Mathematical Biosciences Institute (MBI) Ohio-State University

Ph.D. Candidate (September 18, 2009). Mathematical, Computational and Modeling Sciences Center (MCMSC).
Dissertation Title: A Mathematical Model of Dopamine Neurotransmission.
Dissertation Co-Chairs: Prof. Sharon M. Crook and Prof. Priscilla E. Greenwood.
Committee Members: Prof. Steve Baer, Prof. Edward Castaneda, and Prof. Carlos Castillo-Chavez.

M.S. in Mathematics (April 2003). University of Michigan 2001-2004. Ann Arbor, MI.
B.S. in Mathematics (July 2001). University of Illinois at Chicago 1995-2001. Chicago, IL.
H.S. Diploma (June 1995). Theodore Roosevelt High School 1993-1995. Chicago, IL.

RESEARCH PROFILE

I am a computational neuroscientist, in training, studying the neurotransmission dynamics of midbrain dopamine neurons (MDNs) through computational and mathematical modeling.

Dopamine (DA) is a catecholamine neurotransmitter abundant in the central nervous system, which is primarily concentrated in the midbrain area [9]. The distribution of the cell bodies of DA neurons varies dramatically between different mammals (rodents, primates, and humans) and even more among different vertebrates [11]. Though most neuroanatomical studies on DA systems have been carried out in rats, other studies have shown that the general anatomical features of the DA system revealed in the rat are also preserved in other mammals [45]. The anatomy of a DA neuron consists of a cell body called a soma, from which highly branched extensions called dendrites emerge [27,59,134]. The axon of a DA neuron rises out from a major dendrite [27,59,134,143] originating at the axon hillock and contains swellings along the length called varicosities [9,34,37,63,134,140,143,166].

Midbrain DA neurons are involved in attention, goal oriented behavior, motor abnormalities, reward learning, and short and working memory [39,45,143,174]. The cell bodies of these DAneurons are located in the retrorubal area, substantia nigra and ventral tegmental area. MDNs projecting pathways that originate in the substantia nigra-ventral tegmental area are classified into three distinct systems that target the neostriatum, limbic cortex, and other limbic areas. These are typically referred to as the nigrostriatal (also known as mesostriatal), mesolimbic and mesocortical pathways, respectively [11].

DOPAMINE NEUROTRANSMISSION DYNAMICS. DA neurotransmission is a biochemical processes often referred to as chemical transmission (synaptic and non-synaptic) or volume transmission [161,163]. During DA synaptic transmission, presynaptic electrical signals result in increments in DA concentration and receptor occupation, resulting in electrical activity in the postsynaptic neuron [154]. DA dynamics are affected by two distinct mechanisms: (1) the amount of DA escaping from release sites via changes in release minus reuptake and degradation, and (2) DA neuron firing rate which is affected by feedback signals emitted by the receptors (from axonal terminals in the target areas and somatodendritic area located in the midbrain) [154,164]. It is well accepted that MDNs of the substantia nigra-ventral tegmental area have three different firing patterns: regular, irregular and bursting [12,58,59,60,61,66,95]. Furthermore, there is experimental evidence that a single DA neuron is able to switch from one pattern to another [53]. The natural pattern switch exhibited by DA neurons raises a need to quantify the complex behavior of the interspike intervals (ISIs) of MDNs, since evidence shows that different release modes are associated with different firing patterns [12,53,57,58,71]. Collaborative efforts to understand the transient changes in extracellular DA concentration lead to a number of questions. (1) Are there temporal differences in DA concentrations at release sites? (2) Is DA transmission differently affected by the different DA firing patterns? (3) How are changes within firing trains translated into changes in DA delivery?. Previous efforts have sought answers to these questions while modeling changes in extracellular DA concentration [161] or while modeling the interactions of extracellular DA concentration with DA firing rates [107].

DOPAMINE RESEARCH OVERVIEW. Collaborative, ongoing research efforts have shown the value of mathematical modeling for the interpretation and understanding of experimental data [28,167]. Regarding the importance of mathematical modeling in DA research, Professor Gordon Arbuthnott of the Department of Anatomy & Structural Biology at the University of Otago states [167] that "a quantitative analysis of the sub-cellular anatomical arrangements in the striatum together with a formulation of thediffusion and degradation of DA in the extracellular medium leads to a radical reevaluation of the DA signal." There are a vast number of computational and mathematical models constructed over the past 35 years where the main focus is DA dynamics. These models target specific aspects of the kinetics of DA neurons and have the common goal of understanding the dynamics of DA neurons by exploring the channel kinetics, the firing rate, and the functional organization found experimentally in vitro and in vivo among MDNs.

GOOD REFERENCES:

• Birth, Life and Death of Dopaminergic Neurons in the Substantia Nigra (Journal of Neural Transmission. Supplementa). This book provides a unique and timely multidisciplinary synthesis of our current knowledge of the anatomy, pharmacology, physiology and pathology of the substantia nigra pars compacta (SNc) dopaminergic neurons. The single chapters, written by top scientists in their fields, explore the life cycle of dopaminergic neurons from their birth to death, the cause of Parkinson's disease, the second most common and disabling condition in the elderly population. Nevertheless, the intracellular cascade of events leading to dopamine cell death is still unknown and, consequently, treatment is symptomatic rather than preventive. The mechanisms by which alterations cause neuronal death, new therapeutic approaches and the latest evidence of a possible de novo neurogenesis in the SNc are reviewed and singled out in different chapters. This book bridges basic science and clinical practice and will prepare the reader for the next few years, which will surely be eventful in terms of the progress of dopamine research. Publisher: Springer; 1 edition (October 1, 2009)
• DOPAMINE, REWARD PREDICTION ERROR, AND ECONOMICS by Andrew Caplin and Mark Dean. Abstract: The neurotransmitter dopamine has been found to play a crucial role in choice, learning and belief formation. The best developed current theory of dopaminergic function is the "reward prediction error" hypothesis that dopamine encodes the difference between the experienced and predicted "reward" of an event. We provide axiomatic foundations for this hypothesis to help bridge the current conceptual gap between neuroscience and economics. Continued research in this area of overlap between social and natural science promises to overhaul our understanding of how beliefs and preferences are formed, how they evolve, and how they play out in the act of choice (August 9, 2007).
• Fifty years of dopamine research. Edited by A. Bjorklund and S.B. Dunnet. Trends in Neurosciences, Volume 30, Issue 5, Pages 185-250 (May 2007).

PEOPLE WORKING ON DOPAMINE RELATED MODELS

Spiking Neuron Models People

• Carmen C. Canavier, Louisiana State University School of Medicine.
• Nancy Kopell, Boston University.
• Alexey Kuznetsov, Indiana University Purdue University Indianapolis.
• Georgi Medvedev, Drexel University.
• Sorinel A. Oprisan,College of Charleston.
• Carlos A. Paladini, The University of Texas at San Antonio.
• Horacio G. Rotstein, New Jersey Institute of Technology.
• Charles J. Wilson, The University of Texas at San Antonio.

• Paul A. Garris, Illinois State University.
• Michael Reed, Duke University.
• Mark Wightman, University of North Carolina at Chapel Hill.