Consensus Guidelines on Rodent Models of Restless Legs Syndrome

Abstract

Restless legs syndrome (RLS) is a chronic sensorimotor disorder diagnosed by clinical symptoms. It is challenging to translate the diagnostic self‐reported features of RLS to animals. To help researchers design their experiments, a task force was convened to develop consensus guidelines for experimental readouts in RLS animal models. The RLS clinical diagnostic criteria were used as a starting point. After soliciting additional important clinical features of RLS, a consensus set of methods and outcome measures intent on capturing these features—in the absence of a face‐to‐face interview—was generated and subsequently prioritized by the task force. These were, in turn, translated into corresponding methods and outcome measures for research on laboratory rats and mice and used to generate the final recommendations. The task force recommended activity monitoring and polysomnography as principal tools in assessing RLS‐like behavior in rodents. Data derived from these methods were determined to be the preferred surrogate measures for the urge to move, the principal defining feature of RLS. The same tools may be used to objectively demonstrate sleep‐state features highly associated with RLS, such as sleep disturbance and number and periodicity of limb movements. Pharmacological challenges and dietary or other manipulations that affect iron availability are desirable to aggravate or improve RLS‐like behavior and lend greater confidence that the animal model being proffered replicates key clinical features of RLS. These guidelines provide the first consensus experimental framework for researchers to use when developing new rodent models of RLS. © 2020 International Parkinson and Movement Disorder Society

Iron deficiency in pregnancy: Influence on sleep, behavior, and molecular markers of adult male offspring

“…Our findings reinforce the importance of studies analyzing iron levels periodically and other mechanisms of possible alterations. Even with the recommendation of the task force (Salminen et al, 2021) in carrying out the experiments on RLS rodent models of both sexes, this is a limitation in our study, since it was not possible to analyze the estrous cycle phase and the hormonal fluctuations, both potential confounders to be taken into account. However, studies indicate pregnancy has a major impact on the risk of developing RLS for those with a family history of RLS.…”

“…Likewise, the iron supplementation diet during pregnancy showed an influence on the increased freezing of offspring. This suggests that the animals that underwent the 8-week training (regardless of diet) and the offspring of the supplementation groups (OSu) experience a lower need to move, which represents a reduction in the core feature of RLS, which is the need for movement (Salminen et al, 2021). Despite studies show changes in fear and anxiety behavior due to fetal iron deficiency (Beard et al, 2002;Texel et al,2012), in the present study, we found no differences in grooming and in time spent in the center between time spent along the walls in the open-field test that report anxious behavior.…”

Consensus guidelines on the construct validity of rodent models of restless legs syndrome

“…Following the compilation of the IRLSSG consensus guidelines on rodent models of RLS ( Salminen et al, 2021 ), the IRLSSG Executive Committee approved a motion in October 2020 that the previously appointed animal models task force continue its work and assess the construct validity of potential RLS models. Twelve of the original 14 members undertook this work.…”

“…Addressing this issue is particularly challenging when developing animal models of RLS with face validity , that is, animal models that closely reproduce the clinical features of human RLS. The challenge of defining parameters for rodent models of RLS with face validity was recently addressed by a task force convened by the International Restless Legs Syndrome Study Group (IRLSSG) ( Salminen et al, 2021 ).

Box 1. International RLS Study Group (IRLSSG) consensus diagnostic criteria for RLS Essential diagnostic criteria: The urge to move the legs usually but not always accompanied by, or felt to be caused by, uncomfortable and unpleasant sensations in the legs.

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“…In addition to face validity, a valid translational rodent model should also have construct validity. Construct validity considers how well the mechanisms used to induce the clinical features of a (neuropsychiatric) disorder in an animal model reflect its currently understood pathophysiology ( Salminen et al, 2021 ). Doing so requires an in-depth understanding of the biological basis of a human disorder.…”