Effects of Inflammatory Molecules on the SCN and Sleep Switch Structures

Certain molecules originally defined on the basis of their role in inflammation display activities in the sleep-wakefulness-promoting structures, namely histamine as well as interleukin (IL)-ip and tumor necrosis factor (TNF)-a.

During peripheral inflammation, the biogenic amine histamine is released from mast cells and is a major mediator of vasodilation and permeability, but in the brain it acts mainly as an excitatory neurotransmitter. Histamine is produced by neurons located in the TMN, which send widespread projections in the brain, including a relatively dense projection to the SCN (Moga and Moore 1997). Histamine plays an essential role in arousal, an effect that may be mediated by direct excitation of cortical neurons or by stimulatory effects on sleep-regulatory centers such as the cholinergic basal forebrain neurons (Haas et al. 2003). It is interesting to note that the rodent SCN contains neurons immunoreactive to histamine, which they receive via TMN fibers through a not yet characterized uptake mechanism (Michelsen et al. 2005). These data suggest that local uptake, storage and release of histamine within the SCN could potentially play a novel role in the function of the biological clock.

The other source of histamine in the brain is provided by a limited number of resident mast cells, which in the rat brain parenchyma are concentrated in the thalamus (Florenzano and Bentivoglio 2000). It is not clear, however, if and how brain histamine is involved in sleep-wakefulness dysregulation occurring during inflammation in the central nervous system (CNS).

IL-ip is released from macrophages/microglial cells during inflammation. It activates T cells, and is the principal cytokine involved in induction of the so-called "sickness behavior," i.e., sleepiness, loss of appetite, and fever. IL-ip is a very potent somnogen and when administered at the anterior preoptic area, which includes the VLPO, IL-ip activates sleep-related neurons in the VLPO; this may, therefore, mediate, at least in part, the non-REM sleep-inducing properties of this cytokine (Alam et al. 2004). In addition, blocking of IL-ipwith neutralizing antibodies inhibits spontaneous non-REM sleep in normal rats, indicating that this cytokine is endogenously produced in the brain and affects its normal function. In line with this, both IL-ip and TNF-a, which are also usually associated with release from activated macrophages/microglial cells, are expressed in the brain with a day/night variation (for review, see Vitkovic, Bockaert, and Jacque (2000)). Systemic administration of TNF-a also increases the time spent in non-REM sleep (Fang, Wang, and Krueger i997). However, mice deficient in the genes encoding either TNF-a or its receptor show no changes in the amount of non-REM sleep, and show instead a reduction in REM sleep episode frequency (Deboer, Fontana, and Tobler 2002).

In contrast to well-documented roles of histamine and of the cytokines IL-ip and TNF-a in sleep-wakefulness regulation, effects of these molecules and other cytokines on circadian rhythms are less well known. Through the above-mentioned direct projections of TMN neurons to the SCN, which may be excitatory or inhibitory, histamine may have effects on neuronal activities in the biological clock (Liou, Shibata, Yamakawa, and Ueki 1983). Direct application of histamine to the SCN can phase shift the circadian rhythm of the neuronal firing rate (Cote and Harrington 1993), but whether this biogenic amine may modulate the biological clock in relation to arousal activities is not clear.

The response of the SCN to inflammatory mediators such as lipopolysaccharide (Marpegan, Bekinschtein, Costas and Golombek 2005), interferon (IFN)-a (Ohdo, Koyanagi, Suyama, Higuchi, and Aramaki 2001), or an IFN-y/TNF-a cocktail displays day/night variation (Sadki, Bentivoglio, Kristensson, and Nygard 2006). Interestingly, the sensitivity of SCN neurons to IFN-y coincides in time with the expression of an immunopositive IFN-y-receptor-like molecule in the SCN (Lundkvist, Robertson, Mhlanga, Rottenberg, and Kristensson 1998). That IFN-y may affect the SCN is indicated by induction of Fos protein (a marker of neuronal activity) in SCN neurons following intracerebroventricular injection of the cytokine (Robertson, Kong, Peng, Bentivoglio, and Kristensson 2000), and by the observation that IFN-y can cause reduced synaptic activity in the ventral part of the SCN after application on slice preparations (Lundkvist, Hill, and Kristensson 2002). The IFN-y-receptor-like molecule is localized to the ventrolateral part of the rat SCN, which is also the site of innervation from the TMN. In turn, the TMN contains a molecule that cross-reacts with monoclonal antibodies directed to different epitopes of IFN-y (Bentivoglio, Florenzano, Peng, and Kristensson 1994) but the nature of this IFN-y-immunopositive molecule in the TMN and its potential effects on the SCN remain to be determined. Neither has any role for an IL-6-immunopositive molecule in SCN neurons been determined (Gonzalez-Hernandez et al. 2006).

Thus, although no role has been demonstrated so far for inflammatory cytokines in the normal functioning of the SCN, such molecules may potentially affect SCN synaptic activity during inflammatory diseases, and hence influence the circadian rhythms and sleep-wakefulness states.

In addition, the nuclear factor (NF)-kB, a transcription factor which plays a major role in inflammation, was found to be expressed in the SCN of hamsters, and NF-kB inhibition blocked the light-induced phase advance, suggesting that NF-kB family of proteins could serve a role in the entrainment of circadian rhythms (Marpegan et al. 2004).

In terms of susceptibility to inflammation, a number of recent data suggest that the orexinergic system could be a site of vulnerability in the sleep switch network. Substantial evidence has indicated in the last years that alterations of the orexinergic system play a key role in idiopathic narcolepsy. This disease, which is usually sporadic, is characterized by chronic sleepiness and intrusions into wakefulness of manifestations of REM sleep, cataplexy, sleep paralysis, and hypnagogic hallucinations (for reviews, see Sutcliffe et al. (2002), Scammell (2003), and Baumann and Bassetti (2005)). Impaired orexin signaling (with loss of orexin-

producing neurons in the LH, low or undetectable levels of orexin in the cerebrospinal fluid, and orexin ligand deficiency) is considered to hallmark narcolepsy. The cause of such degeneration of orexin neurons is still unknown. Interestingly, the disease is associated with strong linkage to the human leukocyte antigen (HLA) complex, since most narcoleptic patients have a HLA-DR2 haplotype (Lin, Hungs and Mignot 2001). TNF-a signaling has also been implicated in the disease since polymorphisms in the TNF-a and TNF receptor 2 genes are associated with some cases of narcolepsy (Scammell 2003). This has led to the proposal of an autoimmune pathogenesis of loss of orexin-producing neurons in narcolepsy, but no immune changes have been found in the patients. Experimentally, chronic infusion of lipopolysaccharide in the LH of rats resulted in neuronal loss which included orexinergic neurons but it was not selective for these cells, suggesting that also other factors may be involved in the pathology of narcolepsy (Gerashchenko and Shiromani 2004).

We are at present examining experimentally the vulnerability of orexin-contain-ing neurons in systemic and CNS inflammatory conditions.

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