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.

Rapid Modulation of Protein Expression in the Rat Hippocampus Following Deep Brain Stimulation of the Fornix

“…entorhinal cortex (EC) or anterior nucleus of the thalamus (ANT), modulate hippocampus-dependent memory and neurogenesis [8,9,23,24]. Recent work has also demonstrated that DBS at other targets, including the subthalamic nucleus (STN), the ventromedial prefrontal cortex (vmPFC) and the cerebellum, modulates gene and protein expression [25][26][27][28]. However, the mechanisms of action of DBS in general and for forniceal stimulation in particular remain unknown.…”

Optogenetic Approaches to Target Specific Neural Circuits in Post-stroke Recovery

“…Deep brain stimulations targeting the thalamus (Th) and periaqueductal gray matter for post-stroke movements and neuropathic pain have demonstrated efficacy in human studies [59][60][61]. Deep brain stimulations in the cerebellar dentate nucleus in rats have also been shown to promote post-stroke recovery and enhance synaptic plasticity and reorganization in the perilesional cortex [62][63][64][65].…”

“…2). Electrical stimulation of the dentate nucleus in rats has been shown to promote recovery and enhance plasticity [62][63][64][65]. Tracing studies using the rabies virus have indicated that different divisions of the dentate nucleus mediate different functions.…”

Differential frequency modulation of neural activity in the lateral cerebellar nucleus in failed and successful grasps

“…Such findings have important physiological implications, as LCN LFPs during reaching and grasp have not been studied to date. Furthermore, these findings represent an important technical milestone by advancing ongoing translational work in chronic stimulation of the LCN as a treatment for post-injury motor rehabilitation (Cooperrider et al, 2014; Machado et al, 2013) towards a closed-loop stimulation therapy, wherein stimulation is triggered by a neural signal.…”