Elsevier

Experimental Neurology

Volume 221, Issue 2, February 2010, Pages 307-319
Experimental Neurology

Beta frequency synchronization in basal ganglia output during rest and walk in a hemiparkinsonian rat

https://doi.org/10.1016/j.expneurol.2009.11.016Get rights and content

Abstract

Synchronized oscillatory neuronal activity in the beta frequency range has been observed in the basal ganglia of Parkinson's disease patients and hypothesized to be antikinetic. The unilaterally lesioned rat model of Parkinson's disease allows examination of this hypothesis by direct comparison of beta activity in basal ganglia output in non-lesioned and dopamine cell lesioned hemispheres during motor activity. Bilateral substantia nigra pars reticulata (SNpr) recordings of units and local field potentials (LFP) were obtained with EMG activity from the scapularis muscle in control and unilaterally nigrostriatal lesioned rats trained to walk on a rotary treadmill. After left hemispheric lesion, rats had difficulty walking contraversive on the treadmill but could walk in the ipsiversive direction. During inattentive rest, SNpr LFP power in the 12–25 Hz range (low beta) was significantly greater in the dopamine-depleted hemisphere than in non-lesioned and control hemispheres. During walking, low beta power was reduced in all hemispheres, while 25–40 Hz (high beta) activity was selectively increased in the lesioned hemisphere. High beta power increases were reduced by l-DOPA administration. SNpr spiking was significantly more synchronized with SNpr low beta LFP oscillations during rest and high beta LFP oscillations during walking in the dopamine-depleted hemispheres compared with non-lesioned hemispheres. Data show that dopamine loss is associated with opposing changes in low and high beta range SNpr activity during rest and walk and suggest that increased synchronization of high beta activity in SNpr output from the lesioned hemisphere during walking may contribute to gait impairment in the hemiparkinsonian rat.

Introduction

Oscillatory neuronal activity in the 12–30 Hz beta frequency range is prominent in recordings from the subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) in Parkinson's disease (PD) patients undergoing implantation of deep brain stimulation (DBS) electrodes. The presence of these patterns in STN and GPi recordings has lead to the hypotheses that excessive beta range activity contributes to the symptomatology of PD and is antikinetic in nature. This view is supported by evidence that beta activity in local field potential (LFP) recordings is reduced in the STN and GPi of PD patients during movement or following dopaminergic therapies (Alegre et al., 2005, Alonso-Frech et al., 2006, Brown, 2003, Brown, 2007, Brown et al., 2001, Brown and Williams, 2005, Cassidy et al., 2002, Doyle et al., 2005, Foffani et al., 2005, Kempf et al., 2007, Kuhn et al., 2004, Levy et al., 2000, Levy et al., 2002, Marsden et al., 2001, Priori et al., 2002, Priori et al., 2004, Weinberger et al., 2006, Williams et al., 2003). Additional studies in PD patients have explored relationships between STN beta range activity and PD symptoms, showing that l-DOPA's therapeutic effects on bradykinesia and rigidity, but not tremor, correlate with reduction of STN peak LFP power within the 8–35 Hz range (Bronte-Stewart et al., 2009, Foffani et al., 2005, Kuhn et al., 2009, Priori et al., 2004, Ray et al., 2008; for review, see Brown and Eusebio, 2008).

Collectively, these observations have provided incentive to determine the extent to which animal models of PD show similar changes in beta activity in the basal ganglia in conjunction with loss of dopamine and motor dysfunction. Such models allow direct comparisons of synchronized activity in basal ganglia circuitry in control and dopamine-depleted subjects over a range of behaviors, and permit insight into the origins and consequences of increased synchronization in basal ganglia output in the beta range.

To date, studies in the rodent model of PD have supported the hypothesis that loss of dopamine has a significant effect on synchronization and oscillatory activity in basal ganglia circuits. Marked increases are observed in the incidence of oscillatory activity in the ∼ 1 Hz range in basal ganglia spike trains recorded throughout the lesioned hemisphere of systemically anesthetized rats with unilateral dopamine cell lesions. This activity is coherent with the ∼ 1 Hz oscillatory firing patterns dominant in the cortex of the anesthetized rat, and phase relationship data show that loss of dopamine dramatically affects the extent to which the 1 Hz cortical oscillations entrain activity throughout the basal ganglia and modify basal ganglia output (Belluscio et al., 2003, Kasanetz et al., 2002, Magill et al., 2001, Mallet et al., 2006, Murer et al., 2002, Parr-Brownlie et al., 2007, Parr-Brownlie et al., 2009, Tseng et al., 2001b, Walters and Bergstrom, 2009, Walters et al., 2007, Zold et al., 2007). Increased beta frequency activity has also been observed in the STN and the external segment of the globus pallidus (GPe) of the anesthetized hemiparkinsonian rats during periods of desynchronized cortical activity (Mallet et al., 2008a, Mallet et al., 2008b). In awake immobilized, locally anesthetized rats increases in oscillatory activity in the 4–30 Hz range in the entopedunclular nucleus (EPN, the rat homolog of the GPi), GPe and STN in the dopamine cell lesioned hemisphere have been reported (Ruskin et al., 2002, Tierney et al., 2003, Walters et al., 2009). Enhanced synchronization between GPe and STN (Mallet et al., 2008a, Tierney et al., 2003, Walters et al., 2009) and between STN and cortex (Sharott et al., 2005) in beta frequencies has also been observed in the dopamine-depleted hemisphere.

