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: Under development.

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 new non-dopaminergic antiparkinsonian treatments.

In Parkinson's disease, loss of dopamine in the basal ganglia (particularly the striatum) results in profound changes in the neuronal activity in the basal ganglia, as well as in other areas that are linked to the basal ganglia (specifically the ventrolateral nuclear group in the thalamus). Most of the pharmacological and surgical treatments that are currently available were designed to address these abnormalities, either by replacing dopamine, or by altering the influence of basal ganglia output, for instance by lesioning or stimulating specific basal ganglia nuclei with DBS. The clinical use of many of these therapies is empiric. The rational optimization of the use of these treatments will only be possible if our understanding of their mechanisms of action improves.

A shortcoming of many current attempts to understand the mechanisms by which existing therapies act is the focus on their effects on just the basal ganglia, while the impact of these therapies on elements of the brain circuitry downstream from the basal ganglia (thalamus and cortex) remains largely unexamined. Several of the studies of the Udall Center at Emory University are focused on assessing the effects of basal ganglia interventions such as lesioning, deep brain stimulation, and pharmacological interventions, on the thalamus, in both rodent and nonhuman primate models of dopamine loss in the basal ganglia. The other projects in this Udall Center are aimed at developing new non-dopaminergic antiparkinsonian drugs, and will assess the effects of these drugs on the circuitry and cellular function in the basal ganglia and thalamocortical system.

With these systems-level studies, the Emory Udall Center brings together researchers from several departments at Emory University and Vanderbilt University with complementary expertise in systems-oriented Parkinson's disease research. The center creates an environment that encourages collaboration and synergy, with sharing of ideas and resources, which lead to increased efficiency and productivity in the research. The center also serves an important function of educating 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. The two other projects, including one that is carried out at Vanderbilt University (Project 4), are already well under way in the development of novel non-dopaminergic therapies for Parkinson's disease.

Project 1 (PI: Dieter Jaeger, PhD) involves in vivo studies, brain slice electrophysiologic recording experiments and optogenetic 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 rodent model in which dopamine loss in the basal ganglia is produced by the dopaminergic neurotoxin, MPTP, and a 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 having 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 activity. 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 (the binding sites that mediate the neurotrophic effects 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 involving 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 interactions among the different investigators and their laboratories, and interactions of Emory's Udall Center with the larger Udall Center network, the funding agency, and local and external advisors. This core also organizes local meetings, 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) performs the detailed anatomical studies that are integral to each project, and carries out some of the primate behavioral testing for Project 3.

Recent Significant Advances

• The Jaeger group successfully performed preliminary electrophysiological recordings of cells in the basal ganglia-receiving areas of the mouse thalamus, in slice preparations and in vivo. In addition, they have conducting optogenetic experiments with viral-mediated transfection of neurons in the substantia nigra pars reticulata with channelrhodopsin-2 (ChR2) and optical stimulation of ChR2-expressing SNr neurons or their axons.
• An extensive study of the effects of subthalamic nucleus stimulation on pallidal activities has been completed in the Wichmann lab. These experiments required the development of new methods to analyze in detail the entrainment of pallidal spiking patterns by subthalamic nucleus stimulation. These studies lay the groundwork for the studies planned in the Udall Center and are currently under review for publication.
• In recently published studies, the Miller lab demonstrated that the orally active TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) is neuroprotective in MPTP-treated mice. These studies will be followed up in project 3, with studies in chronically parkinsonian VMAT2LO mice, and MPTP-treated nonhuman primates.
• The Conn lab has developed several highly selective M1 receptor antagonists (such as VU0255035) and M1 allosteric modulators (such as VU0357017). Together with M4-selective allosteric activators (such as VU0152100), these are essential tools for the electrophysiological and behavioral studies planned for project 4.

