Parkinson's disease (PD) is the second most common neurodegenerative disease in the U.S., extracting an enormous human and economic toll. PD has no cure and nothing is known to slow the progression of the disease. Moreover, the therapeutic strategies for treating PD are limited. Building upon mechanistic insights gained in the last grant period, this Udall Center competitive renewal application proposes two major lines of study with strong translational potential. The first line of study focuses on the mechanisms underlying the pathological rhythmic bursting activity patterns in the basal ganglia network formed by the external segment of the globus pallidus (GPe) and the sub-thalamic nucleus (STN). This activity is thought to be responsible for the motor symptoms of PD. Our group has identified molecular adaptations in the GPe-STN network in PD models that could be responsible for this pathophysiology. The proposed studies will pursue this discovery and attempt to translate it into a gene therapy appropriate for late stage PD patients. The second line of study builds upon recent insights gained into the factors underlying vulnerability of dopaminergic neurons in the substantia nigra pars compacta (SNc) that are lost in PD. These studies suggest that the reliance upon voltage calcium channels to drive autonomous pace-making renders SNc neurons vulnerable to mitochondrial insults. These studies also suggest this reliance can be reversed with a drug that is approved for human use. The proposed studies examine the cellular and molecular basis for this linkage and pursue questions that should be answered prior to a clinical neuroprotection trial. The Udall Center brings together five principal investigators (Pis) with complementary expertise from three research institutions. Three theme-based projects are proposed, each with three or more Pis contributing to the plan of attack. Projects 1 and 2 pursue the first line of study, one focusing on the adaptations in GPe neurons, the other focusing on adaptations in STN neurons in rodent and monkey models of PD. Project 3 pursues the second line of study, focusing on mechanisms controlling the vulnerability of SNc dopaminergic neurons in rodent models. In addition to three research projects, the Center has an Administrative Core to coordinate activities of the projects and a Molecular Core to serve the genetic profiling and gene therapy aims of the projects.

Public Health Relevance

The proposed studies are focused on why dopamine neurons die in PD and what happens to The brain circuitry they control. Our near term goal is to develop therapeutic strategies that will slow the loss of dopamine neurons and to re-engineer the networks these neurons control so that they perform correctly, even in the absence of dopamine.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northwestern University at Chicago
United States
Zip Code
Hegeman, Daniel J; Hong, Ellie S; Hernández, Vivian M et al. (2016) The external globus pallidus: progress and perspectives. Eur J Neurosci 43:1239-65
Glajch, Kelly E; Kelver, Daniel A; Hegeman, Daniel J et al. (2016) Npas1+ Pallidal Neurons Target Striatal Projection Neurons. J Neurosci 36:5472-88
Higgs, Matthew H; Wilson, Charles J (2016) Unitary synaptic connections among substantia nigra pars reticulata neurons. J Neurophysiol 115:2814-29
Surmeier, D James; Schumacker, Paul T; Guzman, Jaime D et al. (2016) Calcium and Parkinson's disease. Biochem Biophys Res Commun :
Cooper, Garry; Lasser-Katz, Efrat; Simchovitz, Alon et al. (2015) Functional segregation of voltage-activated calcium channels in motoneurons of the dorsal motor nucleus of the vagus. J Neurophysiol 114:1513-20
Chu, Hong-Yuan; Atherton, Jeremy F; Wokosin, David et al. (2015) Heterosynaptic regulation of external globus pallidus inputs to the subthalamic nucleus by the motor cortex. Neuron 85:364-76
Hernández, Vivian M; Hegeman, Daniel J; Cui, Qiaoling et al. (2015) Parvalbumin+ Neurons and Npas1+ Neurons Are Distinct Neuron Classes in the Mouse External Globus Pallidus. J Neurosci 35:11830-47
Surmeier, D James; Graves, Steven M; Shen, Weixing (2014) Dopaminergic modulation of striatal networks in health and Parkinson's disease. Curr Opin Neurobiol 29:109-17
Gittis, Aryn H; Berke, Joshua D; Bevan, Mark D et al. (2014) New roles for the external globus pallidus in basal ganglia circuits and behavior. J Neurosci 34:15178-83
Wilson, Charles J (2014) Oscillators and Oscillations in the Basal Ganglia. Neuroscientist :

Showing the most recent 10 out of 96 publications