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Review
. 2023 Dec;32(6):e13845.
doi: 10.1111/jsr.13845. Epub 2023 Feb 7.

Animal models of human insomnia

Fabian-Xosé Fernandez  1 , Michael L Perlis  2
Affiliations
Review

Animal models of human insomnia

Fabian-Xosé Fernandez et al. J Sleep Res. 2023 Dec.

Abstract

Insomnia disorder (chronic sleep continuity disturbance) is a debilitating condition affecting 5%-10% of the adult population worldwide. To date, researchers have attempted to model insomnia in animals through breeding strategies that create pathologically short-sleeping individuals or with drugs and environmental contexts that directly impose sleeplessness. While these approaches have been invaluable for identifying insomnia susceptibility genes and mapping the neural networks that underpin sleep-wake regulation, they fail to capture concurrently several of the core clinical diagnostic features of insomnia disorder in humans, where sleep continuity disturbance is self-perpetuating, occurs despite adequate sleep opportunity, and is often not accompanied by significant changes in sleep duration or architecture. In the present review, we discuss these issues and then outline ways animal models can be used to develop approaches that are more ecologically valid in their recapitulation of chronic insomnia's natural aetiology and pathophysiology. Conditioning of self-generated sleep loss with these methods promises to create a better understanding of the neuroadaptations that maintain insomnia, including potentially within the infralimbic cortex, a substrate at the crossroads of threat habituation and sleep.

Keywords: fly; infralimbic; insomnia; rodent; sleep disorder; stress perpetuation.

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Figures

Figure 1.
Figure 1.
The Shaw Drosophila Model. The figure represents the lab selection process responsible for the creation of short-sleeping insomnia flies (ins-l) from a colony of Canton-S (Cs) females. Histograms represent sleep time across 60-min bins from 0 to 1360 min. Most females from the original colony met experimental criteria for sleep for 9 hours or more. After repeated rounds of selection for short-sleeping individuals, those in the ins-l line generally slept less than 5 hours, with many not sleeping more than 1 hour.
Figure 2.
Figure 2.
(A) A representation of the Cano-Saper Model. In this model, stress-naïve male rats are temporarily placed in a cage that had been occupied for a week by another male rat. Acute insomnia is triggered within 5 hours of this placement (2:00–3:00 pm). Relative to control rats moved to a clean cage, those moved to a dirty donor cage show increases in percent time spent awake and number of wake bouts. Significant reductions in both nREM and REM sleep are observed. (B) Changes in the brain resulting from stress-induced insomnia. During normal sleep, circadian and homeostatic drives enhance the activity of the brain’s sleep-promoting centers while also inhibiting the arousal network, favoring the sleep state (the homeostatic effect is mediated in part by adenosine acting on A1 and A2a receptors). Stress activates parts of the arousal system (e.g., LC, TMN) by way of cortical and limbic inputs, thus opposing promotion of the sleep state by the circadian and homeostatic drives. During stress-induced insomnia, cortical and limbic-mediated arousal persists, but homeostatic sleep pressure is stronger than usual because the rats are partially sleep-deprived; On balance, the circadian drive still favors the sleep state. Because these forces are opposing and strong, the sleep-wake switch wavers in an unstable position, leading to an intermediate state in which both sleep and wake circuitries are activated simultaneously. Each state is unable to sufficiently inhibit the other to prevent it from firing. One of the end results of this instability is the increased presence of high frequency EEG activity in the cerebral cortex during what is otherwise global sleep. A1R, A1 receptor; his, histamine; LC, locus coeruleus; NE, norepinephrine; NREM, non–rapid eye movement; REM, rapid eye movement; TMN, tuberomammillary nucleus; VLPOc, ventrolateral preoptic nucleus core; VLPOex, ventrolateral preoptic nucleus extended.
Figure 3.
Figure 3.
(Conceptual Model) The top panel represents the three measures that factor into “good and bad” sleep continuity: sleep opportunity (SO), sleep ability (SA), and sleep need (SN). For short sleepers, sleep continuity is optimized when these factors are closely matched (SO=SA=SN). However, chronic insomnia can result when one’s sleep opportunity exceeds their need and ability to sleep. (Experimental Results) The bottom panel summarizes experimental observations made by Belfer and Kayser using short-sleeping mutant flies averaging 4 hours of total sleep time (TST) per 24-hour day. Sleep continuity was poor in these diurnal animals when they were maintained under a light:dark cycle providing 12 hours of light and 12 hours of darkness (12:12). It was significantly improved, however, when the animals were housed under a photoperiod that provided only 4 hours of darkness, affording a length of sleep opportunity that matched the flies’ sleep ability.
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