The Morris K. Udall Center of Excellence for Parkinson’s Disease Research at Emory University

Director: Thomas Wichmann, M.D.

Title: Udall Parkinson's Disease Center at Emory University: Circuitry to Therapy

Website URL: www.udall.emory.edu

Central Theme

The Udall Center at Emory University examines the pathophysiology of Parkinson’s disease, and the mechanisms by which antiparkinsonian treatments work, from a brain circuit perspective, and aims to develop promising lines of non-dopaminergic antiparkinsonian treatments.

Parkinson’s disease is known as a condition in which dopamine loss in the basal ganglia (particularly in the striatum) results in profound changes in the neuronal activity in the basal ganglia, as well as in brain areas that are linked to the basal ganglia, specifically the ventrolateral nuclear group in the thalamus.  Most of the currently available pharmacological or surgical treatments were designed to modify or minimize these abnormalities, either by replacing dopamine, or by altering the influence of basal ganglia output on thalamocortical activity, for instance, by lesioning or stimulation of specific basal ganglia nuclei. The clinical use of many of these therapies is empiric.  Optimization of the use of these treatments is only possible if their mechanism of action is better understood.

A shortcoming of current attempts to understand the mechanisms of action of existing therapies is that their effects are usually only considered in terms of the changes they exert on the basal ganglia, while their impact on brain network elements downstream from the basal ganglia (thalamus and cortex) remains largely unknown.  Several of the studies of the Udall Center at Emory University assess the effects of basal ganglia interventions such as lesions, deep brain stimulation, or pharmacological interventions, both in rodent and nonhuman primate models of dopamine loss in the basal ganglia.  Other projects in this Udall Center aim to develop new non-dopaminergic drugs as new therapies against parkinsonism, and assess their circuit and cellular effects in the basal ganglia thalamocortical system.

Through these systems-level studies, the Emory Udall Center brings together researchers from several departments at Emory University and Vanderbilt University with complementary strong expertise in systems-centered Parkinson’s disease research.  The center fosters a collaborative, efficient, and productive environment for such research, allowing easy sharing of information and resources.  An additional important goal of the center is to educate young researchers and the larger public about Parkinson’s disease research.

Center Structure

The Udall Center at Emory University consists of four research projects (Project 1-4) and two cores (cores A and B).  Two of the research projects examine the impact of parkinsonism and the effects of restorative surgical and pharmacological antiparkinsonian therapies on the thalamus, the main gateway through which dysfunctional basal ganglia outflow is conveyed to the cerebral cortex in Parkinson’s disease.  Two other projects, including one that is carried out at Vanderbilt University (Project 4), are already well on the path to the development of novel non-dopaminergic therapies in Parkinson’s disease.

Project 1 (PI: Dieter Jaeger, PhD) consists of in vivo and brain slice electrophysiologic recording experiments to investigate the impact of basal ganglia output on thalamic activity, and to assess how abnormal basal ganglia output translates into dysfunctional thalamic activity in parkinsonism.  These studies are carried out in two different rodent models, including a model in which dopamine loss in the basal ganglia is produced by the dopaminergic neurotoxin, MPTP, and a second mouse model in which chronic progressive parkinsonism is induced by a genetic modification of VMAT2, one of the molecules involved in dopamine storage and release in the central nervous system.  Project 2 (PI: Thomas Wichmann, MD) explores changes in thalamic activity in parkinsonian primates, and the effects of different neurosurgical interventions in the basal ganglia on this activity. This project is motivated by the observation that lesions and deep brain stimulation of the basal ganglia output nuclei have similar clinical antiparkinsonian effects, despite different mechanisms of action in the basal ganglia.  These experiments test the hypothesis that the similar therapeutic effects of these procedures are due to similarities in their (downstream) effects on thalamic activities.  Project 3 (PI: Gary Miller, PhD) is the Center’s most directly translational project.  It examines the efficacy and pharmacokinetic properties of a new group of orally active agonists at TrkB receptors (i.e., the binding sites mediating neurotrophic activities of brain derived neurotrophic factor [BDNF]) in protecting dopaminergic neurons and mitigating the signs of parkinsonism in rodent and primate models.  Project 4 (PI: P. Jeffery Conn, PhD, Vanderbilt University) is another highly translational project that uses electrophysiological and behavioral studies to examine the involvement of cholinergic dysfunction in parkinsonism and to test the potential antiparkinsonian efficacy of novel highly subtype-selective muscarinic receptor agents in rodent models of Parkinson’s disease.    

The Center’s administrative core (core A, PI: Thomas Wichmann, MD) coordinates the interactions between the different investigators and their laboratories, is in charge of interactions with the overall Udall Center network, the funding agency, as well as local and external advisors.  The core also organizes local meetings, administers the center’s pilot grant program, maintains the center’s website, and organizes the center’s education and outreach activities.  The Center’s anatomy and behavior core (core B, PI: Yoland Smith, PhD) conducts the extensive anatomical studies in each project, and carry out some of the primate drug testing studies for Project 3.

