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

Jessica Cooperrider, Havan Furmaga, Ela Plow, Hyun Joo Park, Zhihong Chen, Grahame Kidd, Baker Kenneth, John T. Gale, Andre G. Machado

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

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 groupspseudorandomlyto balance severity of poststrokemotordeficits:REGULAR: stimulation,BURSTstimulation, 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.

Original languageEnglish (US)
Pages (from-to)9040-9050
Number of pages11
JournalJournal of Neuroscience
Volume34
Issue number27
DOIs
StatePublished - 2014

Keywords

  • Cerebello-thalamo-cortical
  • Deep brain stimulation
  • Focal lesion
  • Plasticity
  • Reorganization

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