Disrupted sleep in dystonia depends on cerebellar function but not motor symptoms in mice

Abstract

Although dystonia is the third most common movement disorder, patients often also experience debilitating nonmotor defects including impaired sleep. The cerebellum is a central component of a ″dystonia network″ that plays various roles in sleep regulation. Importantly, the primary driver of sleep impairments in dystonia remains poorly understood. The cerebellum, along with other nodes in the motor circuit, could disrupt sleep. However, it is unclear how the cerebellum might alter sleep and mobility. To disentangle the impact of cerebellar dysfunction on motion and sleep, we generated two mouse genetic models of dystonia that have overlapping cerebellar circuit miswiring but show differing motor phenotype severity:Ptf1aCre;Vglut2fx/fxandPdx1Cre;Vglut2fx/fxmice. In both models, excitatory climbing fiber to Purkinje cell neurotransmission is blocked, but only thePtf1aCre;Vglut2fx/fxmice have severe twisting. Usingin vivoECoG and EMG recordings we found that both mutants spend greater time awake and in NREM sleep at the expense of REM sleep. The increase in awake time is driven by longer awake bouts rather than an increase in bout number. We also found a longer latency to reach REM in both mutants, which is similar to what is reported in human dystonia. We uncovered independent but parallel roles for cerebellar circuit dysfunction and motor defects in promoting sleep quality versus posture impairments in dystonia.

Cerebellar deep brain stimulation as a dual-function therapeutic for restoring movement and sleep in dystonic mice

“…Consequently, a primary objective of our study was to investigate how cerebellar nuclei DBS might improve overall sleep quality in Ptf1a Cre ;Vglut2 fx/fx and Pdx1 Cre ;Vglut2 fx/fx mice. At baseline (Pre-DBS), representative hypnograms indicate that both Ptf1a Cre ;Vglut2 fx/fx and Pdx1 Cre ;Vglut2 fx/fx mice display overall greater time awake and less time asleep relative to controls, similar to our previous findings 16 . Remarkably, during DBS, the proportions of wakefulness and sleep time began to converge across all mouse groups, demonstrating a rectification of sleep dysfunction.…”

“…Echoing our previous research 16 , these results point to cerebellar dysfunction, rather than motor impairment alone, as the likely origin of sleep deficits, given that both mutant mouse types, regardless of their motor condition, showed comparable sleep improvements during DBS.…”

“…Indeed, individuals with dystonia frequently experience sleep disturbances, including insomnia (indicative of a difficulty in falling asleep), parasomnias (indicative of a difficulty in staying asleep), and notably, pronounced deficits in the duration and quality of rapid eye movement (REM) sleep [13][14][15] . Analogous observations are reported in mouse models of dystonia, in which mutant mice exhibit an increase in awake time (driven by longer wake bouts), diminished REM duration (driven by fewer REM bouts), and increased latency to initiate REM sleep 16 . These data underscore the multifaceted role of the cerebellum in dystonia and suggest that it may have a broader neurological impact that extends beyond motor control to include the regulation of sleep.…”

“…Recent studies, including our own, propose a bidirectional role for the cerebellum in dystonia, influencing both motor and non-motor (sleep) impairments 11,16 . Given this dual function, the cerebellum emerges as an appealing target for DBS intervention to address both motor and sleep dysfunctions in dystonia.…”

Cerebellar nuclei cells produce distinct pathogenic spike signatures in mouse models of ataxia, dystonia, and tremor

“…Next, we set out to identify whether the dystonia signature was shared across mice with overt dystonic phenotypes. We included two dystonia models in our analyses; Pdx1 Cre ;Vglut2 fl/fl mice exhibit mild dystonic symptoms only in response to a stressful event (32,33) (Figure 3A-B), whereas mice that receive ouabain applied to the surface of the cerebellum exhibit continuous severe dystonic features (34,35) (Figure 3A-B). We found that the proportion of neurons that exhibited the control signature was greater in Pdx1 Cre ;Vglut2 fl/fl mice than in ouabain infusion mice (7/23 vs. 13/21, z=-2.094, p=0.0366) (Figure 3C).…”