TY - JOUR TI - Purkinje cell misfiring generates high-amplitude action tremors that are corrected by cerebellar deep brain stimulation AU - Brown, Amanda M AU - White, Joshua J AU - van der Heijden, Meike E AU - Zhou, Joy AU - Lin, Tao AU - Sillitoe, Roy V A2 - Ivry, Richard B A2 - Carey, Megan R A2 - Hoebeek, Freek E VL - 9 PY - 2020 DA - 2020/03/17 SP - e51928 C1 - eLife 2020;9:e51928 DO - 10.7554/eLife.51928 UR - https://doi.org/10.7554/eLife.51928 AB - Tremor is currently ranked as the most common movement disorder. The brain regions and neural signals that initiate the debilitating shakiness of different body parts remain unclear. Here, we found that genetically silencing cerebellar Purkinje cell output blocked tremor in mice that were given the tremorgenic drug harmaline. We show in awake behaving mice that the onset of tremor is coincident with rhythmic Purkinje cell firing, which alters the activity of their target cerebellar nuclei cells. We mimic the tremorgenic action of the drug with optogenetics and present evidence that highly patterned Purkinje cell activity drives a powerful tremor in otherwise normal mice. Modulating the altered activity with deep brain stimulation directed to the Purkinje cell output in the cerebellar nuclei reduced tremor in freely moving mice. Together, the data implicate Purkinje cell connectivity as a neural substrate for tremor and a gateway for signals that mediate the disease. KW - tremor KW - cerebellum KW - purkinje KW - optogenetics KW - electrophysiology KW - deep brain stimulation JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -