Deep brain stimulation of different pedunculopontine targets in a novel rodent model of parkinsonism
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The pedunculopontine tegmental nucleus (PPTg) has been proposed as a target for deep brain stimulation (DBS) in parkinsonian patients, particularly for symptoms such as gait and postural difficulties refractory to dopaminergic treatments. Several patients have had electrodes implanted aimed at the PPTg, but outcomes have been disappointing, with little evidence that gait and posture are improved. The PPTg is a heterogeneous structure. Consequently, exact target sites in PPTg, possible DBS mechanisms, and potential benefits still need systematic investigation in good animal models. We have investigated the role of PPTg in gait, developed a refined model of parkinsonism including partial loss of the PPTg with bilateral destruction of nigrostriatal dopamine neurons that mimics human pathophysiology, and investigated the effect of DBS at different PPTg locations on gait and posture using a wireless device that lets rats move freely while receiving stimulation. Neither partial nor complete lesions of PPTg caused gait deficits, underlining questions raised previously about the status of PPTg as a motor control structure. The effect of DBS in the refined and standard model of parkinsonism were very different despite minimal behavioral differences in nonstimulation control conditions. Anterior PPTg DBS caused severe episodes of freezing and worsened gait, whereas specific gait parameters were mildly improved by stimulation of posterior PPTg. These results emphasize the critical importance of intra-PPTg DBS location and highlight the need to take PPTg degeneration into consideration when modeling parkinsonian symptoms. They also further implicate a role for PPTg in the pathophysiology of parkinsonism.
Gut , N K & Winn , P 2015 , ' Deep brain stimulation of different pedunculopontine targets in a novel rodent model of parkinsonism ' The Journal of Neuroscience , vol 35 , no. 12 , pp. 4792-4803 . DOI: 10.1523/JNEUROSCI.3646-14.2015
The Journal of Neuroscience
Copyright © 2015 the authors. This article is freely available online through the J Neurosci Author Open Choice option. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) license (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
This research was supported by Medical Research Council Grant G0901332 (P.W.), part of an ERA-NET NEURON grant. N.K.G. was also supported by a studentship from the School of Psychology, University of St. Andrews and by an award from a Scottish Universities Life Sciences Alliance Strategic Research Development Grant to the University of Strathclyde. Date of Acceptance: 22/01/2015
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