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Paul D. Shepard, PhD

Academic Title:

Professor

Primary Appointment:

Psychiatry

Secondary Appointment(s):

Pharmacology

Location:

Maryland Psychiatric Research Center, Maple and Locust Streets, Room B-25, Baltimore, MD 21228

Phone (Primary):

(410) 402-7753

Education and Training

  • Ph.D. Medical Physiology, University of Texas Health Southwestern Graduate School of Biomedical Sciences, 1986
  • NRSA Postdoctoral Fellowship, Neuropsychopharmacology, Yale University School of Medicine, 1986-1989

  

Biosketch

For nearly three decades, my work has centered on defining the role of dopamine neurons in neuropsychiatric disease and its treatment.  As a doctoral student with Dwight German, I developed a strong interest in the cellular mechanisms regulating neuronal firing pattern and whether drugs capable of altering the temporal organization of spike trains could be used to modulate neurotransmitter release and thus dopamine’s effects on behavior. During a post-doctoral fellowship with Steve Bunney, my work became increasingly focused on the cell autonomous biophysical mechanisms that regulate dopamine cell excitability. As an independent investigator at the Maryland Psychiatric Research Center, I have maintained an active interest in exploring the potential of individual voltage and ligand-gated ion channels to serve as therapeutic targets.  For the past decade, our lab has also been interested in the habenula and its connections with the rostromedial tegmental area in the context of salience/reward processing and major depressive disorder.  

We use a multidisciplinary approach to record and manipulate activity in the rodent brain including in vivo single unit and in vitro whole cell patch recording techniques, conventional and optogenetic stimulation techniques, and immunohistochemical methods.  We also collaborate with investigators using a variety of behavioral methods, conductance-based computational modeling techniques, magnetic resonance imaging and transcranial magnetic stimulation.

Research/Clinical Keywords

Schizophrenia, Depression, Dopamine, Habenula, Animal Models, Antidepressants

Highlighted Publications

  • Brown, PL Palacorolla H Brady D Riegger K Elmer GI, Shepard PD. Habenular-induced inhibition of midbrain dopamine neurons is diminished by lesions of the rostromedial tegmental nucleus. Journal of Neuroscience 2017 37:217-225.
  • Brown PL, Shepard PD Functional evidence for a direct excitatory projection from the lateral habenula to the ventral tegmental area in the rat. J. Neurophysiology 2016 116:1161-1174.
  • Wang L Lu H Rea W Brown PL Vaupel B Yang Y Stein E, Shepard PD. Activity-independent and activity-dependent labeling of the habenulomesencephalic pathway in the rat using manganese-enhanced magnetic resonance imaging. PLoS ONE. 2015 10: e0127773. 
  • Ji H Tucker K Putzier I Levitan ES Canavier CC HornJP, Shepard PD. Functional Characterization of ERG Channels in Midbrain Dopamine Neurons: Implications for a Role in Depolarization Block. European Journal of Neuroscience. 2012 36:2906-2916. 
  • 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. CyPPA, a positive SK3/SK2 modulator, reduces activity of dopaminergic neurons, inhibits dopamine release, and counteracts hyperdopaminergic behaviors induced by methylphenidate. Front Neuropharmacol. 2012 3:11. 
  • Ji HF, Hougaard C, Herrik KF, Strøbæk D, Christophersen P, Shepard P. Tuning the excitability of midbrain dopamine neurons by modulating the Ca2+ sensitivity of SK channels. European Journal of Neuroscience. 2009 29:1883-1895.
  • Ji HF, Shepard PD. Lateral habenula stimulation inhibits rat midbrain dopamine neurons through a GABAA receptor-mediated mechanism.  Journal of Neuroscience. 2007 27:6923-6930.
  • Shepard PD, Holcomb HH, Gold JM. The presence of absence: habenular regulation of dopamine neurons and the encoding of negative outcomes. Schizophrenia Bulletin. 2006 32:417-421.

 

Research Interests

My research interests have broadened during my tenure at the University of Maryland School of Medicine and the Maryland Psychiatric Research Center but have always centered on the role of dopamine-containing neurons in neurological and psychiatric disease.  We use a variety of methods to assess changes in neuronal activity ranging from the expression of immediate early genes to whole cell patch clamp recording in brain slices and both conduct and collaborate with investigators using complementary behavioral methods and animal models of psychopathology.  In the paragraphs below, I have summarized some of our work to illustrate the range of my scientific interests and technical repertoire. I have also briefly described my sense of where we are headed in the immediate future.  

Ion Channels as Potential Therapeutic Targets Midbrain dopamine (DA) neurons have been implicated in a variety of neurological and psychiatric disorders including Parkinson's disease, substance abuse and addiction. While excitatory and inhibitory inputs to DA neurons play an important role in modulating their activity, our early work focused on elucidating the contributions made by specific ion channels to integrated electrical properties of the neuron.  In my earliest work as an independent investigator, I described the influence of a small conductance Ca2+-activated K+ channel on pacemaker activity and showed that an atypical dihydropyridine-sensitive Ca2+ conductance was responsible for producing the intrinsic oscillation in membrane potential that supports bursting activity in DA neurons.  In collaboration with colleagues in Denmark, we showed that allosteric modulation of SK channels alters the firing pattern of DA cells in vivo and in vitroand could represent a novel strategy for treating Parkinson’s disease. Working with collaborators at LSU, a computational model of the intrinsic electrical properties of DA neurons was devised and used to predict the involvement of other ion channels in regulation of neuronal activity. These studies led to the identification of an ether-a-go-go related gene K+ channel in DA neurons and the identification of a novel role for these channels in mediating the therapeutic efficacy of first and second generation antipsychotic drugs. 

