It is commonly acknowledged that during infectious diseases we tend to sleep more and more deeply. The explanation of this phenomenon lies in the interaction between the immune system and the serotoninergic system involved in sleep regulation.
Serotonin in the sleep-wake cycle.
The role of 5HT in sleep-wake cycle can be summarized in three main points:
- 5HT cell bodies in dorsal raphe nucleus( DRN) act as wake promoting neurons as their direct, early effects promote wakefulness:these neurons, together with noradrenergic neurons from locus coeruleus and orexinergic neurons from hypothalamus, inhibit sleep promoting neurons in the preoptic area and basal forebrain;
- However 5HT also induces the release of sleep inducing factors that are responsible for NREM sleep as an indirect, delayed effect. Moreover these factors (including IL1) and (probably also serotonin released in the preoptic area and basal forebrain) inhibit the cholinergic system and therefore reduce cortical activation, enhancing slow wave sleep; sleep and serotonin: an unfinished story. 1999
- 5HT inhibits the neurons involved in the generation of REM sleep.
Role of the immune system.
The immune system interacts with serotoninergic circuits mainly through two cytokines, interleukin(IL1) and tumor necrosis factor alfa (TNFa), whose receptors have been found in the hypothalamus, the hippocampus and the brainstem, regions involved in the sleep-wake cycle. Interleukin 1 receptors in the brain:characterization by quantitative in situ autoradiography.1994
Central nervous system is influenced by the levels of circulating cytokines, but also synthesizes them de novo both in neurons and glia. Their main role is to increase NREM sleep, and consequently to suppress REM sleep during pathological conditions. There are several experiments that confirm this activity: when antibodies, antagonists or soluble receptors of IL1 and TNF are given to laboratory animals, a reduction of spontaneous NREM sleep is observed. Cytokines and sleep.2005
In order to study cytokines response during infection, structural components such as bacterial cell wall, lipid A, muramyl peptide and LPS are administered to laboratory animals, because they induce strong antigenic response with the upregulation of IL1 and TNF, even in the absence of replicating pathogens. The main advantage with this method is that it’s possible to decide the dose of structural component administered and the effects occur in few hours instead of days. Microbial products and cytokines in sleep and fever regulation. 1994
IL1 and TNF act in both the DRN and in the POA/BF, but with different mechanisms:
A) In the dorsal raphe nucleus they potentiates GABA inhibitory postsynaptic potential to 5HT cell bodies, therefore increasing the inhibition on serotoninergic wake promoting neurons. It is, as well, remarkable that lower 5HT levels are also due to an increased catabolism of tryptophan during infectious diseases, which brings to a reduction of 5HT synthesis.
B) On the contrary in the preoptic area and basal forebrain IL1 stimulates 5HT release from axon terminals( through a local action not dependent on the circuit in DRN): this both inhibits the cholinergic system( and consequently cortical activation) and stimulates IL1 synthesis. Indeed the precursor of serotonin, 5-hydroxytryptophan,induces IL1 mRNA transcription selectively in this area. More IL1 determines the stimulation of sleep promoting neurons and the inhibition of wake promoting neurons in this area. Moreover IL1 stimulates adenosine production, which contributes to the inhibition of wake promoting neurons in the basal forebrain. How (and why) the immune system makes us sleep.2009
The result is a reduction of wakefulness and an increase on slow wave sleep, which however is more fragmented than in physiological conditions.
New hypothesis.
The main consequence of this immune system induced sleep alteration is the facilitatory effect on the generation of fever as a host defence. Indeed fever is energetically demanding. First of all it requires an increase in thermogenetic processes in order to reach and mantain the new set point of body temperature. Moreover fever enhances the immune response itself:
- fastening the syntesis of antibodies;
-inducing the expression of heat shock proteins (HSP), which interact with antigen presenting cells (APC) in order to increase the secretion of cytokines and NO by macrophages and dentritic cells; Hyperthermia on immune regulation: a temperature story. 2008
- increasing the response of macrophages to endotoxines such as LPS (increase of cytokine production). Elevation in body temperature to fever range enhances and prolong subsequent responsivness of macrophages to endotoxines challenge. 2012
Consequently, an increased amount on NREM sleep means reducing other energy consuming process, such as locomotion or intense cortical activity.If the body is not involved in these processes, the whole protein syntesis can be directed to the production of antibodies and to the repair of tissues. On the other hand, a more fragmented NREM sleep brings to a reduction of heat loss(as usually body temperature decreases during slow wave sleep) facilitating the increase of body temperature. Moreover the reduction of REM sleep allows shivering( which does not occur during this phase). Thermoregulation and sleep.2003
To summarize in conclusion, not only both IL1 and TNFa act directly as endogenous pyrogenes during infectious diseases, but they are also involved in setting the proper conditions for the generation of fever, by altering the sleep wake cycle. It is now clear that infection causes alteration in sleep, and it seems likely that these alterations actually promote recovery.So now a new question may arise: if patients were able to sleep better, would they recover more quickly?
