The basal ganglia are part of larger circuits that also involve thalamus and cortex. Cortical inputs reach striatum and subthalamic nucleus (STN), and are transmitted via external and internal pallidal segments (GPe, GPi, resp.) and substantia nigra pars reticulata to influence the activity of thalamocortical neurons. The function of this circuitry is disturbed in Parkinson's disease because of loss of dopamine in the basal ganglia. Besides changes in discharge rates, basal ganglia neurons also develop abnormalities in their firing patterns. One of the most salient abnormalities is the appearance of synchronized oscillatory activity. The synchrony of ensembles of basal ganglia neurons can be measured with local field potential (LFP) recordings. Studies in humans, using implanted deep brain stimulation (DBS) electrodes to record LFPs, have suggested that high-amplitude, low frequency oscillations develop in parkinsonism which can be ameliorated by systemic dopaminergic medications. Uncertainties persist, however, regarding the temporal and causal relationship between circuit synchrony and parkinsonism, as well as the location at which dopamine loss exerts its synchronizing effects. We propose to study the development and long-term stability of LFP characteristics of parkinsonism in MPTP-treated primates, using multiple chronically implanted LFP electrodes throughout striatum, GPe, GPi and STN, combined with pharmacologic manipulation of dopaminergic transmission (aim 1). We will also study the local effects of dopaminergic drugs on neuronal synchrony in these nuclei, using a microdialysis/LFP recording probe which allows us to assess the effects of drugs, applied locally via reverse microdialysis, on LFPs in the vicinity of the probe. These studies will be done to assess drug-effects on spontaneous LFP production (aim 2), and on event-related LFP fluctuations in motor tasks (aim 3). These experiments will help us to better understand the origin(s) and functional significance of neuronal ensemble activity in parkinsonism. This knowledge will also be useful in the development of antiparkinsonian treatments targeting synchronous basal ganglia activity, and may help us to develop criteria to detect the presence of parkinsonism in LFP signals from the basal ganglia. Conceivably, such criteria could be used in the next generation of DBS devices to trigger 'on-demand'stimulation.

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National Institute of Neurological Disorders and Stroke (NINDS)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Sieber, Beth-Anne
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Emory University
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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
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
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
Devergnas, Annaelle; Pittard, Damien; Bliwise, Donald et al. (2014) Relationship between oscillatory activity in the cortico-basal ganglia network and parkinsonism in MPTP-treated monkeys. Neurobiol Dis 68:156-66
McMillan, Jennifer L; Perlman, Jaine E; Galvan, Adriana et al. (2014) Refining the pole-and-collar method of restraint: emphasizing the use of positive training techniques with rhesus macaques (Macaca mulatta). J Am Assoc Lab Anim Sci 53:61-8
Sanders, Teresa H; Devergnas, Annaelle; Wichmann, Thomas et al. (2013) Canonical Correlation to Estimate the Degree of Parkinsonism from Local Field Potential and Electroencephalographic Signals. Int IEEE EMBS Conf Neural Eng 2013:158-161
Rubin, Jonathan E; McIntyre, Cameron C; Turner, Robert S et al. (2012) Basal ganglia activity patterns in parkinsonism and computational modeling of their downstream effects. Eur J Neurosci 36:2213-28
DeLong, Mahlon; Wichmann, Thomas (2012) Deep brain stimulation for movement and other neurologic disorders. Ann N Y Acad Sci 1265:1-8
Wichmann, Thomas; DeLong, Mahlon R; Guridi, Jorge et al. (2011) Milestones in research on the pathophysiology of Parkinson's disease. Mov Disord 26:1032-41
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