I received my Ph.D. in Medical Physiology from the Southwestern Graduate School of Biomedical Sciences in Dallas, Texas. As a student in the laboratory of Dr. Dwight German, I developed what has become a life-long interest in the physiological properties of midbrain dopamine neurons and their role in neuropsychiatric disease. After completing my graduate training in 1986, I undertook a post-doctoral fellowship in neuropsychopharmacology with Steve Bunney, M.D. and Robert Roth, Ph.D. at the Yale University School of Medicine. I joined the University of Maryland School of Medicine and the Maryland Psychiatric Research Center as an Assistant Professor in 1989.
The research conducted in our laboratory is currently supported by R01 grants from the National Institutes of Mental Health, the National Institute of Neurological Disorders and Stroke and by an Independent Investigator Award from the Brain and Behavioral Research Foundation. Past support has included grants from the National Institute on Drug Abuse, The Stanley Foundation and the National Alliance for Research on Schizophrenia and Depression. Mr. Leon Brown, a graduate student in the Program in Neuroscience, recently received the prestigious and highly competitive Ruth L. Kirschstein National Research Service award to support his training in our laboratory.
Our laboratory is investigating the physiological mechanisms through which dopamine-containing neurons in the ventral midbrain encode information. Located in the pars compacta of the substantia nigra and in the adjacent ventral tegmental area, these cells form reciprocal connections with neurons in the basal ganglia, cortex and limbic forebrain. Dopamine neurons and their circuits are critically involved in the regulation of motor activity and in the motivational processes underlying learning and execution of goal-directed behaviors. Understanding the basic mechanisms involved in regulating the electrical activity of these cells and their neuronal targets is an essential step in the development of new strategies for treating a variety of clinical syndromes including Parkinson's disease, schizophrenia and drug abuse.
Much of our current research is focused on study of the ionic currents that produce the complex firing patterns exhibited by dopamine neurons with an emphasis on those responsible for generating bursting activity. To accomplish this, we use a variety of contemporary electrophysiological and pharmacological techniques including intracellular and extracellular recording, in vitro brain slice techniques, microstimulation and microiontophoresis. Our research has shown that bursts of action potentials are generated intrinsically by a repetitive oscillation in membrane potential driven by voltage dependent calcium channels expressed in the dopamine neurons themselves. Currently, we are examining the interplay between these intrinsic mechanisms and the influence of afferents that contain neurotransmitters and modulators capable of modifying dopamine cell activity. Future studies are aimed at identifying the cellular mechanisms responsible for switching the firing pattern of dopamine neurons between bursting and nonbursting modalities and applying this knowledge to advance our current understanding of the influence of dopamine on target neurons throughout the forebrain.
Lab Techniques and Equipment:
Much of the research conducted in our laboratory involves single unit electrophysiological recording techniques. Two laboratories are currently dedicated to in vivo recording and microstimulation while a third is devoted to conducting visualized whole cell patch clamp recording. We are actively collaborating with Drs. Carmen Canavier (LSU School of Medicine) and Edwin Levitan (University of Pittsburgh School of Medicine) in refining a computational model of dopamine cell activity. Our laboratory is also equipped to conduct a variety of behavioral studies and we are currently collaborating with Dr. Greg Elmer on a project involving deep brain stimulation and learned helplessness.
Brown PL and Shepard PD (2013) Lesions of the fasciculus retroflexus alter footshock-induced cFos expression in the mesopontine rostromedial tegmental area of rats. PLoS One 8(4):e60678
Danna CD, Shepard PD and Elmer GE (2013) The habenula governs the attribution of incentive salience to reward predictive cues. Frontiers in Human Neuroscience doi: 10.3389/fnhum.2013.00781
Yu N, Tucker KR, Levitan ES, Shepard PD, and Canavier CC. (2013) Implications of Cellular Models of Dopamine Neurons for Schizophrenia. Computational Molecular Neuroscience: Novel Approaches to Understanding Diseases of the Nervous System (K. Blackwell, Volume Editor). In: Progress in Molecular Biology and Translational Science (P. M. Conn, Series Editor) Elsevier Press, Amsterdam.
Ji H, Tucker KR, Putzier I, Huertas MA, Horn JP, Canavier CC, Levitan ES, Shepard PD (2012) Functional characterization of ether-à-go-go-related gene potassium channels in midbrain dopamine neurons - implications for a role in depolarization block. Eur J Neurosci.
Brown PL, Shepard PD, Elmer GI, Stockman S, McFarland R, Mayo CL, Cadet JL, Krasnova IN, Greenwald M, Schoonover C, Vogel MW (2012) Altered spatial learning, cortical plasticity and hippocampal anatomy in a neurodevelopmental model of schizophrenia-related endophenotypes. . Eur J Neurosci .
Herrik KF, Redrobe JP, Holst D, Hougaard C, Sandager-Nielsen K, Nielsen AN, Ji H, Holst NM, Rasmussen HB, Nielsen EØ, Strøbæk D, Shepard PD, Christophersen P. (2012) CyPPA, a Positive SK3/SK2 Modulator, Reduces Activity of Dopaminergic Neurons, Inhibits Dopamine Release, and Counteracts Hyper-dopaminergic Behaviors Induced by Methylphenidate. Front Pharmacol. 2012.
Herrik KF, Christophersen P, Shepard PD (2010) Pharmacological modulation of the gating properties of small conductance Ca2+-activated K+ channels alters the firing pattern of dopamine neurons in vivo. Journal of Neurophysiology, 104 (3):1726-1735.
Ji HF, Hougaard C, Herrik KF, Strøbæk D, Christophersen P and Shepard P (2009) Tuning the excitability of midbrain dopamine neurons by modulating the Ca2+ sensitivity of SK channels. European Journal of Neuroscience, 29:1883-1895.
Hong LE, Buchanan RW, Thaker GK, Shepard PD and Summerfelt A (2007) Beta (~16Hz) frequency neural oscillations mediate auditory sensory gating in humans. Psychophysiology, 45:197-204.
Hikosaka O, Sesack SR, Lecourtier L, and Shepard PD (2008) Habenula: crossroad between the basal ganglia and the limbic system. Journal of Neuroscience, 28:11825-11829.
Shepard PD and Trudeau MC (2008) Emerging roles for ether-a-go-go-related gene potassium channels in the brain. Journal of Physiology, 20:4785-4786.
Ji HF and Shepard PD (2007) Lateral habenula stimulation inhibits rat midbrain dopamine neurons through a GABAA receptor-mediated mechanism. Journal of Neuroscience, 27:6923-6930.
Canavier CC, Oprisan SA, Callaway JC, Ji HF and Shepard PD (2007) Computational model predicts a role for ERG current in repolarizing plateau potentials in dopamine neurons: implications for modulation of neuronal activity. Journal of Neurophysiology, 98:3006-3022.
Shepard PD, Holcomb HH and Gold JM (2006) The presence of absence: habenular regulation of dopamine neurons and the encoding of negative outcomes. Schizophrenia Bulletin, 32:417-421.
Shepard PD (2006) Modeling negative symptoms: What’s missing. Schizophrenia Bulletin, 32:403-404.
Ji HF and Shepard PD (2006) SK Ca2+ activated K+ channel ligands alter the firing pattern of dopamine-containing neurons in vivo. Neuroscience, 140:623-633.
Links of Interest:The Maryland Psychiatric Research Center
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