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 UH2/UH3 MH109334 is to develop new translational assessments of reward and cognition in which the neurophysiological and behavioral metrics are identical across species. We have addressed 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 have developed (or modified), tested and optimized human and rodent versions of a flanker task (cognitive control) and a probabilistic reversal learning task (PRL; cognitive flexibility), such that task parameters are analogous between humans and rats. Additionally, we have recorded EEG data in both humans and rats during performance of each task. In both species, EEG data were analyzed using several techniques, including time- frequency wavelet analyses and time-domain event-related potential (ERP) analyses. These analyses yielded a priori EEG and behavioral variables (e.g., theta oscillations, error-related negativity, feedback-related negativity) that were manipulated in the UH3 phase, which included modafinil (Year 3) and methylphenidate (Year 4) challenges. Due to the COVID-19 pandemic, the human methylphenidate studies could not be started owing to work- from-home orders from Partners HealthCare and McLean Hospital. Similarly, the preclinical methylphenidate component at McLean Hospital (target: Flanker Task) was severely affected, with only limited research activities allowed between mid-March and mid-August. The preclinical methylphenidate component at UCSD (target: Probabilistic Reversal Learning Task) was also affected, although less severely. The current administrative supplement requests funding to complete the Year 4 methylphenidate experiments at all sites. 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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Cooperative Agreement Phase II (UH3)
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Winsky, Lois M
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Mclean Hospital
United States
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