Restless legs syndrome

Abstract

Restless legs syndrome (RLS) involves abnormal limb sensations that diminish with motor activity, worsen at rest, have a circadian peak in expression in the evening and at night, and can severely disrupt sleep. Primary treatment is directed at CNS dopaminergic systems, particularly activation of D(2)-like (D(2), D(3), and D(4)) receptors. Although RLS affects 2% to 15% of the general population, the neural circuitry contributing to RLS remains speculative, and there is currently no accepted animal model to enable detailed mechanistic analyses. Traditional views suggest that RLS arises from supraspinal sources which favor facilitation of the flexor reflex and emergence of the RLS phenotype. The authors forward the hypothesis that RLS reflects a dysfunction of the little-studied dorsoposterior hypothalamic dopaminergic A11 cell group. They assert that, as the sole source of spinal dopamine, reduced drive in this system can lead to spinal network changes wholly consistent with RLS. The authors summarize their recent investigations on spinal cord dopamine dysfunction that rely on lesions centered on A11, and on studies in D(3) receptor knockout (D(3)KO) mice. Excessive locomotor behavior is evident in both sets of animals, and D(3)KO mice exhibit facilitation rather than the expected depression of spinal reflexes in the presence of dopamine as well as a reversal in their circadian expression of the rate-limiting enzyme for dopamine synthesis, tyrosine hydroxylase. Taken together, these findings are consistent with an involvement of spinal dopamine dysfunction in the etiology of RLS, and they argue that the D(3)KO mouse might serve as a relevant animal model to study the underlying mechanisms of RLS.

Deep-brain photoreception links luminance detection to motor output in Xenopus frog tadpoles

“…However, melanopsin was also found more caudally in zebrafish, in neurons of the PT (16), an area that is present in the light-sensitive Xenopus preparations. This finding is particularly relevant because the cells in question were A-11-type dopaminergic neurons that comprise a diencephalospinal population implicated in motor control (28). However, they are unlikely to mediate the phototransduction we document here.…”

“…The expression of the UV/blue light-sensitive proteins OPN5 and CRY1 was located in relatively close proximity to a set of dopaminergic neurons potentially related to the A-11-type population, known to project to the spinal cord and control motor output in other species (28). However, it is also plausible that OPN5-and/or CRY-positive neurons activate other supraspinal centers involved in vertebrate locomotion, such as the mesencephalic locomotor region (MLR) in the midbrain and/or reticulospinal nuclei in the hind brain (29), for example.…”

Is autonomic nervous system involved in restless legs syndrome during wakefulness?

“…The link between RLS and hypertension may rest in the neurological circuits supposed to be involved in the pathophysiology of this disorder [29]. Clemens et al suggested that clinical aspects of RLS and its association with cardiovascular diseases, including hypertension, lie in the dopaminergic neurons of the hypothalamic A11 nucleus [29].…”

“…Clemens et al suggested that clinical aspects of RLS and its association with cardiovascular diseases, including hypertension, lie in the dopaminergic neurons of the hypothalamic A11 nucleus [29]. The dopaminergic inhibitory descending pathways project in all regions of the spinal cord and preferentially to the dorsal and ventral horns and to the intermediate-lateral nucleus (IML) of the spinal gray matter that represents the final common pathway of the sympathetic system.…”

“…Moreover, the disinhibition of IML leads to an increase in sympathetic output that might explain the alteration of ANS observed by some authors [11,29]. In addition, there is wide evidence that the dopaminergic system dysfunction induces hypertension [30][31][32], as supported by experimental studies in dopamine D3 knockout mice that has been proposed as a potential animal model for RLS [33].…”