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The Levinson Emerging Scholars Program

Denis Smirnov- Biochemistry, Neurobiology

Denis Smirnov Denis Smirnov is a senior at the University of Washington majoring in Biochemistry and Neurobiology. Having grown up in Russia, he has spent the last 10 years of his life in Seattle, attending Juanita High School in Kirkland before coming to UW. He is currently working in the laboratory of John Neumaier, MD., PhD. in the Department of Psychiatry and Behavioral Sciences, on a project aimed to understand the neural circuitry underlying addiction and relapse to drugs of abuse. He recently presented this research at the Society for Neuroscience conference in San Diego, and was an author of a recent publication in the Journal of Clinical Investigation, detailing a novel microPET imagine technique to map whole brain function in both anesthetized and awake, freely-moving animals in a highly sensitive manner. Involved in research for over 3 years across three different labs ranging to biochemistry, to chemistry, to neurobiology, Denis has worked extensively to prepare himself for a career in academic medicine. Upon graduating in the Spring of 2014, he plans to pursue an MD at a research oriented medical school, with the hope of one day becoming a neurologist or neurosurgeon.

Mentor: John Neumaier, Psychiatry

Project Title: The Role of the Lateral Habenula and the Rostromedial Tegmental Nucleus in Cocaine Addiction

Abstract: An important problem in the treatment of cocaine addiction is the vulnerability of previously addicted individuals to relapse to cocaine use months or even years after abstinence. The lateral habenula (LHb), part of the habenular complex in the dorsal diencephalon, and the rostromedial tegmental nucleus (RMTg), a recently identified nucleus in the reticular formation, are important regulators of the midbrain dopaminergic systems that are known to be involved in cocaine taking and relapse behaviors. However, very little is known about the precise role of these nuclei in cocaine reinforced behaviors. Here, I initially characterize the anatomical location of the RMTg using expression of the transcription factor cFos, as a marker of neuronal activation in response to cocaine. Next, we utilize the Designer Receptor Activated Exclusively by Designer Drug (DREADD) technology, to investigate the role of modulating the activity of the LHb on cocaine-self administration in rats. We demonstrate that DREADD-mediated transient silencing of the LHb through the activation of a Gi-coupled signaling pathway increases cocaine self-administration, while transient stimulation through the activation of the Gq-coupled signaling pathway decreases self-administration on a progressive ratio schedule, suggesting a reciprocal role between LHb and VTA activity. We further show that inactivation of the LHb to VTA projections has no effect on cocaine self-administration. Given this, we propose to investigate the indirect LHb projections to the VTA through the RMTg using our newly developed dual-virus strategy to specifically target the LHb to RMTg projection for DREADD-mediated modulation on self-administration and reinstatement.