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. 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 additional neuromodulators found within the PFC, including corticotropin-releasing factor (CRF). The PFC contains a high density of CRF receptors. Currently, we know little about the actions of PFC CRF on frontostriatal neuronal function, which presents a significant gap in our understanding of the neurobiology of the PFC, CRF and goal-directed behavior. In recent studies, we observed that CRF acts locally within the caudal dorsomedial PFC to impair PFC-dependent higher cognitive function in rats as measured in a test of spatial working memory. Preliminary studies indicate that infusion of a CRF antagonist improves working memory, 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 determine the broader cognitive actions of CRF signaling in the PFC and to examine the electrophysiological effects of CRF signaling in the PFC on frontostriatal neuronal coding in rats engaged in a spatial working memory task. Our studies will apply a variety of advanced computational analyses of spike trains and local field potentials. The frontostriatal-dependent tasks of spatial working memory and sustained attention used to test cognitive function in the proposed studies offer translationally relevant insight into the mechanisms underlying behavioral deficits in frontostriatal psychopathology, satisfying the Research Domain Criteria (RDoC) initiative of the NIMH. Ultimately, this research program will provide new insight into the neurobiology of frontostriatal- dependent cognition/behavior that may lead to novel treatment strategies for frontostriatal dysfunction.
The prefrontal cortex (PFC) and extended frontostriatal circuitry play a pivotal role in higher cognitive function, with frontostriatal dysfunction being implicated 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 corticotropin-releasing factor (CRF) signaling within the PFC on frontostriatal circuit function. Information gained in these studies may lead to development of novel treatment strategies for frontostriatal dysfunction.
| Hupalo, Sofiya; Berridge, Craig W (2016) Working Memory Impairing Actions of Corticotropin-Releasing Factor (CRF) Neurotransmission in the Prefrontal Cortex. Neuropsychopharmacology 41:2733-40 |
