What Are the Links Between Immune Brain Interfaces and Sleep Neurocircuitry

In order for peripherally generated immune signals to influence sleep, immuno-sensory interfaces must connect with the arousal-related neurocircuitry outlined above. The following describes immune-responsive brain regions that likely relay immune-related information to the brain regions that control arousal and the pathways by which they target these regions.

Figure 6.1. Schematic representations (modified after Saper et al. 2005) of key components of the "ascending reticular arousal system" mediating wakefulness and arousal states (panel A) and the inhibitory control on these components by the ventrolateral preoptic nucleus (VLPO) situated at the bottom of the anterior hypothalamus, as well as by ascending projections from the lower brainstem (panel B). The histaminergic neurons in the ventral tuberomammillary nucleus (TMV) at the bottom of the posterior hypothalamus provide a strong inhibitory influence on the VLPO (panel A) with the cotransmitter GABA, as the VLPO lacks histamine receptors. Activation of ascending projections from the lower brainstem, as indicated with the arrow in B, may represent a key mechanism for enhancement of sleep as a result of peripheral immune challenge. Inhibition of the histaminergic neurons in the TMV would subsequently disinhibit the VLPO, thus facilitating the transition from waking to sleep and suppressing the reverse switch. The components of the ascending reticular activating system further include the raphe nuclei (serotonergic and dopaminergic neurons), the locus coeruleus (LC, noradrenergic neurons), the pedunculopontine and laterodorsal tegmenti (PPT/LDT), and the basal forebrain (BF, cholinergic neurons), including the nucleus basalis of Meynert (NBM).

Cholinergic Neuron Nbm Pedunculopontine Reticular

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nmune Ilmuli

6.4.1 Primary Sensory Relay Nuclei

Sensory fibers associated with the vagal and glossopharyngeal ganglia collect signals from the tissues that they innervate, and via sensory neurotransmitter glutamate (Sykes, Spyer, and Izzo 1997), convey this information to brainstem dorsal vagal complex (DVC) (Beckstead and Norgren 1979; Chernicky, Barnes, Ferrario, and Conomy 1984) which consists of the nucleus of the solitary tract (NTS) and the area postrema (a circumventricular organ). Both of these brainstem structures express activation markers (e.g., c-Fos) following peripheral and central administration of a variety of immune stimulants (Elmquist, Scammell, Jacobson, and Saper 1996; Goehler et al. 2005; Wan, Janz, Vriend, Sorensen, Greenberg, and Nance 1993), and both IL-1 and LPS induce the release of glutamate into the DVC (Mascarucci, Perego, Terrazzino, and DeSimoni 1998). These nuclei coordinate local, protective reflexes, such as emesis and gastric retention, and relay immune-related viscerosensory signals to forebrain regions concerned with integration of visceral information with ongoing behavior and other sensory inputs.

In addition to neural input, immune-derived activation of dorsal vagal complex also occurs via humoral routes. The area postrema is a circumventricular organ, in which the blood-brain barrier is weak (hence it is sensitive to circulating signals unavailable to the brain parenchyma), and it contains immune cells that respond to peripherally administered LPS by expressing IL-1 immunoreactivity (Goehler et al. 2006). In addition, it has been suggested that the NTS may respond to cytokine signals directly (Banks 2005). Thus, the dorsal vagal complex is situated to function as a crossroads for converging immune-related signaling.

A functional role of the DVC in brain responses to illness is supported by findings that lesions of the area postrema can attenuate HPA axis responses or hypothalamic norepinephrine increase to systemic immune activation (Ishizuka, Ishida, Kunitake, Kato, Hanamori, Mitsuyama, and Kannan 1997; Lee, Whiteside, and Herkenham 1998), and that inactivation of the DVC, using a local anesthetic, blocks sickness-induced behavioral depression, psychomotor retardation and c-Fos expression in the brain (Marvel, Chen, Badr, Gaykema, and Goehler 2004). A role for the NTS and area postrema in the regulation of sleep is supported by findings that stimulation of the caudal NTS synchronizes EEG (Golanov and Reis 2001), and that activity in the area postrema corresponds to that in the cortex during SWS (Bronzino, Stern, Leahy, and Morgane 1976).

Whereas the DVC is uniquely situated to transduce both neural and humoral signals derived from immune activation, to convey these signals to forebrain regions that regulate arousal, other brain regions likely also play a role. However, the neural pathways by which other immunosensory interfaces modulate arousal or sleep are less well documented. For example, neurons residing in forebrain CVOs, such as the OVLT or SFO may project to hypothalamic regions that control sleep-waking states, and thus may contribute to immune-related influences on them.

In addition, or alternatively, sleep-modulating cytokines could be produced in the brain (by local microglia) or transported across the blood-brain barrier (Banks 2005). It should be noted however, that local production of cytokines is unlikely to play a role in the induction of somnolence and NREM/SWS states, based on the time course of cytokine induction in the brain parenchyma (Quan, Whiteside and

Herkenham 1998), which lags the induction of somnolescence and sleep, but may play a role in the maintenance of sleep states.

6.4.2 Ascending Pathways Influencing Arousal

Ascending pathways arising from the dorsal vagal complex and VLM, which are primarily catecholaminergic (Riche, De Pommery, and Menetrey 1990), respond to peripheral immune stimulation (Buller, Xu, Dayas, and Day 2001). The association of increased catecholamine release in the hypothalamic and preoptic regions with immune activation is well established.

Lower brainstem projection neurons provide a significant source of these catecholamines, based on findings that noradrenergic and adrenergic neurons within the nTS and ventrolateral medulla (VLM) target the hypothalamus and respond to IL-1 (Buller et al. 2001), and that ascending catecholaminergic projections originating in the nTS and VLM appear crucial in the initiation of HPA axis responses to immune challenges (Ericsson, Kovacs and Sawchenko 1994). These findings support an important role for brainstem-derived catecholamines as molecules mediating behavioral symptoms of illness, although a role for cotransmitter molecules (such as neuropeptide Y and ATP) cannot be ruled out.

Given the important role of tuberomammillary histamine neurons in arousal associated with behavior, and in the transitions between arousal and sleep, it was important to determine whether these histamine neurons are influenced by immune challenge, and whether caudal medullary projection neurons target these neurons. To address this issue, we recently demonstrated that activation of histaminergic neurons concomitant with behaviors, such as exploration of a novel environment or social interaction, is inhibited by the immune stimulant LPS (Fig. 6.2A and B). Moreover, these tuberomammillary neurons are targeted by LPS-responsive catecholamine neurons in the VLM and NTS (Gaykema et al. submitted; see Fig. 6.2C to E).

Thus, during illness, caudal brainstem projection neurons may act to inhibit tuberomamillary neurons that normally serve as a brake on sleep-inducing VLPO neurons. This disinhibition would allow VLPO neurons to inhibit neural systems that maintain wakefulness, resulting in somnolence and increased SWS.

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