Director: Thomas Wichmann, M.D.

 Title: Udall Parkinson's Disease Research Center at Emory University

 Website:http://www.udall.emory.edu/
 

Central Theme

Research at the Udall Center at Emory University is concerned with the pathophysiology of Parkinson’s disease, and the (circuit) mechanisms by which antiparkinsonian treatments work.

Parkinsonism arises from dopamine loss in the basal ganglia which then results in changes in the electrical neuronal activity in the basal ganglia themselves, and in brain areas that are linked to them, specifically the ventrolateral nuclear group in the thalamus, and related areas of the supplementary motor area and the primary motor cortex. Most of the currently available pharmacological or surgical treatments were designed to modify or minimize basal ganglia firing abnormalities, either by replacing dopamine, or by altering the influence of basal ganglia output, for instance, by lesioning or stimulation of specific basal ganglia nuclei. However, the clinical use of these therapies remains empiric. Treatment optimization is only possible if the biology of the basal ganglia thalamocortical circuitry under normal and parkinsonian conditions and the effects of therapeutic interventions such as deep brain stimulation are better understood.

A specific shortcoming of current pathophysiologic models of parkinsonism is that they tend to concentrate on the basal ganglia, while their impact on other brain network elements (thalamus and cortex) is much less understood. These parkinsonism-related changes ‘downstream’ from the basal ganglia are the focus of studies at the Emory Center. The projects focus on anatomical and functional changes in synaptic transmission in thalamus and cortex, and the effects of basal ganglia interventions such as deep brain stimulation on these circuit elements in rodent and nonhuman primate models of Parkinson’s disease.

Additional important goals of the Center are to facilitate communication and discussions among all investigators involved in Parkinson's disease reserach at Emory University, and to educate young researchers adn the general public about research in this field.

Center Structure

The Center brings together researchers from several departments at Emory University with complementary expertise in systems-centered Parkinson’s disease research. The Udall Center at Emory University consists of three tightly linked research projects and two cores. The research sheds light on the poorly understood parkinsonism-related activity changes in thalamus and cortex which, in turn, help us to better understand the pathophysiology of parkinsonism, to optimize existing neuromodulation strategies, and to develop new antiparkinsonian therapies. Project 1 (Dieter Jaeger) utilizes brain slice and in vivo recordings in rodents, as well as a neural computational approach to develop mechanistic models of thalamocortical dysfunction in parkinsonism. Project 2 (Thomas Wichmann) explores thalamic and cortical abnormalities in parkinsonian monkeys, using selective optogenetic and other activation and inactivation approaches to study corticothalamic, pallidothalamic and thalamocortical information transfer. Based on exciting new findings of parkinsonism-related anatomical abnormalities of the interactions between thalamus and cortex, Project 3 (Yoland Smith) examines morphological changes in the thalamic and cortical microcircuitry in parkinsonian primates.

The Center’s Administrative Core (Dr. Wichmann) coordinates the interactions between the different investigators and their laboratories, is in charge of interactions with the overall Udall Center network, the NIH, 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 (Adriana Galvan) provides immunohistochemistry and electron microscopy services to projects 1-3, and standardized MPTP treatment and quantification of parkinsonism to the primate experiments in projects 2 and 3.
 

Recent Advances

• Dr. Dieter Jaeger’s laboratory (Project 1) characterized the intrinsic properties of neurons in the basal ganglia receiving portion of the thalamus in rodents (the ventromedial thalamus) in normal and dopamine-depleted (6-OHDA lesioned) mice.A clear increase in excitability observed 8-16 weeks after lesioning may represent a compensatory mechanism to offset the increased inhibitory input to these neurons from the basal ganglia under parkinsonian conditions.The change may result from a reduction in a potassium current (likely KCNQ).
• In ongoing studies, Dr. Wichmann and colleagues (Project 2) found that optogenetic stimulation of either the terminals or the somas of thalamocortical neurons that were transfected to express opsins strongly altered the coupling of the amplitude of cortical local field potentials in the gamma band to the phase of oscillations in the beta band. Activation of thalamic inputs to the frontal cortex may temporarily entrain gamma oscillatory activity to oscillations at lower frequencies. Current studies examine whether this function is altered in the parkinsonian state.
• In ultrastructural studies, Dr. Smith and his team (Project 3) found that the thalamocortical innervation of cortical layer V in the primary motor cortex (M1) and the supplementary motor area (SMA) is substantially reduced in the parkinsonian state (as compared to controls) while cortico-cortical connections to this layer are retained. In the SMA, the remaining thalamocortical inputs preferentially form axo-dendritic synapses in the parkinsonian state, while they form preferentially axo-spinous inputs in M1.These plastic changes may signal a shift in the balance of thalamocortical inputs to GABAergic interneurons or glutamatergic neuronsand are mirrored by similar changes of corticothalamic projections.

 Public Health Statement

One goal of research at the Emory Udall Center is to develop a better understanding of how the loss of dopamine and other biochemical and structural changes in the brain lead to the physical manifestations of parkinsonism, and how existing surgical and medical treatments for patients with Parkinson’s disease work. While previous studies in this field have largely focused on disease- or treatment-related changes on the activity of nerve cells in the basal ganglia, i.e., the brain areas that are immediately affected by dopamine loss in Parkinson’s disease, some of the Center’s studies examine the downstream effects of these interventions, focusing on the thalamus and cerebral cortex. 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 studies will teach us how basal ganglia output affects thalamic and cortical nerve cell activity under normal conditions and determine the mechanisms by which activity changes in the basal ganglia alter thalamic and cortical firing in parkinsonism. Another focus of Center research is to follow up on exciting new discoveries of changes in the anatomical structure of thalamo-cortical and cortico-thalamic connections, with studies aimed at quantifying these changes, and elucidating their (potential) impact on information processing in the basal ganglia-thalamocortical network. Knowledge gained from the coordinated efforts of Center researchers will help to develop new pharmacologic and surgical therapies to treat parkinsonian symptoms, and to optimize existing treatment approaches.

Budget End Date: 2021/07/31

NIH Grant Number: P50 NS098685