Abnormal cerebellar output in rats with an inherited movement disorder

A role for cerebellum in the hereditary dystonia DYT1

“…We found, similar to what was noted some twenty years ago in the dystonic rat and more recently in dystonic mouse models of RDP, that cerebellar-induced dystonia is associated with bursting cerebellar output (Fremont et al, 2014, 2015; LeDoux and Lorden, 1998). Our data along with a number of other mouse models of dystonia suggest that a bursting cerebellar output may be a hallmark of cerebellar-induced dystonia (Fremont et al, 2014; LeDoux et al, 1998; LeDoux and Lorden, 1998; Lorden et al, 1992). Notably, similar bursting cerebellar output has also been documented in a dystonic patient undergoing surgery (Slaughter et al, 1970).…”

Bilateral stimulation of the caudal zona incerta nucleus for tremor control

“…The exact mechanisms of its generation are unclear but, typically, there is widespread demyelination involving the olivocerebellar circuit 98. In CT, a structural or functional abnormality in the interpositus nucleus is thought to cause the <5 Hz intention tremor that predominantly affects proximal limb movements 99 – 102. HT is both a resting and kinetic tremor (<4.5 Hz) and results from lesions involving both the basal ganglia thalamocortical and the cerebello-thalamocortical loop.…”

Animal models of generalized dystonia

“…22,24,119 In contrast, the models of dystonia implicating the cerebellum predict abnormal cerebellar signaling, including Purkinje cells and deep cerebellar nuclei, with involvement of the entire olivocerebellar system. 56,59,115 Moreover, selectively eliminating cerebellar output in these cases blocks the dystonia. 74,75,113,114 Considering that both systems serve to modulate movement, the notion that simultaneous dysfunction of basal ganglia and cerebellum may be involved in different manifestations of dystonia is not unreasonable.…”

“…55 This reduction, which is observed in older dystonic animals, is likely due to feeding deficits rather than a degenerative process, 55 because histological examination of striatum, cerebellum, and deep cerebellar nuclei reveals no significant evidence of cells loss within the dt rat brain. 55,[57][58][59] However, cytological studies demonstrate that Purkinje cell soma are significantly smaller in dt rat brain, implicating the cerebellum in the motor phenotype. 58,60 Although abnormal metabolic activity is detected throughout the dt rat motor system, including striatum, 61 there is little evidence to suggest that the basal ganglia are specifically affected.…”

“…The olivocerbellar network is also the site of neurophysiological irregularities including abnormal spontaneous activity from the dt rat IO, Purkinje cell layer, and DCN. 59,69,70 Single unit recordings from dt rat Purkinje neurons reveal a reduced rate of complex spiking and abnormal patterns of simple spike bursting. 71 In addition, the increase in complex spike activity normally observed in response to harmaline is absent in dt rat Purkinje cells, 60,71 which is consistent with the failure of harmaline to induce tremor in these animals.…”