Chronic deep cerebellar stimulation promotes long-term potentiation, microstructural plasticity, and reorganization of perilesional cortical representation in a rodent model

Control over postinjury CNS plasticity is a major frontier of science that, if conquered, would open new avenues for treatment of neurological disorders. Here we investigate the functional, physiological, and structural changes in the cerebral cortex associated with chronic deep brain stimulation of...

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Bibliographic Details
Published in:The Journal of neuroscience 2014-07, Vol.34 (27), p.9040-9050
Main Authors: Cooperrider, Jessica, Furmaga, Havan, Plow, Ela, Park, Hyun-Joo, Chen, Zhihong, Kidd, Grahame, Baker, Kenneth B, Gale, John T, Machado, Andre G
Format: Article
Language:English
Subjects:
Animals
Appetitive Behavior - physiology
Brain Ischemia - physiopathology
Brain Mapping
Cerebellar Nuclei - physiopathology
Cerebral Cortex - physiopathology
Deep Brain Stimulation
Dominance, Cerebral
Electrodes, Implanted
Electron Microscope Tomography
Long-Term Potentiation - physiology
Male
Nerve Tissue Proteins - physiology
Random Allocation
Rats
Rats, Long-Evans
Synapses - metabolism
Wound Healing
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Summary:Control over postinjury CNS plasticity is a major frontier of science that, if conquered, would open new avenues for treatment of neurological disorders. Here we investigate the functional, physiological, and structural changes in the cerebral cortex associated with chronic deep brain stimulation of the cerebellar output, a treatment approach that has been shown to improve postischemia motor recovery in a rodent model of cortical infarcts. Long-Evans rats were pretrained on the pasta-matrix retrieval task, followed by induction of focal cortical ischemia and implantation of a macroelectrode in the contralesional lateral cerebellar nucleus. Animals were assigned to one of three treatment groups pseudorandomly to balance severity of poststroke motor deficits: REGULAR stimulation, BURST stimulation, or SHAM. Treatment initiated 2 weeks post surgery and continued for 5 weeks. At the end, animals were randomly selected for perilesional intracortical microstimulation mapping and tissue sampling for Western blot analysis or contributed tissue for 3D electron microscopy. Evidence of enhanced cortical plasticity with therapeutically effective stimulation is shown, marked by greater perilesional reorganization in stimulation- treated animals versus SHAM. BURST stimulation was significantly effective for promoting distal forepaw cortical representation. Stimulation-treated animals showed a twofold increase in synaptic density compared with SHAM. In addition, treated animals demonstrated increased expression of synaptic markers of long-term potentiation and plasticity, including synaptophysin, NMDAR1, CaMKII, and PSD95. These findings provide a critical foundation of how deep cerebellar stimulation may guide plastic reparative reorganization after nonprogressive brain injury and indicate strong translational potential.
ISSN:0270-6474
1529-2401
DOI:10.1523/jneurosci.0953-14.2014