Lipopolysaccharide suppresses activation of the tuberomammillary histaminergic system concomitant with behavior: a novel target of immune-sensory pathways.

Infection and inflammation strongly inhibit a variety of behaviors, including exploration, social interaction, and food intake. The mechanisms that underlie sickness behavior remain elusive, but appear to involve fatigue and a state of hypo-arousal. Because histaminergic neurons in the ventral tuberomammillary nucleus of the hypothalamus (VTM) play a crucial role in the mediation of alertness and behavioral arousal, we investigated whether the histaminergic system represents a target for immune activation and, if so, whether modulation by ascending medullary immune-sensitive projections represents a possible mechanism. Rats were injected intraperitoneally with either the pro-inflammatory stimulus lipopolysaccharide (LPS) or saline, and exposed to one of various behavioral tests that would induce motivated behavior (exploration, play behavior, social interaction, sweetened milk consumption). Upon kill, brains were processed for c-Fos and histidine decarboxylase immunoreactivity. LPS treatment reduced behavioral activity and blocked behavioral test-associated c-Fos induction in histaminergic neurons of the VTM. These effects of LPS were prevented by prior inactivation of the caudal medullary dorsal vagal complex (DVC) with a local anesthetic. To determine whether LPS-responsive brainstem projection neurons might provide a link from the DVC to the VTM, the tracer Fluorogold was iontophoresed into the VTM a week prior to experiment. Retrogradely labeled neurons that expressed c-Fos in response to LPS treatment included catecholaminergic neurons within the nucleus of the solitary tract and ventrolateral medulla. These findings support the hypothesis that the histaminergic system represents an important component in the neurocircuitry relevant for sickness behavior that is linked to ascending pathways originating in the lower brainstem.

Neural-immune interface in the rat area postrema.

The area postrema functions as one interface between the immune system and the brain. Immune cells within the area postrema express immunoreactivity for the pro-inflammatory cytokine, interleukin-1beta following challenge with immune stimulants, including lipopolysaccharide (from bacterial cell walls). As a circumventricular organ, the area postrema accesses circulating immune-derived mediators, but also receives direct primary viscerosensory signals via the vagus nerve. Neurons in the area postrema contribute to central autonomic network neurocircuitry implicated in brain-mediated host defense responses. These experiments were directed toward clarifying relationships between immune cells and neurons in the area postrema, with a view toward potential mechanisms by which they may communicate. We used antisera directed toward markers indicating microglia (CR3/CD11b; OX-42), resident macrophages (CD163; ED-2), or dendritic cell-like phenotypes (major histocompability complex class II; OX-6), in area postrema sections from lipopolysaccharide-treated rats processed for light, laser scanning confocal, and electron microscopy. Lipopolysaccharide treatment induced interleukin-1beta-like immunoreactivity in immune cells that either associated with the vasculature (perivascular cells, a subtype of macrophage) or associated with neuronal elements (dendritic-like, and unknown phenotype). Electron microscopic analysis revealed that some immune cells, including interleukin-1beta-positive cells, evinced membrane apposition with neuronal elements, including dendrites and terminals, that could derive from inputs to the area postrema such as vagal sensory fibers, or intrinsic area postrema neurons. This arrangement provides an anatomical substrate by which immune cells could directly and specifically influence individual neurons in the area postrema, that may support the induction and/or maintenance of brain responses to inflammation.

Individual variation in hypothalamus-pituitary-adrenal responsiveness of rats to endotoxin and interleukin-1 beta.

Intraperitoneal (i.p.) administration of lipopolysaccharide (LPS) or interleukin (IL)-1 beta induces activation of the hypothalamus-pituitary-adrenal (HPA) axis. In some experiments, a marked individual variation has been observed in HPA responses to these stimuli. We reasoned that only parameters that correlate with this variability may reflect signals involved in HPA activation. Although IL-1 beta is found in the peritoneal cavity and has been implicated in the HPA response to i.p. LPS, IL-1 beta levels in peritoneal lavage fluid did not correlate with the variation in HPA responsiveness and neither did IL-1 beta concentrations in plasma. In contrast, IL-6 concentrations in plasma, but not in peritoneal lavage fluid, correlated with this variation to i.p. LPS or IL-1 beta. We conclude that IL-6 in the plasma represents a major determinant of the individual variation in HPA responses to i.p. LPS or IL-1 beta. Because of its positive correlation with Fos expression in various brain-stem nuclei, we suggest that circulating IL-6 may facilitate the generation of signals in vagal afferents or potentiate vagal information transfer to lower brain-stem nuclei.