The basal ganglia are a series of inter-connected brain nuclei that control voluntary movement through the coordination of two parallel neural circuits, the 'direct pathway'that facilitates movement and the 'indirect pathway'that suppresses movement. Imbalances between these two pathways are hypothesized to underlie movement disorders such as Parkinson's disease, Huntington's disease, Tourette syndrome, and dystonia. My long-term goal is to identify cellular mechanisms of direct and indirect pathway regulation to better understand the neuronal basis of motor control in both health and disease. Neuronal circuits in the striatum, the input nucleus of the basal ganglia, are particularly important in determining direct and indirect pathway activity, but their organizing principles remain poorly understood. The objective of this proposal is to identify the role of fast-spiking (FS) interneurons in regulating striatal output.
In Aim 1, I will use a novel pharmacological approach to perform circuit-level and behavioral analyses of FS interneuron regulation of direct and indirect pathway activity. Because interneurons are powerful regulators of circuit function and are intimately involved in the pathology of several basal ganglia disorders, this pharmacological dissection of their role will provide new insights into Parkinson's disease and other disorders and may lead to new pharmaceutical treatments.
In Aim 2 -3, I will use optogenetics combined with slice and in vivo electrophysiology to challenge long-standing hypotheses about the organization of FS microcircuits. Long- standing theories about inputs to FS interneurons from the cortex and thalamus have shaped thinking about the organization of striatal microcircuits, but these dogmatic theories are based largely on experiments in other systems and have not been directly tested in the striatum. Using optogenetics in Aim 2, I will directly measure feedforward inhibition recruited by cortical and thalamic inputs to the striatum to directly challenge old ideas about the role of feedforward inhibition in striatal function and disease.
In Aim 3, I will turn to FS inputs from the globus pallidus (GPe);although inputs from the GPe were identified anatomically over ten years ago, a detailed functional characterization of this projection has been sorely lacking. The identification of novel neural circuits that connect the GPe and striatum could challenge long-standing assumptions about information processing in the basal ganglia. Together, all of these experiments will advance our understanding of the neural circuitry that underlies motor control and potentially identify new targets for disease therapy.

Public Health Relevance

Movement disorders of the basal ganglia, including Parkinson's disease, Huntington's disease, dystonia, and Tourette syndrome, affect millions of Americans but their eteology remains poorly understood. This proposal seeks to advance our understanding of inhibitory neural circuits in the basal ganglia that regulate motor control and contribute to the pathology of these diseases. Elucidation of these understudied neural circuits could lead to the development of more specific targets for disease therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Transition Award (R00)
Project #
4R00NS076524-03
Application #
8587526
Study Section
Special Emphasis Panel (NSS)
Program Officer
Sieber, Beth-Anne
Project Start
2012-12-15
Project End
2015-11-30
Budget Start
2012-12-15
Budget End
2013-11-30
Support Year
3
Fiscal Year
2013
Total Cost
$240,288
Indirect Cost
$82,100
Name
Carnegie-Mellon University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
052184116
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Mastro, Kevin J; Bouchard, Rachel S; Holt, Hiromi A K et al. (2014) Transgenic mouse lines subdivide external segment of the globus pallidus (GPe) neurons and reveal distinct GPe output pathways. J Neurosci 34:2087-99
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