How (and why) the immune system makes us sleep

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Abstract

Good sleep is necessary for physical and mental health. For example, sleep loss impairs immune function, and sleep is altered during infection. Immune signalling molecules are present in the healthy brain, where they interact with neurochemical systems to contribute to the regulation of normal sleep. Animal studies have shown that interactions between immune signalling molecules (such as the cytokine interleukin 1) and brain neurochemical systems (such as the serotonin system) are amplified during infection, indicating that these interactions might underlie the changes in sleep that occur during infection. Why should the immune system cause us to sleep differently when we are sick? We propose that the alterations in sleep architecture during infection are exquisitely tailored to support the generation of fever, which in turn imparts survival value.

Key Points

  • Serotonin promotes wakefulness but is necessary for sleep.

  • Cytokines, such as interleukin 1 (IL-1) and tumor necrosis factor, are involved in regulating physiological non-rapid eye movement (NREM) sleep.

  • IL-1 contributes to the regulation of NREM sleep in part through interactions with serotonin.

  • Interactions between IL-1 and serotonin are amplified during infection, and sleep is altered.

  • During infection, NREM sleep is fragmented and REM sleep is suppressed.

  • Changes induced in sleep architecture by infectious agents support the generation of fever, and fever imparts survival value.

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Figure 1: Serotonin initially increases wakefulness and subsequently increases non-rapid eye movement sleep.
Figure 2: Interleukin 1 and serotonin interact at multiple sites in the brain to regulate non-rapid eye movement sleep.
Figure 3: Sleep architecture is altered during fever.
Figure 4: Proposed principles by which changes in sleep architecture promote recovery from infection.

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Acknowledgements

The authors were supported by US National Institutes of Health Grants MH64843 and HL080972, the Department of Anesthesiology of the University of Michigan Medical School, and the Ministero dell'Istruzione, dell'Universita' e della Ricerca, Italy.

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Correspondence to Mark R. Opp.

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Glossary

Encephalitis lethargica

An infectious process and an associated inflammatory response involving the brain and characterized by pronounced somnolence. The first cases were described in 1916 by the Viennese neurologist von Economo. The pathology is typical of viral infections and is localized principally to the midbrain, the subthalamus and the hypothalamus. The causative agent has not been definitively determined.

Trypanosomiasis

A disease caused by the protozoan Trypanosoma brucei and transmitted by several species of the tsetse fly. When the brain and meninges become involved, usually in the second year of infection, a chronic progressive neurologic syndrome results. Complete loss of the timing of sleep, alterations in sleep architecture, and later apathy, stupor and coma characterize the syndrome.

Sleep fragmentation

Interruption of sleep bouts by brief arousals such that the duration of the bout is reduced and transitions from one behavioural state to another occur more frequently.

Lipid A

The innermost, hydrophobic, lipid component of lipopolysaccharide. Lipid A anchors the lipopolysaccharide to the outer membrane of the Gram-negative bacterial cell wall.

Lipopolysaccharide

A component (also known as endotoxin) of the outer wall of Gram-negative bacterial cell walls. It is composed of a lipid and polysaccharides joined by covalent bonds. It elicits strong immune responses through signalling pathways coupled to Toll-like receptor 4.

Muramyl dipeptide

The synthetic analogue of muramyl peptides, the monomeric building blocks of bacterial cell wall peptidoglycan. Muramyl peptides are released by mammalian macrophages during the digestion of bacterial cell walls.

Inhibitory postsynaptic potential

(IPSP). Hyperpolarization of the membrane potential of a postsynaptic neuron. IPSPs are induced by a neurotransmitter released by a presynaptic neuron. Hyperpolarization reduces neuronal excitability because it is more difficult to trigger an action potential in a hyperpolarized neuron.

Acute-phase response

The reaction that develops in response to an injury or infection. It is mediated by pro-inflammatory cytokines (such as IL-1) and is characterized by a local response (inflammation) and a systemic component, which includes the production of acute-phase proteins by hepatocytes, leukocytosis, fever and profound changes in lipid, protein and carbohydrate metabolism.

Sickness behaviour

The constellation of symptoms (decreased food intake, depressed activity, loss of interest in usual activities, disappearance of self-maintenance behaviours and altered sleep) that accompany responses to infection.

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