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

Abstract

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 proinflammatory stimulus lipopolysaccharide (LPS) or saline, exposed to one of various behavioral tests that would induce motivated behavior (exploration, play behavior, social interaction, sweetened milk consumption). Upon sacrifice, brains were processed for c-Fos and histidine decarboxylase immunoreactivity. LPS treatment reduced behavioral activity and blocked behavioral testassociated 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. Keywordsarousal; sickness behavior; hypothalamus; dorsal vagal complex; dopamine-beta-hydroxylase; c-fos Converging lines of evidence strongly implicate histamine in the mammalian brain in behavioral arousal, wakefulness, metabolic homeostasis, and learning (Haas and Panula, 2003). The activity of the histaminergic neurons in the ventral tuberomammillary nucleus (VTM) is strongly and positively correlated with an alert waking state and behavioral activity,

Leptin in the hindbrain facilitates phosphorylation of STAT3 in the hypothalamus

“…A recent study (40) has shown that overexpression of ⌬FosB in the ventral hypothalamus of wild-type mice is sufficient to significantly increase energy expenditure, and this supports our finding of increased ⌬FosB immunoreactivity being restricted only to hypothalamic nuclei and within the VTM of LL rats. It has been established that catecholaminergic projections ascend directly from the NTS and indirectly from the dorsal vagal complex through the ventral medulla to the VTM (14). Activity of these neurons has been studied in the context of fatigue and hypoarousal behaviors associated with sickness, but it would be interesting to investigate the importance of leptin-mediated activation of these ascending pathways and their contribution to the control of energy balance.…”

Sepsis-induced morbidity in mice: Effects on body temperature, body weight, cage activity, social behavior and cytokines in brain

“…These brain regions are implicated in the regulation/modulation of many facets of sickness behavior. For example, within the context of sickness the hypothalamus is critical for the regulation of body temperature, locomotor activity, feeding, drinking, and energy metabolism (Klir et al, 1993; Myers et al, 1993; Gayle et al, 1999; Elmquist et al, 2000; Gaykema et al, 2008; Szymusiak and McGinty, 2008; Thaler et al, 2012), as well as the timing of when these physiological and behavioral processes occur (Beynon and Coogan, 2010). The hippocampus is involved in aspects of cognition, learning and memory (Chen et al, 2008) that may be relevant to altered social exploration, and the brainstem is critical for aspects of autonomic responses to this insult (Kafa et al, 2010).…”

Integrity of hypothalamic fibers and cognitive fatigue in multiple sclerosis

“…Fibers between the posterior hypothalamus and the mesencephalon include afferent fibers of the vagal nerve. Afferents of the vagal nerve transmit information about peripheral inflammation to the CNS, resulting in suppressed histaminergic activity and in the initiation of symptoms of sickness behavior including fatigue (Gaykema et al, 2008). Marvel et al (2004) have shown that mice with interrupted afferents of the vagal nerve do not experience sickness behavior, such as fatigue.…”

“…They found a significant correlation between T1 relaxation time in the hypothalamus and the Fatigue Severity Scale (FSS) score, indicating an association between pathological changes in the hypothalamus and MS-related fatigue. Finally, inflammation-induced suppression of histaminergic neurons was found to be associated with impaired arousal (Gaykema et al, 2008).…”