title: Chronic deep cerebellar stimulation promotes long-term potentiation, microstructural plasticity, and reorganization of perilesional cortical representation in a rodent model.
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 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.
authors.affiliation: Center for Neurological Restoration, Neurological Institute and Departments of Neuroscience and.
authors.forename: Jessica
authors.initials: J
authors.lastname: Cooperrider
authors.affiliation: Center for Neurological Restoration, Neurological Institute and Departments of Neuroscience and.
authors.forename: Havan
authors.initials: H
authors.lastname: Furmaga
authors.affiliation: Center for Neurological Restoration, Neurological Institute and Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, and.
authors.forename: Ela
authors.identifier: http://orcid.org/0000-0001-7788-7760
authors.initials: E
authors.lastname: Plow
authors.affiliation: Departments of Neuroscience and.
authors.forename: Hyun-Joo
authors.identifier: http://orcid.org/0000-0001-8484-7652
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Departments of Neuroscience and.
authors.forename: Zhihong
authors.identifier: http://orcid.org/0000-0001-7403-7015
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Departments of Neuroscience and.
authors.forename: Grahame
authors.initials: G
authors.lastname: Kidd
authors.affiliation: Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Kenneth B
authors.identifier: http://orcid.org/0000-0002-6735-2911
authors.initials: KB
authors.lastname: Baker
authors.affiliation: Center for Neurological Restoration, Neurological Institute and Departments of Neuroscience and.
authors.forename: John T
authors.identifier: http://orcid.org/0000-0002-6159-6835
authors.initials: JT
authors.lastname: Gale
authors.affiliation: Center for Neurological Restoration, Neurological Institute and Departments of Neuroscience and Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, and machada@ccf.org.
authors.forename: Andre G
authors.identifier: http://orcid.org/0000-0002-8132-5610
authors.initials: AG
authors.lastname: Machado
mesh_terms: D000818:Animals; D001070:Appetitive Behavior / Q000502:physiology; D002545:Brain Ischemia / Q000503:physiopathology*; D001931:Brain Mapping; D002529:Cerebellar Nuclei / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000503:physiopathology*; D046690:Deep Brain Stimulation; D004292:Dominance, Cerebral; D004567:Electrodes, Implanted; D055032:Electron Microscope Tomography; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D020318:Rats, Long-Evans; D013569:Synapses / Q000378:metabolism; D014945:Wound Healing
chemical_list: D009419:Nerve Tissue Proteins
keywords: cerebello-thalamo-cortical; deep brain stimulation; focal lesion; plasticity; reorganization