Targeted disruption of supraspinal motor circuitry reveals a distributed network underlying Restless Legs Syndrome (RLS)-like movements in the rat

Abstract

In this study we uncovered, through targeted ablation, a potential role for corticospinal, cerebello-rubro-spinal, and hypothalamic A11 dopaminergic systems in the development of restless legs syndrome (RLS)-like movements during sleep. Targeted lesions in select basal ganglia (BG) structures also revealed a major role for nigrostriatal dopamine, the striatum, and the external globus pallidus (GPe) in regulating RLS-like movements, in particular pallidocortical projections from the GPe to the motor cortex. We further showed that pramipexiole, a dopamine agonist used to treat human RLS, reduced RLS-like movements. Taken together, our data show that BG-cortico-spinal, cerebello-rubro-spinal and A11 descending projections all contribute to the suppression of motor activity during sleep and sleep-wake transitions, and that disruption of these circuit nodes produces RLS-like movements. Taken together with findings from recent genomic studies in humans, our findings provide additional support for the concept that the anatomic and genetic etiological bases of RLS are diverse.

Phenotypical predictors of Restless Legs Syndrome in pregnancy and their association with basal ganglia and the limbic circuits

“…As the whole-brain results of our study show, the most important and interhemispheric variations occur in the basal ganglia, with the medial and lateral striata contributing the most to the clinical and anamnestic differences in the pregnancyrelated RLS group. Along with our results, the human lesion studies (Lee et al, 2009;Shiina et al, 2019;Woo et al, 2017) as well as the recent RLS animal model studies (Guo et al, 2017) underscore the crucial role of the basal ganglia in the manifestation of the RLS spectrum. Based on the brain phenotype model, we conclude therefore that different factors such as stress response, history of SLE or life circumstances (e.g.…”

Phenotypical predictors of pregnancy-related restless legs syndrome and their association with basal ganglia and the limbic circuits

“…The most important and interhemispheric variations occur in the basal ganglia, with the medial and lateral striatum contributing the most to the clinical and anamnestic differences in individuals experiencing RLS symptoms in pregnancy. Along with our results, the human lesion studies 39 – 41 as well as the recent RLS animal model studies 42 underscore the crucial role of the basal ganglia in the manifestation of the RLS spectrum. Based on the brain-phenotype model, we conclude therefore that different factors such as severity and history of RLS symptoms, stress response, history of SLE or life circumstances (e.g.…”

Circadian-based Treatment Strategy Effective in the BACHD Mouse Model of Huntington’s Disease

“…In addition, given the well-established dysfunction in the basal ganglia circuits in HD patients and animal models, deficits in these circuits could be the site of action for some of the sleep deficits. There is a variety of evidence indicating that dopamine signaling within the striatum and the external globus pallidus (GPe) plays an important role in suppressing movements during sleep, and dysfunction in these pathways has been implicated in restless leg syndrome (e.g., Jones and Cavanna, 2013;Guo et al, 2017) and REM sleep disorder (e.g., Arnulf, 2012;Rolinski et al, 2016). Neurons in the GPe exhibit alterations in GABA-mediated synaptic transmission in the R6/1 HD mouse model (Du et al, 2016), and deep-brain stimulation of this same region promotes sleep (Qiu et al, 2016a(Qiu et al, , 2016b.…”