PT  - JOURNAL ARTICLE
AU  - Amanda M Brown
AU  - Joshua J White
AU  - Meike E van der Heijden
AU  - Tao Lin
AU  - Roy V Sillitoe
TI  - Cerebellar Purkinje cell microcircuits are essential for tremor
AID  - 10.1101/770321
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 770321
4099  - http://biorxiv.org/content/early/2019/09/15/770321.short
4100  - http://biorxiv.org/content/early/2019/09/15/770321.full
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 activity 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 output 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.