Elsevier

Experimental Neurology

Volume 261, November 2014, Pages 563-577
Experimental Neurology

Regular Article
Functional correlates of exaggerated oscillatory activity in basal ganglia output in hemiparkinsonian rats

https://doi.org/10.1016/j.expneurol.2014.07.010Get rights and content

Highlights

  • Oscillatory activity in basal ganglia output is increased in the hemiparkinsonian rat.

  • Increases in LFP power are modulated by repetitive motor activity.

  • Spike-LFP entrainment frequencies vary with rest, alert, walking, and anesthesia.

  • l-Dopa effect on LFP-spike entrainment is modulated by 5HT1a receptor stimulation.

Abstract

Exaggerated beta range (13–30 Hz) synchronized activity is observed in the basal ganglia of Parkinson's disease (PD) patients during implantation of deep brain stimulation electrodes and is thought to contribute to the motor symptoms of this disorder. To explore the translational potential of similar activity observed in a rat model of PD, local field potentials (LFPs) and spiking activity in basal ganglia output were characterized in rats with unilateral dopamine cell lesion during a range of behaviors. A circular treadmill was used to assess activity during walking; hemiparkinsonian rats could maintain a steady gait when oriented ipsiversive to the lesioned hemisphere, but were less effective at walking when oriented contraversive to lesion. Dramatic increases in substantia nigra pars reticulata (SNpr) LFP oscillatory activity and spike-LFP synchronization were observed within the beta/low gamma range (12–40 Hz) in the lesioned hemisphere, relative to the non-lesioned hemisphere, with the dominant frequency of spike-LFP entrainment and LFP power varying with behavioral state. At 3 weeks postlesion, the mean dominant entrainment frequency during ipsiversive treadmill walking and grooming was 34 Hz. Other behaviors were associated with lower mean entrainment frequencies: 27–28 Hz during alert non-walking and REM, 17 Hz during rest and 21 Hz during urethane anesthesia with sensory stimulation. SNpr spike-LFP entrainment frequency was stable during individual treadmill walking epochs, but increased gradually over weeks postlesion. In contrast, SNpr LFP power in the 25–40 Hz range was greatest at the initiation of each walking epoch, and decreased during walking to stabilize by 6 min at 49% of initial values. Power was further modulated in conjunction with the 1.5 s stepping rhythm. Administration of l-dopa improved contraversive treadmill walking in correlation with a reduction in SNpr 25–40 Hz LFP power and spike synchronization in the dopamine cell lesioned hemisphere. These effects were reversed by the serotonergic 1A agonist, 8-OH-DPAT. While the prominent spike-LFP phase locking observed during ongoing motor activity in the hemiparkinsonian rats occurs at frequencies intriguingly higher than in PD patients, the synchronized activity in the SNpr of this animal model has much in common with oscillatory activity recorded from the basal ganglia of the PD patients. Results support the potential of this model for providing insight into relationships between synchronization of basal ganglia output induced by loss of dopamine and motor symptoms in PD.

Introduction

Recordings of neuronal activity from the subthalamic nucleus (STN) and internal globus pallidus (GPi) of Parkinson's disease (PD) patients during implantation of deep brain stimulation electrodes show exaggerated synchronized and oscillatory activity in the beta frequency range (13–30 Hz) (Alonso-Frech et al., 2006, Brown, 2003, Brown et al., 2001, Kuhn et al., 2005, Levy et al., 2002, Priori et al., 2004). Evidence that this beta range oscillatory activity is reduced by l-dopa treatment in the STN and GPi of PD patients (Alonso-Frech et al., 2006, Brown, 2003, Brown et al., 2001, Levy et al., 2002, Priori et al., 2004) in conjunction with improvement in motor function (Brown and Williams, 2005, Kuhn et al., 2006, Weinberger et al., 2006) has led to considerable interest in the source of this activity and its role in the development of parkinsonian symptoms.

