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High-Frequency Stimulation of the Rat Entopeduncular Nucleus Does Not Provide Functional or Morphological Neuroprotection from 6-Hydroxydopamine.

Fischer DL, Collier TJ, Cole-Strauss A, Wohlgenant SL, Lipton JW, Steece-Collier K, Manfredsson FP, Kemp CJ, Sortwell CE - PLoS ONE (2015)

Bottom Line: Outcome measures included quantification of contralateral forelimb use, stereological assessment of SNpc neurons and BDNF levels.EP DBS 1) did not ameliorate forelimb impairments induced by 6-OHDA, 2) did not provide neuroprotection for SNpc neurons and 3) did not significantly increase BDNF levels in any of the structures examined.These results are in sharp contrast to the functional improvement, neuroprotection and BDNF-enhancing effects of STN DBS under identical experimental parameters in the rat.

View Article: PubMed Central - PubMed

Affiliation: Department of Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America; MD/PhD and Neuroscience Graduate Programs, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America.

ABSTRACT
Deep brain stimulation (DBS) is the most common neurosurgical treatment for Parkinson's disease (PD). Whereas the globus pallidus interna (GPi) has been less commonly targeted than the subthalamic nucleus (STN), a recent clinical trial suggests that GPi DBS may provide better outcomes for patients with psychiatric comorbidities. Several laboratories have demonstrated that DBS of the STN provides neuroprotection of substantia nigra pars compacta (SNpc) dopamine neurons in preclinical neurotoxin models of PD and increases brain-derived neurotrophic factor (BDNF). However, whether DBS of the entopeduncular nucleus (EP), the homologous structure to the GPi in the rat, has similar neuroprotective potential in preclinical models has not been investigated. We investigated the impact of EP DBS on forelimb use asymmetry and SNpc degeneration induced by 6-hydroxydopamine (6-OHDA) and on BDNF levels. EP DBS in male rats received unilateral, intrastriatal 6-OHDA and ACTIVE or INACTIVE stimulation continuously for two weeks. Outcome measures included quantification of contralateral forelimb use, stereological assessment of SNpc neurons and BDNF levels. EP DBS 1) did not ameliorate forelimb impairments induced by 6-OHDA, 2) did not provide neuroprotection for SNpc neurons and 3) did not significantly increase BDNF levels in any of the structures examined. These results are in sharp contrast to the functional improvement, neuroprotection and BDNF-enhancing effects of STN DBS under identical experimental parameters in the rat. The lack of functional response to EP DBS suggests that stimulation of the rat EP may not represent an accurate model of clinical GPi stimulation.

No MeSH data available.


Related in: MedlinePlus

Electrodes implanted in the EP remain in position over the two-week stimulation interval.Representative photomicrographs illustrate unilateral electrode placement in the EP following Kluver-Barrera staining. (A) Low magnification image shows the approximate placement of the stimulating electrode prior to its removal post mortem and the tissue damage related to the removal process. The active electrode tip diameter is 150 μm whereas the shaft of the electrode is 400 μm in diameter. (B) High magnification of the electrode tip’s position in the EP. (C) EP neurons are visible in a nearby coronal section (≈160 μm caudal), indicating that a significant portion of the EP remained intact. Rats in which electrodes were found to be positioned more than 250 μm away from the EP were excluded from analysis based on previous estimates of current spread [20]. Scale bar in A = 1000 μm, C = 500 μm.
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pone.0133957.g002: Electrodes implanted in the EP remain in position over the two-week stimulation interval.Representative photomicrographs illustrate unilateral electrode placement in the EP following Kluver-Barrera staining. (A) Low magnification image shows the approximate placement of the stimulating electrode prior to its removal post mortem and the tissue damage related to the removal process. The active electrode tip diameter is 150 μm whereas the shaft of the electrode is 400 μm in diameter. (B) High magnification of the electrode tip’s position in the EP. (C) EP neurons are visible in a nearby coronal section (≈160 μm caudal), indicating that a significant portion of the EP remained intact. Rats in which electrodes were found to be positioned more than 250 μm away from the EP were excluded from analysis based on previous estimates of current spread [20]. Scale bar in A = 1000 μm, C = 500 μm.

Mentions: Every sixth section of the entopeduncular nucleus (EP) was stained using Kluver-Barrera histochemistry [24] to evaluate for appropriate targeting of the electrode to the EP. Only rats with correctly positioned electrodes were included in the data analysis for Experiment 2. Electrode location was considered to be appropriate if the tip of the electrode was observed within 250 μm of the border of the EP within any of the sections based on previous studies in which current spread was determined [19]. A representative histological section is shown in Fig 2.


