Pharmacology And Physiology Of The Substantia Nigra And Basal Ganglia

National Institute Of Neurological Disorders And Stroke

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Abstract

Research conducted in the Pharmacology and Physiology of the Substantia Nigra and Basal Ganglia Project over the past year in the Neurophysiological Pharmacology Section (NPS) has continued to focus on using rodent models to explore the sources and consequences of changes in basal ganglia neurophysiological function in Parkinson disease (PD). We have published one manuscript under this project this year and are currently engaged in two ongoing studies as well as the completion of three additional manuscripts involving collaborations with recent lab trainees. These endeavors have taken advantage of a strategy developed in our lab for studying activity in motor circuits while the rat performs a continuous walking task. We can quantitate bilateral changes in gait in conjunction with changes in local field potentials (LFP) and spiking activity in rats with unilateral dopamine cell lesions (mimicking unilateral PD) through the use of a circular treadmill. A paddle is lowered over the rotating circular track to encourage the rat to keep walking. The rats' ability to walk in the direction contralateral to the unilateral dopamine cell lesion with his affected paws on the inside of the track is typically very limited and provides a read-out of the motor disability. The affected limbs have difficulty adjusting to the more rapid stepping on the inside of the turns. The rats can, however, walk in the circular treadmill in the direction ipsilateral to the lesion with his affected paws on the outside of the track. This allows us to monitor basal ganglia circuit spiking and local field potential (LFP) activity continuously in both the intact and lesioned hemispheres as the animal walks and rests. 1. A major focus this year was the completion and publication of manuscript in Neurobiology of Disease, addressing the changes in high beta range oscillatory activity over the hours and days following 6-hydroxydopamine induced dopamine cell lesion in the rat hemiparkinsonian model. The goal of this study was to investigate the hypothesis that increases in beta (13-35Hz) range oscillatory and synchronized activity in the basal ganglia contributes to the emergence of bradykinesia after loss of dopamine. Notably, however, when we examined the correlation between the onset of motor deficits and the emergence of the exaggerated beta range activity in MCx and basal ganglia circuits hypothesized to induce motor deficits, the data showed that increases in LFP oscillatory power in MCx and SNpr in the high beta 30-40 Hz range emerge more slowly than the motor deficits. In contrast, we have observed an early loss of significant MCx LFP peaks in the mid-gamma 41-45 Hz range in the lesioned hemisphere which is more consistently correlated with the emergence of marked deficits in ipsilateral walking, Twice-daily chronic dopamine antagonist treatment induced rapid onset of catalepsy and also reduced MCx 41-45 Hz LFP activity at 1 h, with increases in MCx and SNpr 29-40 Hz power/coherence emerging gradually over 7 days, as assessed during periods of walking before the morning antagonist treatments. Thus, increases in high beta power in these parkinsonian models emerge gradually and are not linearly correlated with motor deficits. The study highlights a potentially important role of early modulation of cortical mid-gamma activity in contrast to elevated levels of high beta activity in the emergence of the rats bradykinetic motor state following loss of dopamine. 2. The main ongoing study in the NPS this past year has been a collaboration with Dr. Emmanuel Akano, a MD fellow doing preclinical research in Dr. David Sibley's lab in NINDS, involving the use of our circular treadmill strategy to test the efficacy of a novel dopamine D3 receptor agonist in the unilateral parkinsonian rats. It has previously been difficult to explore the functional significance of the D3 subtype of dopamine receptors because drugs with affinity for D3 receptors have also, to date, been partially effective at D2 receptors. Dr. Sibley's newly developed drug, ML 147, is showing us, for the first time, how an agent highly selective for the D3 dopamine receptor subtype will affect motor deficits and/or L-dopa-induced dyskinesias, a common side effect of drugs used to treat PD. We have been examining the efficacy of this drug in reducing parkinsonian bradykinesia, as well as the dyskinesia associated with chronic treatment with L-dopa in our hemiparkinsonian rats. To date, L-dopa is the drug typically most effective at reducing bradykinesia in PD patients but remains a treatment with a strong potential for inducing serious dyskinesia over time. There are indications in the literature that a D3 dopamine agonist might counteract this effect, but really selective D3 drugs have not previously been available for study. These studies are near completion and data analysis is under way. 3. Another endeavor has involved a collaboration with Dr. Ana Cruz, previously a Postdoc in the NPS and now a researcher at the Champalimaud Foundation in Portugal, describing the exaggerated beta range LFP rhythms which appear in LFPs in some parts of the striatum in the parkinsonian rats. Contrary to expectations, this synchronized LFP does not appear to be entraining correlated spiking in the striatal output neurons. Ana is preforming some final analysis of this data for changes in spike timing and entropy, to further characterize the impact of dysfunctional effects of alterations in cortical input to the striatum after loss of dopamine, as we prepare the study for publication. This ongoing analysis is addressing questions about the relative role of the motor cortex input to the striatum and the direct pathway form the striatum to basal ganglia output in mediating bradykinesia in the parkinsonian rats as opposed to the role of the hyper-direct pathways from cortex to STN and globus pallidus-STN subcircuits as more critical to the motor dysfunction. 4. An additional collaboration is on-going with Michael Preston, currently a graduate student in the Neuroscience Dept., Univ. California San Diego and previously a postbac trainee in the NPS and co-author Heysol Bermudez, Ph.D., currently an employee at and previously a graduate student in the NPS in the NIH/Brown Univ. Graduate Ph.D Program. Analysis of the LFP activity recorded from the MCx of the lesioned hemisphere of our hemiparkinsonian rat model showed that during circular treadmill walking, the rats display bursts of beta range activity similar to those seem in human patients; the distribution of beta bursts and their features periodically fluctuate as the animals walk. These results support the view that beta burst duration is an effective biomarker for parkinsonian dysfunction and are consistent with observations in patients with parkinsonian syndromes showing that adaptive deep brain stimulation of the STN both ameliorates motor dysfunction and reduces the average duration of beta bursts. They support the utility of the hemiparkinsonian rat as a model for PD with face validity and potential for studying therapeutics and underlying mechanisms. This material is currently being written up for submission for publication.