Recent Significant Advances

• The technically demanding in vivo single unit and local field potential recordings from normal controls and MPTP-treated mice, as well as optogenetic experiments are producing exciting results, delineating the conditions under which basal ganglia output contributes to pathological burst activities in the thalamus in Parkinson’s disease.
• An extensive series of recordings of cortical evoked potentials and thalamic single unit recordings in the ventrolateral thalamus (the basal-ganglia receiving region of the thalamus) was carried out while the subthalamic nucleus was stimulated.  Similar studies of pallidal interventions are underway.  The studies will help us to define the responses of the thalamocortical network to basal ganglia output under normal and parkinsonian conditions, before and after neurosurgical interventions (pallidotomies or electrical stimulation of the internal pallidal segment or subthalamic nucleus).
• Development of a hardware stimulus and line noise removal device which will make stimulation experiments substantially easier and faster to analyze.
• Experiments show a role of M1 receptors in cholinergic excitation of striatal output neurons and neurons in the subthalamic nucleus and the substantia nigra pars reticulata.
• Completion of the first study of the antiparkinsonian activity of a new selective M1 antagonist (VU025035) in rodent models of Parkinson’s disease was completed with promising results.

Other Accomplishments

• Successful completion of three pilot projects, focusing on (1) immunologic factors in the development of a specific newly discovered form of Parkinson’s disease (PIs: Boss/Tansey), (2) environmental factors that may lead to loss of noradrenergic neurons in Parkinson’s disease (PI: Roede), and (3) new efforts to image the locus coeruleus in Parkinson’s disease patients (PI: Huddleston).
• The center was able to fund four new pilot projects, researching (1) the potential role of influenza infections in Parkinson's disease (PIs: Koutsonanos/Tansey), (2) the possible neuroprotective role of MEF2D activators in Parkinson’s disease (PI: Li), (3) the motion of microglia in the substantia nigra pars compacta in MPTP-treated mice, and (4) a new balance-improving rehabilitative strategy for Parkinson's disease patients (PIs: McKay/Hackney/Ting).
• In conjunction with its outreach board, the center organized and participated in a variety of outreach efforts, including talks to patients, physicians and nurses, small-group educational sessions with patients, and participations in multiple local and national Parkinson’s disease support groups.
• The center continues to provide research education for students, fellows and physicians, using a variety of formats, ranging from hands-on bench research to participation in journal club activities to seminar talks.

Resources Available

Members of the Emory Udall Parkinson’s Disease Center share analysis algorithms, and publish the study data in a timely manner.  It is also our policy to make reagents such as the compounds used under projects 3 and 4 available (within the limits of patent right restrictions). The VMAT2LO mouse model is another available resource.

Plans for the Coming Year

The coming year will be the center’s third year. All projects will continue to pursue their original goals.  Under project 1, brain slice recordings and in vivo studies will be carried out to study the impact of the activity of substantia nigra neurons on thalamic activities, with a focus on genetic models of Parkinson’s disease.  In project 2, animals have now been treated to develop parkinsonism, and will be intensely studied in the parkinsonian state, using in vivo brain recording techniques.  Project 3 personnel will continue to study TrkB agonist effects on parkinsonism in MPTP-treated and VMAT2LO mice, and will focus on a better definition of the precise location(s) of action of these agents.  In project 4, muscarinic M1 receptor and muscarinic M4 receptor ligands will be tested in brain slice recording studies, and in in vivo experiments in parkinsonian rodents.  Core B continues to support the projects with anatomic studies, helping with a variety of tasks, including the reconstruction of electrode tracks, as well as light- and electron microscopic immunochemical studies of the anatomy of the basal ganglia and thalamus experiments.  Core A will continue to help with administrative tasks, organize the pilot project program, and interact with the public.

Select Recent Publications

Edgerton, J. R. and Jaeger, D. (2011). "Dendritic Sodium Channels Promote Active Decorrelation and Reduce Phase Locking to Parkinsonian Input Oscillations in Model Globus Pallidus Neurons." Journal of Neuroscience 31(30): 10919-10936.

Wichmann, T., Devergnas, A. (2011). A novel device to suppress electrical stimulus artifacts in electrophysiological experiments. J Neurosci Methods, 201: 1-8.

Wichmann T (2011) Functional Aspects of the basal ganglia. In: Movement Disorders (D Burn, ed.; series: Oxford Textbooks in Clinical Neurology). Oxford University Press, Oxford.

Lebois, E., Digby, G., Sheffler, D., Melancon, B., Tarr, J., Cho, H., Miller, N., Morrison, R., Bridges, T., Xiang, Z., Daniels, S., Wood, M., Conn, P.J., and Lindsley, C. (2011). Development of a highly selective, orally bioavailable and CNS penetrant M1 agonist. Bioorg Med Chem Lett. 21: 6451-5.

Reid, P., Bridges, T., Sheffler, D., Cho, H., Lewis, L., Days, E., Daniels, J.S., Jones, C., Niswender, C., Weaver, C.D., Conn, P.J., Lindsley, C.W., and Wood, M. (2011). Discovery and optimization of a novel, selective and brain penetrant M(1) positive allosteric modulator. Bioorg Med Chem Lett. 21: 2697-701.