The present study was undertaken to determine whether expression of beta range activity is increased in basal ganglia output from the substantia nigra pars reticulata (SNpr) in the rodent model of PD, as observed in STN and GPi of PD patients, and whether beta activity is differentially expressed during rest, during episodes of walking on a circular treadmill and after l-DOPA treatment. The SNpr nucleus, through its main projection sites (the motor and parafascicular nuclei of the thalamus, the superior colliculus and the pedunculopontine nucleus) is thought to play a role in behaviors affected in the unilateral rodent model of PD, such as motor activity, orientation, axial posture and gait (Anderson and Yoshida, 1977, Arnt and Scheel-Kruger, 1979, Aziz et al., 1998, Bentivoglio et al., 1979, Burbaud et al., 1998, Deniau and Chevalier, 1992, Di Chiara et al., 1977, Henderson et al., 2005, Herkenham, 1979, Hikosaka and Wurtz, 1983, Lestienne and Caillier, 1986, Takakusaki et al., 2003, Wichmann et al., 2001). For these studies, LFP and unit activity was recorded bilaterally from chronically implanted electrodes in the SNpr nuclei of hemiparkinsonian rats. Unilateral or bilateral SNpr recordings were also conducted in neurologically intact (control) rats. SNpr activity was recorded while rats were at rest and while walking on a circular treadmill. Electromyographic (EMG) activity was recorded bilaterally from the scapularis muscles to confirm motor activity.

Section snippets

Materials and methods

All experimental procedures were conducted in accordance with the NIH Guide for Care and Use of Laboratory Animals and approved by the NINDS Animal Care and Use Committee. Every effort was made to minimize the number of animals used and their discomfort.

Materials

Atipamezole HCl (Antisedan) was purchased from Pfizer Orion Pharma, New York, NY, USA; benserazide, desmethylimipramine HCl, l-DOPA, potassium hexacyanoferrate, urethane and 6-OHDA HBr from Sigma-Aldrich Co., St. Louis, MO, USA; ketamine (Ketaved) from Vedco, St. Joseph, MO, USA; medetomidine HCl (Domitor) from Pfizer Animal, Exton, PA, USA; mepivacaine (Polocaine) from AstraZeneca LP, Wilmington, DE, USA. The ocular lubricant Lacrilube was purchased from Allergan Pharmaceuticals, Irvine, CA,

Effect of 6-OHDA-induced dopamine cell lesion on step test and TH loss

One week post-6-OHDA infusion, dopamine cell lesion was associated with a marked unilateral deficit in motor function as assessed by the step test (Olsson et al., 1995). For the rats used in the present study, the total number of adjusting steps made by the contralateral limb ranged from 0 to 1.5% and averaged 0.4% of those made by the ipsilateral limb (33.3 ± 3.0 mean total steps taken by the ipsilateral limb per test), reflecting marked depletion of dopamine in the ipsilateral striatum (

Discussion

In the present study, recordings from electrodes implanted bilaterally in the SNpr of unilaterally lesioned rats show that loss of dopamine is associated with increased LFP power and spiking activity in the beta frequency range. This increase is specifically focused in a high beta frequency range during epochs when the rat is walking on a circular treadmill and most evident in a low beta frequency range during periods of inattentive rest. The increase in high beta power in the SNpr in the

Summary

Results demonstrate that recordings in behaving rats can lend insight into how changes in basal ganglia network correlate with motor dysfunction after loss of dopamine. In sum, data from the hemiparkinsonian rat show that loss of dopamine is associated with increased expression of low beta frequency activity during rest, which is reduced with movement. Moreover, recordings from rodent SNpr demonstrate increased expression of high beta activity in basal ganglia output associated with transition

Acknowledgments

The Intramural Research Program of the NINDS, NIH supported this research. We would like to thank Stacey Poloskey, Kalynda Gonzales and Jaime Ahluwalia for assistance in these experiments, Dr. Tilman Rosales for wavelet programming consultation and Newlin Morgan, Tom Talbot and Daryl Bandy in the Research Services Branch for design and fabrication of the rotary treadmill.

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