Animal models of PD also show increases in synchronized and oscillatory activity in the basal ganglia (Avila et al., 2010, Belluscio et al., 2013, Bergman et al., 1994, Brazhnik et al., 2012, Delaville et al., 2014, Kita and Kita, 2011a, Mallet et al., 2008b, Murer et al., 2002, Raz et al., 2001, Sharott et al., 2005, Tachibana et al., 2011, Tseng et al., 2001, Walters et al., 2007). Ideally, these models should be able to provide insight into how loss of dopamine triggers such dramatic changes in basal ganglia activity and whether firing patterns in specific frequency ranges are ultimately pathological, compensatory, or simply confounding. One caveat, however, is that the peak frequencies of abnormal oscillations observed in animal models of PD show substantial variability across species and behavioral states, prompting questions about whether the increased oscillatory activity evident in animal models is translationally relevant to the oscillatory activity thought to be pathological in human PD. For example, in dopamine-depleted non-human primates, dominant frequencies of oscillatory spiking activity recorded from the STN and GPi are typically bimodally distributed in the 3–15 Hz range (Gatev et al., 2006, Heimer et al., 2006, Leblois et al., 2007, Raz et al., 2000, Tachibana et al., 2011), lower than the 13–30 Hz peak frequencies noted most commonly in local field potential (LFP) recordings from alert PD patients (Alonso-Frech et al., 2006, Brown, 2003, Kuhn et al., 2009, Levy et al., 2002, Priori et al., 2004, Weinberger et al., 2006). Moreover, peak frequencies of exaggerated oscillatory activity are in the 30–35 Hz range in LFP recordings from basal ganglia output nuclei in hemiparkinsonian rats during treadmill walking (Avila et al., 2010, Brazhnik et al., 2012), while studies in urethane-anesthetized hemiparkinsonian rats report synchronization in the 1 Hz range during deep anesthesia (Tseng et al., 2001, Walters et al., 2007) and in the 20 Hz range during states of global activation (Mallet et al., 2008a, Mallet et al., 2008b, Moran et al., 2011). On the other hand, recordings from PD patients also show some variability in peak frequency from patient to patient under seemingly similar recording conditions, prompting questions about whether the specific frequency at which basal ganglia output becomes synchronized is critical, or even relevant, to the nature of the motor deficits in PD patients (Kuhn et al., 2009).

The present study sought to develop a more detailed description of relationships between oscillatory activity in basal ganglia output, behavioral state, and motor dysfunction in a rodent model of PD. Our goal was to determine whether the exaggerated oscillatory activity in the basal ganglia of the hemiparkinsonian rat model appears sufficiently relevant to the oscillations observed in the PD patient be helpful in elucidating how exaggerated oscillatory activity relates to the symptomology of PD. Chronic recordings of spike and LFP activity were performed in the substantia nigra pars reticulata (SNpr) in rats with unilateral 6-hydroxydopamine (6-OHDA)-induced dopamine cell lesion. Simultaneous recordings from the SNpr in the lesioned and non-lesioned hemispheres allowed assessment of the effect of dopamine cell lesion on basal ganglia output over a range of behavioral states. Dominant frequency and power of oscillatory neural activity, spike synchronization, and firing rate in the SNpr were analyzed over different time scales in conjunction with effects of l-dopa treatment on motor symptoms.

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.

Behavioral state-dependent changes in SNpr LFP activity and synchronized spiking after dopamine cell lesion

Chronic recordings from electrodes implanted bilaterally in the SNpr confirmed previous observations (Avila et al., 2010, Brazhnik et al., 2012) of increases in oscillatory LFP activity in this nucleus during rest and treadmill walking after unilateral 6-OHDA-induced dopamine cell lesion. As shown in wavelet-based scalograms and FFT-based power spectra (Fig. 1A, left and right panels), SNpr LFP activity in the dopamine-deprived hemisphere was dramatically different from SNpr LFP activity

Discussion

The present study explores the characteristics of the increases in oscillatory activity in the basal ganglia output in the hemiparkinsonian rat. Our goal was to assess the potential of this model to provide insight into the functional significance of similar activity in the basal ganglia in advanced PD. Increases in oscillatory activity in the basal ganglia are of special interest in PD as this activity is modulated during movement and reduced in conjunction with improvement in motor symptoms

Financial disclosures

There are no financial disclosures or conflict of interest for any of the authors. This article has not been submitted elsewhere. All co-authors have seen and agreed with the contents of the manuscript.

Acknowledgments

The Intramural Research Program of the NINDS, NIH supported this research. We wish to thank Newlin, Morgan, Tom Talbot and Daryl Brandy in the Research Services Branch for design and fabrication of the rotary treadmill.

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