Digby, G.J., Noetzel, M.J., Bubser, M., Utley, T.J., Walker, A.G., Byun, N.E., Lebois, E.P., Xiang, Z., Sheffler, D.J., Cho, H.P., Davis, A.A., Nemirovski, M., Mannenga, S.E., Camp, B., Bimonte-Nelson, H.A., Bode, J., Italiano, K., Morrison, R.D., Daniels, J.S., Niswender, C.M., Olive, M.F., Lindsley, C.W. and Jones, C. and Conn, PJ  (2012). Novel allosteric agonists of M1 muscarinic acetylcholine receptors induce brain region-specific responses that correspond with behavioral effects in animal models. J Neurosci. (In Press).

Xiang, Z., Thompson, G., Denise, A., Jones, C., Lindsley, C. and Conn, P.J. (2012). Roles of M1 muscarinic acetylcholine receptor subtype in regulation of basal ganglia function and implications for treatment of Parkinson’s disease. J. Pharmacol. Exp. Ther. 340: 595-603.

Melancon, B.J., Lamers, A.P., Bridges, T.M., Sulikowski, G.A., Utley, J.U., Sheffler, D.J., Noetzel, M.J., Morrison, R.D., Daniels, J.S., Niswender, C.M., Jones, C.K., Conn, P.J., Lindsley, C.W. and Wood, M.R. (2012). Development of a more highly selective M1 antagonist from the continued optimization of the MLPCN probe ML012. Bioorg. & Med. Chem. Lett. 22: 1044-8.

Rubin, JE, McIntyre, CC, Turner, RS, Wichmann T (2012) Basal ganglia activity patterns in parkinsonism and computational modeling of their downstream effects. European J Neuroscience, in press.

Devergnas AD, Sanders TH, Clements MA, Wichmann T (2012) Classification of the severity of parkinsonism based on wavelet packet transform analysis of electroencephalographic and subthalamic local field potential recordings.  Soc Neurosci Meeting Abstr.

Sanders TH, Devergnas AD, Clements MA, Wichmann T (2012) Identifying parkinsonism in monkeys using wavelet packet transform of local field potentials. BMES conference proceedings.

Schultheiss, N.W., Edgerton, J.R., and Jaeger, D. (2012) Robustness, variability, phase dependence, and longevity of individual synaptic input effects on spike timing during fluctuating synaptic backgrounds: A modeling study of globus pallidus neuron phase response properties. In press.

Public Health Statement

One goal of research at the Emory’s Udall Center is to develop a better understanding of how existing surgical and medical treatments for patients with Parkinson’s disease work.  While previous studies in this field have largely focused on the effects of these interventions on the activity of neurons in the basal ganglia, i.e., the brain areas that are immediately affected by dopamine loss in Parkinson’s disease, the studies in two of the center’s projects focus on the downstream effects of these interventions, by examining thalamic activities in animals in which basal ganglia output is altered by lesions, stimulation, or other interventions.  The thalamus is the anatomical bridge by which basal ganglia output is linked to the cerebral cortex.  Abnormalities in the activity of the cerebral cortex directly affect movement, and may lead to the motion abnormalities in Parkinson’s disease.  The planned studies will teach us how the basal ganglia output affects thalamic nerve cell activity under normal conditions, and determine the underlying mechanisms by which activity changes in the basal ganglia alter thalamic firing in parkinsonism. The knowledge gained will enable us to devise better therapies that may act to normalize thalamic activities in parkinsonian subjects.  By identifying the commonalities and differences between antiparkinsonian interventions that differentially alter basal ganglia output and thalamic activity (lesion or stimulation), we will be able to identify and optimize the thalamic firing patterns associated with successful surgical treatments for the disease.

The second goal of the center’s research is to examine the mechanism of action and therapeutic potential of two non-dopaminergic therapies that provide neuroprotective or symptomatic benefits for Parkinson’s disease.  One of the projects examines the symptomatic and neuroprotective effects of a new class of drugs that act at brain receptors for nerve growth factors.  Through research done at Emory, oral agents activating these receptors have recently become available.  Previous experiments have shown that these drugs may protect dopaminergic neurons from damage in animal models of Parkinson’s disease.  The ongoing experiments further explore the use of these drugs in rodent and monkey models of the disease.  Another project studies newly developed ‘cholinergic’ drugs in animal models of Parkinson’s disease.  Currently available medications in this category have been used to treat Parkinson’s disease for decades, but these agents have many side effects which severely limit their clinical use.  Work in Vanderbilt University’s Program in Drug Discovery has recently led to the development of a new group of chemicals that act at cholinergic receptors with much higher specificity than the previously used drugs.  The ongoing studies examine the pharmacological and behavioral effects of these drugs in different rodent models of Parkinson’s disease, with the hope of finding drugs that can be used to treat parkinsonism without inducing side effects.