Sleep and circadian rhythms in Parkinson's disease and preclinical models

Abstract

The use of animals as models of human physiology is, and has been for many years, an indispensable tool for understanding the mechanisms of human disease. In Parkinson's disease, various mouse models form the cornerstone of these investigations. Early models were developed to reflect the traditional histological features and motor symptoms of Parkinson's disease. However, it is important that models accurately encompass important facets of the disease to allow for comprehensive mechanistic understanding and translational significance. Circadian rhythm and sleep issues are tightly correlated to Parkinson's disease, and often arise prior to the presentation of typical motor deficits. It is essential that models used to understand Parkinson's disease reflect these dysfunctions in circadian rhythms and sleep, both to facilitate investigations into mechanistic interplay between sleep and disease, and to assist in the development of circadian rhythm-facing therapeutic treatments. This review describes the extent to which various genetically- and neurotoxically-induced murine models of Parkinson's reflect the sleep and circadian abnormalities of Parkinson's disease observed in the clinic.

Keywords: Non-motor symptoms; Parkinson’s disease; RBD; circadian; insomnia; rapid eye movement; research models; sleep; sleep behavior disorder.

Fig. 1

Possible mechanisms of interplay between circadian and sleep dysfunctions and Parkinson’s disease. The suprachiasmatic nucleus (SCN) acts as the central circadian pacemaker, coordinating peripheral clocks, and assisting in the establishment and maintenance of sleep (through process C), which is also contributed by other factors (process S). The SCN uses molecular mechanisms to generate circadian rhythmicity, with zeitgebers (most importantly light) fine-tuning the rhythm. Sleep dysfunction can disrupt these rhythms. Dysfunction of sleep and of peripheral clocks, such as those in microglial and neuronal cells, leads to subsequent changes within and outside of the brain, including neuroinflammation, increased oxidative stress and reduced metabolic clearance. These outcomes have been proposed to increase risk of Parkinson’s disease onset, and to exacerbate Parkinson’s disease progression. Resultant neurodegeneration due to Parkinson’s disease can negatively affect neural pathways, and subsequently desynchronize (or ‘break’) the clock, contributing to a self-perpetuating loop. Parkinson’s disease is also associated with several sleep disorders, negatively impacting sleep and further contributing to the two-way interplay between circadian rhythms and neurodegeneration

Fig. 2

A simplified depiction of mammalian sleep modulation. The suprachiasmatic nucleus (SCN) takes in stimuli from an array of inputs, most notably photic input via the retinohypothalamic tract (RHT). The SCN acts as the central circadian pacemaker, entraining other brain regions and a large array of peripheral tissues, including the liver and gastrointestinal tract, via, both, neural connections and humoral factors. There are direct projections from the SCN to the lateral hypothalamus (LH), which contains orexin neurons, and to the dorsomedial hypothalamus (DMH). The DMH projects broadly to sleep and arousal centers. Mutual inhibition exists between the arousal-promoting locus coeruleus (LC) and the sleep-promoting ventrolateral preoptic area (VLPO) which facilitates the flip/flop between wakefulness and sleep states