The prefrontal cortex (PFC) plays a pivotal role in higher cognitive processes that guide flexible goal-directed behavior, particularly under ambiguous and/or distracting conditions. These actions involve topographically organized frontostriatal projections. Frontostriatal dysfunction is implicated in a variety of disorders, including addiction, ADHD, and schizophrenia. Anatomical, modeling and limited in vitro evidence suggests that PFC-dependent function involves reverberatory (self-excitatory) activation of PFC neurons that involves recurrent circuitry and/or intracellular signaling cascades. Using a point-process, conditional intensity model we obtained the first empirical evidence that PFC neurons display reverberatory activity in vivo in rats engaged in a task of spatial working memory and that stress-related impairment in working memory is associated with a suppression of reverberatory activity. These and other observations indicate that reverberatory activity of PFC neurons represents a unique form of information coding that contributes to higher cognitive function. Catecholamines exert potent modulatory actions on PFC neuronal function that likely contribute to the therapeutic effects of drugs used to treat a variety of cognitive/behavioral disorders, including ADHD and schizophrenia. However, there are multiple neuromodulators found within the PFC, including corticotropin-releasing factor (CRF). Across cortical regions, the PFC contains a particularly high density of CRF receptors. Currently, we know little about the actions of PFC CRF on frontostriatal neuronal function, representing a significant gap in our understanding of the neurobiology of the PFC, CRF and goal-directed behavior. In preliminary studies, we observed that CRF acts locally within the PFC to impair PFC-dependent higher cognitive function while a CRF antagonist improve PFC- dependent cognition, similar to that seen with ADHD-related pharmacological treatments. Collectively, these observations suggest translationally-relevant actions of endogenous CRF signaling within the PFC. The goal of the proposed studies is to examine the effects of CRF signaling within the PFC on frontostriatal neuronal coding in rats engaged in a spatial working memory task. Methods developed and information gained in these studies will provide a solid foundation for the development of a comprehensive research program aimed at understanding the modulatory actions of CRF on frontostriatal circuit function. Ultimately, this research program will provide new insight into the neurobiology of frontostriatal-dependent cognition/behavior that may lead to novel treatment strategies for PFC dysfunction.

Public Health Relevance

The prefrontal cortex (PFC) and extended frontostriatal circuitry plays a pivotal role in higher cognitive function, with frontostriatal dysfunction implicted in a number of cognitive and behavioral disorders, including schizophrenia, ADHD, and addiction. Using a multidisciplinary approach that combines cognitive testing, electrophysiological recordings and advanced computational analyses, the proposed studies will examine the effects of corticotrophin-releasing factor (CRF) receptor activation within the PFC on frontostriatal circuit function. Information gained in these studies may lead to development of novel treatment strategies for frontostriatal dysfunction.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Osborn, Bettina D
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University of Wisconsin Madison
Schools of Arts and Sciences
United States
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