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)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH043985-26
Application #
8890219
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Nadler, Laurie S
Project Start
1988-04-01
Project End
2016-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
26
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Wayne State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Feliciano, Pedro; Matos, Heidi; Andrade, Rodrigo et al. (2017) Synapsin II Regulation of GABAergic Synaptic Transmission Is Dependent on Interneuron Subtype. J Neurosci 37:1757-1771
Wyskiel, Daniel R; Andrade, Rodrigo (2016) Serotonin excites hippocampal CA1 GABAergic interneurons at the stratum radiatum-stratum lacunosum moleculare border. Hippocampus 26:1107-14
Li, Xiaoyang; Aleardi, Alicia; Wang, Jue et al. (2016) Differentiation of Spiral Ganglion-Derived Neural Stem Cells into Functional Synaptogenetic Neurons. Stem Cells Dev 25:803-13
McGregor, K M; Bécamel, C; Marin, P et al. (2016) Using melanopsin to study G protein signaling in cortical neurons. J Neurophysiol 116:1082-92
Serafini, Ruggero; Andrade, Rodrigo; Loeb, Jeffrey A (2015) Coalescence of deep and superficial epileptic foci into larger discharge units in adult rat neocortex. Neuroscience 292:148-58
Andrade, Rodrigo; Huereca, Daniel; Lyons, Joseph G et al. (2015) 5-HT1A Receptor-Mediated Autoinhibition and the Control of Serotonergic Cell Firing. ACS Chem Neurosci 6:1110-5
Feliciano, Pedro; Andrade, Rodrigo; Bykhovskaia, Maria (2013) Synapsin II and Rab3a cooperate in the regulation of epileptic and synaptic activity in the CA1 region of the hippocampus. J Neurosci 33:18319-30
Andrade, Rodrigo; Haj-Dahmane, Samir (2013) Serotonin neuron diversity in the dorsal raphe. ACS Chem Neurosci 4:22-5
Andrade, Rodrigo; Foehring, Robert C; Tzingounis, Anastasios V (2012) The calcium-activated slow AHP: cutting through the Gordian knot. Front Cell Neurosci 6:47
Villalobos, Claudio; Foehring, Robert C; Lee, Jonathan C et al. (2011) Essential role for phosphatidylinositol 4,5-bisphosphate in the expression, regulation, and gating of the slow afterhyperpolarization current in the cerebral cortex. J Neurosci 31:18303-12

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