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


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Director: Thomas Wichmann, MD

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

Website: 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 electrical 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) develop 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 different rodent models, including a model in which dopamine loss in the basal ganglia is produced by the dopaminergic neurotoxin, MPTP, 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, as well as genetic studies, based on alpha-synuclein overexpression. 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) 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 primate drug testing studies for Project 3.

Recent Significant Advances

  • Dr. Jaeger and his group (Project 1) published their analysis of the nigro-thalamo-cortical pathway in control and alpha-synuclein overexpressing mice, and examined activity patterns in the nigral GABAergic output neurons in mice with unilateral 6-hydroxydopamine (6-OHDA) lesions in both anesthetized and awake mice, with the goal of examining bursting and beta oscillations after 6-OHDA lesioning. These studies showed that the ‘parkinsonian appearing’ motor disability in alpha-synuclein overexpressing mice does not replicate the physiologic hallmark of parkinsonism in primates and humans, but that robust thalamic and nigral robust bursting activity can be induced by 6-OHDA lesioning. Dr. Jaeger’s group also published their optogenetic study of the effects of nigro-thalamic GABAergic inputs on thalamic activity patterns in mouse brain slices.
  • The studies under Project 2 (Dr. Wichmann) showed that firing rates of thalamic neurons are reduced after induction of parkinsonism, and that oscillations at low frequencies (theta- and alpha bands) are increased, while oscillations at higher frequencies (gamma band) are reduced. Stimulation of the subthalamic nucleus or the internal pallidal segment lead to increased firing in the thalamus and a substantial reduction of oscillatory power in the delta band and beta bands. Pallidal lesioning did not affect firing rates, but reduced spectral power in the theta, alpha and beta bands, and increased power in the gamma band. The different surgical interventions thus affect thalamic activities in very different ways: Pallidal lesions directly counteract changes associated with parkinsonism, while the strongest effect of stimulation is a reduction of oscillations in the 1-3 Hz range. The potential arousal benefits of pallidal or subthalamic nucleus interventions are currently under investigation.
  • Dr. Miller’s group (Project 3) has started to study the effects of a novel oral TrkB receptor agonist (R7) with pharmacokinetic properties that are superior to those of the originally studied agent (7,8-DHF). This very promising new compound is currently being tested in the MPTP model of parkinsonism.
  • Dr. Conn’s group (Project 4) found that muscarinic M4 acetylcholine receptors are responsible for the cholinergic regulation of synaptic transmission at cortico-striatal synapse of direct and indirect pathways, as well as thalamostriatal synapses and that M4 receptor activation inhibits stimulus-induced dopamine release in striatal slices. Dr. Conn’s group also showed that activation of M5 receptors affects the activity of the nigrostriatal dopamine system differentially, with excitatory effects on dopamine neurons in the substantia nigra, and inhibitory effects on striatal dopamine release. Based on the available results, pharmacologic interventions at any of these muscarinic receptor subtypes, but particularly at M4 receptors, could have significant antiparkinsonian actions, and will be worthy of further exploration.

Relationship of Center Goals to NINDS PD2014 Research Recommendations

While the Emory Udall Center was initiated well before discussions about the NINDS PD2014 Conference began, its research is already in line with many of the resulting prioritized research recommendations. For instance, the experiments under Projects 1, 2 and 4 examine “how different cell populations change … their coding properties, firing patterns, and neural circuit dynamics over time; how they relate to behavior and motor control; and how therapeutic interventions may affect such changes,” one of the high-priority recommendations of the PD2014 document (Basic Research Recommendation #3). The center also fulfills other recommendations, including that to “… advance our understanding of neural circuits, circuit analysis techniques, PD animal models, and optogenetic and related imaging technologies to improve existing therapies and generate next-generation therapies for PD (Basic Research Recommendation #11).” Specifically, our research uses “sensor technologies … to develop a more precise understanding of the neural circuit dynamics in PD to enable the development of next-generation therapeutic devices”, such as new deep brain stimulation techniques, one of the recommendations (Basic Research Recommendation #9). Finally, while the center’s research is preclinical in approach, we hope that we will be able to develop “effective treatments … for dopa-resistant features of PD” (Clinical Research Recommendation #2).

Other Accomplishments

  • The Center’s pilot grant program was highly successful. Four projects were funded, including projects on (1) Sleep Fragmentation and Nocturnal Hypoxia as biomarkers of worsening motor symptoms in Parkinson’s Disease (PI: D. Bliwise), (2) Alpha-synuclein aggregation in a yeast model system (PI: VP Conticello), (3) the development of the songbird as a novel model of motor control and sensorimotor learning in Parkinsonism (PI: SJ Sober), and (4) the validation of GluN2D-selective inhibitors as therapeutic agents for Parkinson's Disease (PI: SF Traynelis). Besides resulting in several publications, data generated in these experiments helped the investigators to secure external funding (an NIH F31 grant [Project 3], and funding from the Michael J. Fox foundation [Project 4]).
  • The Center was able to fund three new pilot grants this year, including studies of DJ-1-targeting compounds for Parkinson’s disease treatment (PI: LS Chin), a project on the motor effects of a mGluR4 PAM in parkinsonian monkeys (PI: GM Jeyaraj), and a project stuying the activation of cell death pathways in dopaminergic neurons (PI: ES Mocarski).
  • As in previous years, the center organized and participated in several outreach efforts, including talks to patients, small-group educational sessions with patients, and participations in 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 and mouse models used under projects 3 and 4 available (within the limits of patent right restrictions).

Plans for the Coming Year

In the coming (fourth) year of funding, all of the Center’s research 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. Under Project 2, the last few animals will be added to the different study groups, and we will complete and publish the analysis of the data gathered thus far. Project 3 personnel will continue to study TrkB agonist effects on parkinsonism in MPTP-treated and VMAT2LO mice, now focusing on the effects of R7. Most of the research under Project 4 will focus on the further development of muscarinic M4 receptor ligands as these agents are highly promising potential antiparkinsonian drugs. Core B will continue to support the projects with anatomic studies, helping with the reconstruction of electrode tracks, light- and electron microscopic immunochemical studies of the anatomy of the basal ganglia and thalamus experiments, and other tasks. Core A will continue to help with administrative tasks, organize the pilot project program, and interact with the public. The primary outreach event, the ‘Community Conversations with PD Researchers’, will be expanded to reach a much larger audience, helped by additional funding from the Parkinson’s Disease Foundation (PDF).

Select Recent Publications

Center support has contributed to 26 publications this year. A sample of these includes:

Public Health Statement

The center’s research is well aligned with the priorities spelled out in the NINDS PD2014 research recommendations. One goal of research of 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 orally administered drugs that act at brain receptors for nerve growth factors. 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.

Last updated October 1, 2014