Review
Studies of the neural mechanisms of deep brain stimulation in rodent models of Parkinson's disease

https://doi.org/10.1016/j.neubiorev.2007.01.002Get rights and content

Abstract

Several rodent models of deep brain stimulation (DBS) have been developed in recent years. Electrophysiological and neurochemical studies have been performed to examine the mechanisms underlying the effects of DBS. In vitro studies have provided deep insights into the role of ion channels in response to brain stimulation. In vivo studies reveal neural responses in the context of intact neural circuits. Most importantly, recording of neural responses to behaviorally effective DBS in freely moving animals provides a direct means for examining how DBS modulates the basal ganglia thalamocortical circuits and thereby improves motor function. DBS can modulate firing rate, normalize irregular burst firing patterns and reduce low-frequency oscillations associated with the Parkinsonian state. Our current efforts are focused on elucidating the mechanisms by which DBS effects on neural circuitry improve motor performance. New behavioral models and improved recording techniques will aide researchers conducting future DBS studies in a variety of behavioral modalities and enable new treatment strategies to be explored, such as closed-loop stimulations based on real-time computation of ensemble neural activity.

Introduction

Deep brain stimulation (DBS) methodology has been rekindled over the last decade as an effective treatment for a variety of neurological disorders including Parkinson's diseases (PD) (Benabid, 2003). Despite its remarkable therapeutic efficacy, the mechanisms underlying the therapeutic effects of DBS have not been resolved. Animal models are essential for elucidating how DBS alleviates Parkinsonian symptoms. Unfortunately, the development of animal models of DBS has lagged behind clinical applications in the early stages of DBS research. This is partially due to the initial clinical success of treating PD with DBS (Ashkan et al., 2004).

Animal experiments with DBS were first carried out in a primate model of PD. A behavioral scoring method similar to that used in PD patients was employed to measure Parkinsonian symptoms. DBS of the subthalamic nucleus (STN) induced beneficial effects in Parkinsonian non-human primates that were similar to those observed in human PD patients (Benazzouz et al., 1993; Boraud et al., 1996; Gao et al., 1999). DBS research was expanded to include rodent models in which the electrophysiological and neurochemical responses associated with DBS could be examined in more detail. Early studies carried out in in vitro and in in vivo anesthetized rodent preparations provided detailed information about neural responses to high-frequency stimulation (HFS) that mimics clinically applied DBS. However studies of anesthetized models obviously lack behavioral corroboration of the DBS effect, and these non-behavioral studies have produced considerable variability in results depending upon the stimulation parameters applied, and preparation methodology used. The subsequent establishment of DBS models in behaving rats with nigrostriatal dopamine (DA) depletion-enabled DBS effects to be studied in a model that mimics clinical conditions. This review will discuss recent developments and advances in DBS basic research employing rodent models.

Section snippets

Rodent models of DBS

Rodent models have been widely used over the last three decades for PD research. The commonly used unilateral 6-hydroxydopamine (6-OHDA) nigrostriatal lesion model can produce in rat the major symptoms of PD including akinesia, posture abnormality, tremor and dyskinesia (Cenci et al., 2002). Many of these motor deficits can be easily scored to obtain quantitative measures of motor deficits, which can then be correlated with the degree of DA depletion (Schallert and Tillerson, 2000; Montoya et

Mechanism of DBS

A basic model for the occurrence of Parkinson's motor symptoms is that activity in the STN becomes elevated in the absence of adequate DA, and that this leads to increased inhibitory output from the SNr and globus pallidus internal (GPi). This effect has been postulated to lead to enhanced inhibition within the thalamus. This inhibition in turn may suppress or block the spatial temporal patterns of activation that activate motor areas employed to generate intentional movement (Delong, 1990;

Concluding remarks and future directions

Rodent models have been used successfully in PD research for over three decades and continue to contribute to emerging research fields, such as DBS. Several behavioral models have been developed to study the effects of DBS in Parkinsonian rats. Similar to the effects of DBS in human patients, HFS of the rat STN can alleviate motor deficits in a variety of motor tasks. Rat, being quadripedal and human being bipedal, superficially seems to exhibit different motor patterns, but the basic essence

Acknowledgments

Several of the studies presented in this article were supported by NIH Grants NS-43441, NS 40628 and TW-006144 to JYC and NS-19608 to DJW.

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