substantially improve the translational value of preclinical animal testing, which is a critical initial step for the development of much needed treatments for disorders of reward and cognition.
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