Resources Available

While electrophysiologic and behavioral data are difficult to share, members of the Emory Udall Parkinson's Disease Center will make every effort to share analysis algorithms, and to publish the study data in a timely manner. We will also make available reagents such as the novel compounds used in projects 3 and 4 (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 first year, when work on each of the projects will begin. Under project 1, we will carry out brain slice recording, as well as in vivo studies, in which the impact of the activity of substantia nigra neurons on thalamic activity will be examined. In project 2, we will start to compare the impact of pallidal lesions and stimulation on thalamic activity in parkinsonian animals, using in vivo brain recording techniques. The work under project 3 will begin with studies of TrkB agonist effects on parkinsonism in MPTP-treated mice. Towards the end of the year, we may also be able to begin studies on the effects of the TrkB agonist on the behavioral and pathological features of parkinsonism in VMAT2LO mice. In project 4, our work will focus on the effects of muscarinic M1 receptor activation on the excitability and glutamate receptor currents in the subthalamic nucleus and the substantia nigra pars reticulata. All four projects will be supported by anatomic and electron microscopic experiments in the Center's core B. Core A will set up the administrative structure of the Center, produce the Center's website, assemble the community advisory board, and organize Center meetings.

Select Recent Publications

Digby GJ, Shirey JK, Conn PJ (2010) Allosteric activators of muscarinic receptors as novel approaches for treatment of CNS disorders. Mol Biosyst 6:1345-1354.

Schultheiss NW, Edgerton JR, Jaeger D (2010) Phase response curve analysis of a full morphological globus pallidus neuron model reveals distinct perisomatic and dendritic modes of synaptic integration. J Neurosci 30:2767-2782.

Jang SW, Liu X, Yepes M, Shepherd KR, Miller GW, Liu Y, Wilson WD, Xiao G, Blanchi B, Sun YE, Ye K (2010) A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proc Natl Acad Sci U S A 107:2687-2692.

Taylor TN, Caudle WM, Shepherd KR, Noorian AR, Jackson CR, Iuvone PM, Weinshenker D, Greene JG, Miller GW (2009) Non-motor symptoms of Parkinson's disease revealed in an animal model with reduced monoamine storage capacity. J Neurosci 29:8103-8113.

Galvan A, Hu X, Smith Y, Wichmann T (2010) Localization and function of GABA transporters in the globus pallidus of parkinsonian monkeys. Exp Neurol 223:505-515.

Public Health Statement

One goal of research in the Udall Center at Emory University 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 will focus on the effects of these interventions further downstream, in the thalamus, in animals in which basal ganglia output has been altered, as by lesions or stimulation. 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 have two benefits: (1) They will teach us how the basal ganglia output affects thalamic nerve cell activity under normal conditions, and explore the underlying mechanisms by which changes in the activity of 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. (2) By identifying the commonalities and differences between antiparkinsonian interventions that have different effects on basal ganglia output and thalamic activity (lesioning and 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 mechanisms of action and therapeutic potential of two non-dopaminergic therapies that appear to provide neuroprotective or symptomatic benefits for Parkinson's disease. One of the projects will examine 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 (TrkB receptor agonists) have recently become available. Preliminary experiments have shown that these drugs may protect dopaminergic neurons from damage in animal models of Parkinson's disease. The planned experiments will further explore the use of these drugs in rodent and monkey models of the disease. The second drug therapy-related project (project 4) will study novel cholinergic drugs in animal models of Parkinson's disease. Cholinergic drugs have been used as adjunct therapeutic agents for Parkinson's disease for decades, but the currently available agents are non-specific, and have many side effects that severely limit their clinical use. Work in Vanderbilt University's Program in Drug Discovery and in the Conn lab has recently led to the development of a new group of drugs that act at muscarinic cholinergic receptors with much higher specificity than the previously used drugs. The planned studies will examine the pharmacological and behavioral effects of these drugs in different rodent models of Parkinson's disease. Through these experiments, researchers will learn whether it would be worthwhile to try to develop them for use in patients with Parkinson's disease.