Animal Models of Sleep Disturbances:
Intrinsic and Environmental Determinants
Peter Meerlo, Bernard M. Bergmann and Fred W. Inrek
Although each mammalian species has its own sleep characteristics in terms of the total amount and distribution of sleep over the day (Campbell and Tobler, 1984; Zepelin, 2000), most of them share the fundamental regulatory principles with human beings (Borbely, 1982, Mistlberger et al, 1983; Tobler, 2000). First, most species display a daily rhythm in sleep and wakefulness that is under the control of an endogenous biological clock in the brain. Second, within sleep, there is a cyclic alternation of two different states, non-rapid-eye-movement sleep (NREM) and rapideye-movement sleep (REM). And third, there is a homeostatic drive for each of the two sleep states that accumulates when the sleep state is absent. The longer an organism is awake, the higher its need for sleep. Remarkably, the exact functions of NREM and REM sleep are still unknown, but both states apparently serve vital functions. Studies in rats have shown that prolonged deprivation of either or both sleep states ultimately results in death (Rechtschaffen et al, 1983; 1989). Studies of biological rhythms and sleep states in animals have greatly extended our knowledge of the regulatory mechanisms of sleep and provided clues to its functions. In addition, because of the similarities in sleep between human beings and other mammalian species, laboratory animals also provide a useful tool to gain insight into human sleep disorders.
Sleep disturbances can have a variety of underlying causes and contributing factors, and often are the outcome of a complex interplay between intrinsic factors and environmental influences. This chapter will summarize how sleep in animals can be affected by intrinsic factors (e.g., the physiological profile of an individual as determined by its genes, development, and age) as well as external factors (such as stressors and other environmental influences). Animal research allows detailed studies of each of these possible components and, as such, animal models can be a relevant source of information on the aetiology and mechanisms of sleep disorders.
We have chosen to categorize and present the animal literature on sleep disturbances roughly according to their intrinsic or extrinsic cause since that is what many studies use as a starting point. Although there are a number of animal models that mimic a specific sleep disorder (e.g., narcolepsy), a more common approach is to examine the influence of a certain intrinsic factor or environmental condition on sleep rather than modelling a sleep disorder per se (e.g., the influence of ageing or stress). The results of studies using the latter approach do not always allow a symptom-based classification as generally is used for human sleep disorders. For example, since insomnia in humans is often ascribed to stress, studying the influence of stressors on sleep in animals and its possible physiological pathways is highly relevant to the understanding of human sleep disorders. However, studies in mice and rats show that various stressors induce dynamic and complex changes in sleep that cannot simply be listed as insomnia. Therefore, we choose to present these models under the heading of stress, rather than insomnia.
The first sections hereafter describe how sleep disorders may be related to genes and development. The genetic models include successful models of narcolepsy as well as selected lines of rats with changes in particularly REM sleep. The developmental models show how influences during early stages of life can affect adult sleep and potential sensitivity to sleep disorders. These models also are characterized in particular by changes in adult REM sleep regulation. The following section discusses animal models of sleep in ageing, and the paragraphs thereafter deal with alterations in sleep due to disturbances of the circadian clock. Finally, a number of sections summarize the changes and disturbances in sleep that may occur in response to environmental factors, such as light and temperature, and, probably the most commonly cited cause of disturbed sleep, stress.
A variety of genetic tools and approaches are used to study gene effects on sleep in animals, including comparisons of different strains of rats or mice, knockout mice, or mice strains with other mutations. Whereas many of these studies are undertaken to unravel basic physiological mechanisms underlying sleep regulation, some of the models provide relevant information on genetic factors in sleep disturbances or genetic influences on the sensitivity to sleep disorders.
Probably the first true animal model of a sleep disorder was the finding of narcoleptic behaviour in dogs (Mitler et al, 1974). Narcolepsy is a seriously disabling neurological disease that is characterized by disturbed night-time sleep and excessive daytime sleepiness, as well as pathological manifestations of REM sleep and cataplexy, often triggered by emotional expressions (Bassetti and Aldrich, 1996; Guilleminault and Anagnos, 2000). Early studies identified a narcoleptic phenotype in several breeds of dogs, including Doberman pinchers, which have played an important role in unravelling the genetic basis of the disease and also contributed to the development of treatment strategies (Baker et al, 1982; Nishino and Mignot, 1997). More recently, mice were discovered with narcoleptic phenomena similar to those seen in dogs