Neural Basis of Reward Learning and Incentive Salience  The realization that midbrain DA neurons encode a reward prediction signal has led to new insights regarding the neurobiological mechanisms that drive reward learning, incentive motivation and by extension, substance abuse. Several years ago, we became interested in generating a fictive negative reward prediction signal in rats by transiently silencing the spontaneous activity of these neurons.  Supported by an R24 translational research grant from NIMH, we showed that stimulation of the lateral habenula, a relatively obscure and understudied brain region, potently suppressed the activity of DA neurons at a population level. Subsequent work showed that the response is mediated through a disynaptic feedforward inhibition mediated by GABAA neuron in the rostromedial tegmentum. A parallel group of collaborative fMRI studies showing that patients with schizophrenia lack appropriate modulation of habenular activity to negative feedback, led to the first published report of the habenula’s putative role in reinforcement learning and reward processing. Initially envisioned to contribute to the avolition and anhedonia manifest in a variety of psychiatric disorders, we subsequently showed that brief electrical stimulation of the habenula during the presentation of a conditioned stimulus predicting a reward reduced the cue’s incentive salience while lesions of the pathway connecting the habenula to the ventral midbrain had the opposite effect. The contribution made by the habenula in governing the incentive motivational salience to reward predictive cues would seem to imply that pathological changes in its activity contribute to the aberrant pursuit of debilitating goals, avolition and depression-like symptoms. This is an active area of research in our lab that is currently supported by R01 funding from the NIMH.

Translational Animal Models of Neuropsychiatric Disorders Our laboratory has also maintained an active interest in the use of electrophysiological endpoints to assess the construct, face and predictive validity of animal models of neuropsychiatric disease. We showed that elevated levels of kynurenic acid (KYNA), a tryptophan metabolite and antagonist of NMDA and alpha-7 nicotinic receptors disrupt auditory gating in rats.  This was the first published report in which elevated levels of brain KYNA were associated with a deficit similar to that observed in persons with schizophrenia and it served as a lead up to studies that eventually identified elevated levels of KYNA in the brains of persons with the disorder. In a subsequent study, similar techniques were used to assess the effects of prenatal exposure to repeated stressors on adult offspring. Prenatal stress during the third week of pregnancy caused adult rats to show gating deficits in hippocampal auditory evoked potentials; changes that were accompanied by a concomitant reduction in prepulse inhibition of the acoustic startle response. The combined use of behavioral and electrophysiological endpoints proved to be a valuable approach for assessing developmental deficits at the most vulnerable points in gestation and we used a similar tactic to assess functional changes in adult offspring of maternal rats exposed to short-acting antimitotic agents delivered during critical periods of neocortical and hippocampal neurogenesis.  Finally, using an established animal model of depressed behavior, we have preliminary data showing that exposure to isoflurane anesthesia reduces the incidence of learned helplessness in rats.  This work supports and extends earlier clinical studies in which the efficacy of isoflurane anesthesia was found to be equivalent to ECT. We have recently obtained funding from NIMH to support this work and to test a novel mechanism that could provide new insight into the therapeutic actions of ECT. 

Future Directions – Our work with the habenula has led to the identification of a novel circuit that exerts a powerful inhibitory control over the entire midbrain DA cell population.  Recent findings indicate that one of the nodes of this circuit, the rostormedial tegmental area (RMTg) also receives direct nociceptive input from the spinal cord.  Given the growing body of evidence suggesting a role for the habenula in depression, we are preparing a new R01 application to test the hypothesis that the RMTg plays a key role in co-morbidity between depression and response to pain.  This grant will make extensive use of optogenetic methodology which is currently being implemented in the lab to modulate the activity of specific groups of neurons within the RMTg and lateral habenula.  Finally, we have just submitted a new R01 application for support under the NIH BRAIN Initiative to develop a novel, non-invasive and focally precise instrument for deep brain stimulation.  This collaborative endeavor involves a team of investigators with expertise in electrical and mechanical engineering, computational modeling, human neuroimaging, transcranial magnetic stimulation and systems neuroscience.   

Professional Activity

  • 2005 –             Associate Editor, Schizophrenia Bulletin
  • 2011 – 2013   Psychosis Advisory Board, Lilly USA, LLC 
  • 2014                 Ad Hoc Member, NIH Study Section, Biobehavioral Regulation, Learning and Ethology
  • 2015 -              Consultant, Takeda Development Center Americas
  • 2016                 Member, NIH Special Emphasis Panel, Targeting Temporal Dynamics of the Brain Activity for the Treatment of Cognitive Deficits
  • 2016                 Ad Hoc Member, Board of Scientific Councilors, National Institute on Drug Abuse
  • 2017                 Ad Hoc Member, NIH Study Section, Neurobiology of Motivated Behavior
  • 2017                 Invited Participant, RDoC 2.0, National Institute of Mental Health