Physiological and psychological challenges, including inflammation and stress, can induce a constellation of symptoms referred to as “sickness behavior”. This behavioral pattern involves reductions in motivated behavior including food and water intake, social and sexual behavior, exploratory behavior, and motor activity, and an increase in stress hormones. Sickness behavior supports host defense and recuperation by conserving energy, and is considered to be a motivated and adaptive response to physiological challenges (Dantzer and Kelley, 2007
; Miller, 2009
). However, in the context of chronic disease, sickness symptoms can lead to prolonged fatigue or symptoms of behavioral depression.
Although the precise neural substrates responsible for the behavioral manifestations of sickness are still emerging, studies using the activation marker c-Fos have indicated that activity in brain regions that support “positive motivation”, including the nucleus accumbens, and several cortical areas including secondary motor, cingulate and piriform, is reduced in animals treated with the immune stimulant lipopolysaccharide (LPS; Stone et al., 2006
). Conversely, this inhibition of neuronal activity marker expression occurs concomitant with activation in stress-sensitive, viscerosensory and autonomic control regions including the caudal brainstem, hypothalamus, and extended amygdala (Wan et al., 1994
; Stone et al., 2006
; Gaykema et al., 2007
; Gaykema et al., 2008
; Elmquist and Saper, 1996
; Elmquist et al., 1996
; Frenois et al., 2007
). This pattern of inhibition of “positive motivation”-related brain regions and activation of stress-related regions likely contributes to behavioral and mood-related sequelae of infection or inflammation.
The mechanisms by which peripherally generated immune signals are able to influence forebrain neurocircuitry involved in sickness behavior has not been firmly established. Because sickness behavior has been shown to be dependent upon the interaction of cytokines with the brain, constituents of the network of brain regions that subserve sickness behavior must interface with brain regions that can detect central or peripheral cytokines, such as circumventricular organs, vascular endothelium, or viscerosensory relay nuclei.
Of the brain regions that consistently show evidence of activation following immune challenge, the sensory dorsal vagal complex (DVC) located in the dorsomedial caudal medulla [consisting of the nucleus of the solitary tract (NTS) and area postrema], serves as one interface by which peripheral immune-related information influences the brain. The DVC receives immune-sensitive inputs from neural pathways (vagal and spinal) and circulating immune signals via the weak blood barrier in the area postrema (a circumventricular organ). Immune cells within the area postrema that produce interleukin-1 following immune challenge make direct contact with neurons, providing a potential pathway mediating cytokine-neural interface (Goehler et al., 2006
). Additionally, the DVC is interconnected with the caudal ventrolateral medulla (VLM), which relays immune sensory information via activation of vascular endothelial cells within the nucleus predominantly by its catecholaminergic projections to the forebrain (Ericsson et al., 1997
). Together with the VLM, the DVC projects to forebrain regions that mediate stress responses, autonomic control and arousal. Thus, the caudal brainstem is uniquely situated to transduce and propagate immune-related signals to brain regions likely involved in initiation of sickness behavior.
Functional evidence that the DVC mediates components of sickness behavior derives from findings that inactivation of the DVC with a local anesthetic prior to administration of LPS prevented both social withdrawal behavior and the characteristic brain activation pattern typically that occurs in association with immune activation in resting animals (Marvel at el., 2004
). Further, DVC inactivation prevented the suppression of histamine neurons that are normally activated during an exploratory behavior task (Gaykema et al., 2008
). These findings support the idea that activation of the DVC and VLM contribute to brain and behavioral responses to immune challenge. However, the specific links (neuronal pathways) between immune-related activation of brainstem viscerosensory regions and the forebrain nuclei that mediate sickness behavior have not been established.
Neuronal projections from the DVC and VLM to the forebrain follow multiple trajectories of catecholaminergic and non-catecholaminergic neurons (Gaykema et al., 2007
). The catecholamine pathway arises in both the VLM and the DVC. It projects heavily to the hypothalamus and is well established to activate neuroendocrine responses in context of physiological challenges (e.g. Cunningham et al., 1990
; Ericsson et al., 1994
; Bienkowski and Rinaman, 2008
;) including immune-related stimuli (Ericsson et al., 1997
; Elmquist and Saper, 1996
). Its contribution to other brain mediated sickness responses is less clear. In contrast, the non-catecholamine projections -which mainly arise from the DVC-preferentially target the external lateral parabrachial nucleus (PBel) in the pons, which then drives immune-related responses of the amygdala and bed nucleus of the stria terminalis (Tkacs and Li, 1999
; Richard et al., 2005
). This arrangement suggests that separate neurocircuitries, or parallel pathways, could mediate different aspects of sickness behavior.
As noted previously, immune challenge with LPS can lead to marked reductions in motor activity and motivated behavior that could relate to the psychological experience of “fatigue”. Fatigue is common in acute and chronic illness, but the neurological substrates involved have yet to be established. Our previous studies have indicated that suppression of hypothalamic arousal systems may contribute to reductions in behavior associated with immune challenge (Gaykema et al., 2008
; Gaykema and Goehler, 2009
; Park et al., 2008
). For the experiments reported here, we assessed exploratory motor behavior to provide an index of motivation and fatigue (Stone et al., 2006
). To determine functional relationships between the caudal brainstem and the forebrain structures involved in motivation and movement that mediate sickness-induced reductions in exploratory behavior, we addressed three questions. First, can a targeted lesion of the immune-responsive catecholaminergic pathway originating in the caudal medulla prevent LPS-induced deficits in exploratory behavior, as does DVC inactivation? The answer to this question clarifies which of the ascending projections are most relevant for the effects of LPS on behavior. Second, how does LPS change the brain activation patterns normally induced during exploratory behavior, and how does catecholamine lesion or DVC inactivation modify the pattern? The answer to this question establishes potential target brain regions relevant to behavioral deficits during sickness. Finally, if catecholamine lesion is sufficient to ameliorate deficits in exploratory behavior, what are the possible targets of these neurons (i.e. brain regions depleted from catecholaminergic input)? Those brain regions could provide the substrates that link immune challenge and behavior.