The cerebral cortex, including the median prefrontal cortex, receives a dense serotonergic innervation originating from the Dorsal and Median Raphe nuclei of the brainstem. It is now widely recognized that the prefrontal cortex plays an important role in the temporal organization of behavior and thus is an essential contributor to the pathophysiology of mental disorders including autism, anxiety and mood disorders and schizophrenia. Similarly, clinical and preclinical studies have also identified a strong serotonin component in the pathogenesis of these disorders and also in their pharmacological treatment. Thus there is a pressing need to understand how serotonin regulates the function of the prefrontal cortex. Yet, remarkably, our understanding of the cellular mechanisms by which serotonin regulates the activity of the prefrontal cortex remains frustratingly incomplete. Historically our ability to address serotonergic mechanisms in the prefrontal cortex has been hampered by the cellular complexity of the cerebral cortex and the lack of tools to address this complexity. Recent studies using molecular genetic approaches have begun to provide rich insights into the organization of the cerebral cortex and have generated powerful new tools for experimentally dealing with the different cell populations that make up the cerebral cortex. In this application we propose to take advantage of these developments to begin elucidating how serotonin regulates different genetically defined cell populations and hence regulates the neuronal networks that constitute the prefrontal cortex. The long term goal of this application is to contribute to a mechanistic understanding of mental disorders involving serotonin and the prefrontal cortex and the search for novel more efficacious therapeutic approaches.

Public Health Relevance

Many previous studies have implicated the neurotransmitter serotonin in the regulation of the prefrontal cortex, an area thought to be involved in the pathophysiology of mental disorders including autism, schizophrenia, anxiety and depression. Unfortunately our understanding of the neuronal mechanisms by which serotonin regulates the prefrontal cortex remains poorly understood, at least in part due to the technical limitations imposed by the cellular complexity of the cerebral cortex. In this application we propose to build on recent advances in our understanding of the cerebral cortex to begin elucidating the cellular mechanism through which serotonin regulates prefrontal cortex networks. The long term goal of this application is to contribute to the search for more effective treatments for mental disorders involving serotonin and the prefrontal cortex.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01MH043985-25
Application #
8743263
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Nadler, Laurie S
Project Start
Project End
Budget Start
Budget End
Support Year
25
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Wayne State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
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Yang, Huibin; Cooley, Desma; Legakis, Julie E et al. (2003) Phosphorylation of the Ras-GRF1 exchange factor at Ser916/898 reveals activation of Ras signaling in the cerebral cortex. J Biol Chem 278:13278-85