We will examine how the motor thalamus In mouse models of Parkinson's disease (PD) Is Involved In transmitting Parkinsonian activity patterns generated In the basal ganglia to the cerebral cortex. We will use simultaneous electrophysiological recordings from basal ganglia, thalamus, and cortex In anesthetized and awake mice to determine the presence of pathological activity patterns, and their relations between structures. One strength of the proposal consists of the use of in vivo intracellular thalamic recordings, which will allow us to examine the hypothesis that strong basal ganglia bursting activity observed In PD will trigger postlnhibitory rebound bursting In thalamus. Previous work suggests that such bursting in the basal ganglia Is one of the characteristics of pathological activity patterns in PD, but the transmission of this activity through thalamus to cortex remains unclear. We will carry out a detailed analysis of the specific mechanisms of synaptic integration in motor thalamus of the mouse In the brain slice preparation, where we test the control of action potential initiation by Parkinsonian patterns of Input. Finally, we will determine whether pharmacological compounds known to Interact with thalamic cellular properties (M1 and M4 muscarinic receptor agonists or antagonists or selective Cav3 calcium channel blockers) can be used to reduce the transmission of pathological activity from the basal ganglia through thalamus to cortex. This project Is tightly Integrated with the other projects of the overall Emory Udall Center grant application: We share the focus on thalamic processing with project 2, where It will be examined In primates rendered parkinsonian with MPTP. We share the VMAT2L0 mouse model of PD with project 3, where It will be used to determine possible neuroprotective treatment strategies. Our analysis of pathological electrical activity patterns In the VMAT2L0 mouse developed by Dr. Miller at Emory will aid in the validation of this model. We obtain the pharmacological compounds to be tested for specific effect on thalamic processing through our interactions with project 4. These compounds mentioned above are promising novel specific receptor agonists and antagonists as well as channel blockers that are not otherwise available

Public Health Relevance

of this project is the study of novel treatments for Parkinson's disease that target the motor thalamus. In addition, the expected results will help us to better understand how much transgenic mouse models of Parkinson's disease repeat the same pathological activity patterns in the brain as seen in human patients, and to determine which mouse model can be best used for detailed treatment studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS071669-04
Application #
8539093
Study Section
Special Emphasis Panel (ZNS1-SRB-E)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$222,279
Indirect Cost
$68,382
Name
Emory University
Department
Type
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Sanders, Teresa H (2017) Stimulation of Cortico-Subthalamic Projections Amplifies Resting Motor Circuit Activity and Leads to Increased Locomotion in Dopamine-Depleted Mice. Front Integr Neurosci 11:24
Chen, Erdong; Paré, Jean-Francois; Wichmann, Thomas et al. (2017) Sub-synaptic localization of Cav3.1 T-type calcium channels in the thalamus of normal and parkinsonian monkeys. Brain Struct Funct 222:735-748
Masilamoni, Gunasingh Jeyaraj; Groover, Olivia; Smith, Yoland (2017) Reduced noradrenergic innervation of ventral midbrain dopaminergic cell groups and the subthalamic nucleus in MPTP-treated parkinsonian monkeys. Neurobiol Dis 100:9-18
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Devergnas, Annaelle; Chen, Erdong; Ma, Yuxian et al. (2016) Anatomical localization of Cav3.1 calcium channels and electrophysiological effects of T-type calcium channel blockade in the motor thalamus of MPTP-treated monkeys. J Neurophysiol 115:470-85
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Iskhakova, Liliya; Smith, Yoland (2016) mGluR4-containing corticostriatal terminals: synaptic interactions with direct and indirect pathway neurons in mice. Brain Struct Funct 221:4589-4599
Galvan, Adriana; Devergnas, Annaelle; Pittard, Damien et al. (2016) Lack of Antiparkinsonian Effects of Systemic Injections of the Specific T-Type Calcium Channel Blocker ML218 in MPTP-Treated Monkeys. ACS Chem Neurosci 7:1543-1551

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