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| Charles Nichols, Ph.D. |
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| The research in my laboratory focuses on understanding how serotonergic function in the brain modulates behaviors relevant to neuropsychiatric disorders. We follow a systems based approach, utilizing both rodent and Drosophila models, pharmacology, molecular biology, and genetics. |
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| Serotonin (5-HT) regulates a wide range of behaviors including mood, cognition, appetite, sleep, memory, and sex. The effects of serotonin are primarily mediated through interactions with a large number of G-protein coupled receptor proteins, initiating multiple effector pathways. Dysregulation of human serotonin signaling is implicated in many neuropsychiatric disorders such as depression, obsessive compulsive disorder, anorexia, and schizophrenia. A greater understanding of the molecular events underlying normal serotonergic function may lead to insights into both normal cognitive processes and neuropsychiatric disorders. |
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In rodents, we are using a powerful class of serotonin receptor agonist, hallucinogenic drugs, in combination with microarray experiments to examine serotonergic function in the prefrontal cortex. We have shown that the potent serotonin receptor agonist lysergic acid diethylamide (LSD) has a dramatic and dynamic effect on gene expression within the prefrontal cortex of mammalian brain. A common theme of many of these gene products is the process of synaptic plasticity. Ongoing investigations include functional studies of these genes and their proteins, as well as additional gene discovery experiments. |
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To elucidate the molecular events linking serotonin receptor activation to gene expression, and gene expression to behaviors, we are developing the fruit fly, Drosophila melanogaster, to use as a genetic model system to study serotonergic function. By harnessing the powerful genetics of the fly, we anticipate being able to elucidate entire signaling pathways more rapidly and effeciently than in mammalian based systems.
We have shown that, quite remarkably, pharmacological activation of serotonin 5-HT2 receptors in the fly produces robust quantifiable behaviors not unlike those observed in mammalian systems. We have also mapped the 5-HT2 receptor circuitry in the fly, and have identified additional behaviors, like circadian rhythms, that this receptor is involved in. Ongoing investigations include further developing this model by analyzing the role of serotonin in additional behaviors, and developing the genetic tools necessary to begin screens using orthologs of the rat genes identified in our target discovery experiments as molecular entry points into signal transduction pathways linking receptor activation to behavior. Ultimately, key discoveries in the fly will be translated back into mammalian systems. |
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