High-Frequency Stimulation of the Rat Entopeduncular Nucleus Does Not Provide Functional or Morphological Neuroprotection from 6-Hydroxydopamine.

Fischer DL, Collier TJ, Cole-Strauss A, Wohlgenant SL, Lipton JW, Steece-Collier K, Manfredsson FP, Kemp CJ, Sortwell CE - PLoS ONE (2015)

Electrodes implanted in the EP remain in position over the two-week stimulation interval.Representative photomicrographs illustrate unilateral electrode placement in the EP following Kluver-Barrera staining. (A) Low magnification image shows the approximate placement of the stimulating electrode prior to its removal post mortem and the tissue damage related to the removal process. The active electrode tip diameter is 150 μm whereas the shaft of the electrode is 400 μm in diameter. (B) High magnification of the electrode tip’s position in the EP. (C) EP neurons are visible in a nearby coronal section (≈160 μm caudal), indicating that a significant portion of the EP remained intact. Rats in which electrodes were found to be positioned more than 250 μm away from the EP were excluded from analysis based on previous estimates of current spread [20]. Scale bar in A = 1000 μm, C = 500 μm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4519335&req=5

pone.0133957.g002: Electrodes implanted in the EP remain in position over the two-week stimulation interval.Representative photomicrographs illustrate unilateral electrode placement in the EP following Kluver-Barrera staining. (A) Low magnification image shows the approximate placement of the stimulating electrode prior to its removal post mortem and the tissue damage related to the removal process. The active electrode tip diameter is 150 μm whereas the shaft of the electrode is 400 μm in diameter. (B) High magnification of the electrode tip’s position in the EP. (C) EP neurons are visible in a nearby coronal section (≈160 μm caudal), indicating that a significant portion of the EP remained intact. Rats in which electrodes were found to be positioned more than 250 μm away from the EP were excluded from analysis based on previous estimates of current spread [20]. Scale bar in A = 1000 μm, C = 500 μm.
Mentions: Every sixth section of the entopeduncular nucleus (EP) was stained using Kluver-Barrera histochemistry [24] to evaluate for appropriate targeting of the electrode to the EP. Only rats with correctly positioned electrodes were included in the data analysis for Experiment 2. Electrode location was considered to be appropriate if the tip of the electrode was observed within 250 μm of the border of the EP within any of the sections based on previous studies in which current spread was determined [19]. A representative histological section is shown in Fig 2.

Bottom Line: Outcome measures included quantification of contralateral forelimb use, stereological assessment of SNpc neurons and BDNF levels.EP DBS 1) did not ameliorate forelimb impairments induced by 6-OHDA, 2) did not provide neuroprotection for SNpc neurons and 3) did not significantly increase BDNF levels in any of the structures examined.These results are in sharp contrast to the functional improvement, neuroprotection and BDNF-enhancing effects of STN DBS under identical experimental parameters in the rat.

View Article: PubMed Central - PubMed

Affiliation: Department of Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America; MD/PhD and Neuroscience Graduate Programs, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America.

ABSTRACT
Deep brain stimulation (DBS) is the most common neurosurgical treatment for Parkinson's disease (PD). Whereas the globus pallidus interna (GPi) has been less commonly targeted than the subthalamic nucleus (STN), a recent clinical trial suggests that GPi DBS may provide better outcomes for patients with psychiatric comorbidities. Several laboratories have demonstrated that DBS of the STN provides neuroprotection of substantia nigra pars compacta (SNpc) dopamine neurons in preclinical neurotoxin models of PD and increases brain-derived neurotrophic factor (BDNF). However, whether DBS of the entopeduncular nucleus (EP), the homologous structure to the GPi in the rat, has similar neuroprotective potential in preclinical models has not been investigated. We investigated the impact of EP DBS on forelimb use asymmetry and SNpc degeneration induced by 6-hydroxydopamine (6-OHDA) and on BDNF levels. EP DBS in male rats received unilateral, intrastriatal 6-OHDA and ACTIVE or INACTIVE stimulation continuously for two weeks. Outcome measures included quantification of contralateral forelimb use, stereological assessment of SNpc neurons and BDNF levels. EP DBS 1) did not ameliorate forelimb impairments induced by 6-OHDA, 2) did not provide neuroprotection for SNpc neurons and 3) did not significantly increase BDNF levels in any of the structures examined. These results are in sharp contrast to the functional improvement, neuroprotection and BDNF-enhancing effects of STN DBS under identical experimental parameters in the rat. The lack of functional response to EP DBS suggests that stimulation of the rat EP may not represent an accurate model of clinical GPi stimulation.

No MeSH data available.


Related in: MedlinePlus