Physiological and behavioral responses to interleukin-1β and LPS in vagotomized mice
Introduction
One of the more significant discoveries of the past 20 years was that administration of the cytokine, interleukin-1 (IL-1), to animals had the ability to induce marked physiological and behavioral responses. These responses include changes in body temperature [1], activation of the hypothalamo-pituitary-adrenocortical (HPA) axis [2] and certain other endocrine responses [3], activation of the immediate early gene product Fos in various areas of the brain [4], [5], activation of brain noradrenergic and serotonergic systems [6], [7], [8], and a range of behavioral responses [9]. Similar responses are also induced by administration of endotoxin (lipopolysaccharide, LPS) [10].
Very many studies have addressed the mechanisms of these various responses, and a number of them have implicated a role for afferents of the vagus nerve in the brain's responses to peripherally administered IL-1 and LPS. The initial observation was that lesioning of the vagus nerve below the diaphragm prevented the Fos responses in the brain to LPS [11]. This was followed by numerous observations that similar lesions prevented a variety of behavioral responses to IL-1 and LPS [12], and noradrenergic responses to IL-1 in the rat [13].
In a recent study in the rat, we observed that subdiaphragmatic vagotomy prevented the hyperthermia following intraperitoneal administration of IL-1β as well as the increased norepinephrine secretion in the hypothalamus indicated by in vivo microdialysis. It also reduced, but did not prevent, the shivering response and the increases in plasma ACTH and corticosterone [14]. Very few such studies have been performed in mice, so we have now studied the effect of subdiaphragmatic vagotomy on the behavioral, neurochemical and neurochemical responses to peripherally administered IL-1β and LPS. A preliminary account of these results was presented at the 2004 annual meeting of the Society for Neuroscience [15].
Section snippets
Experimental animals
The experiments were performed using male virus antigen-free CD-1 mice obtained from Charles River (VAF+ from Colony R16 of the Raleigh–Durham facility). The animals were housed individually, under controlled environmental conditions of temperature (22 ± 2 °C), humidity (55 ± 5%) and on a 12 : 12 light cycle (lights on at 07:00 AM). Water and Purina rat chow were available ad libitum.
Materials
Mouse interleukin-1β was purchased from R and D Systems Inc (Minneapolis, MN), and injected intraperitoneally (ip) at
Verification of vagotomy
Vagotomy was verified from stomach weights in every batch of vagotomized mice, and using ip FluoroGold as a tracer in the experiments from which the open field and neurochemical and endocrine data are presented. Stomach weights in vagotomized mice averaged 844 ± 95 mg as compared to 444 ± 26 mg in sham-operated mice (F(1,28) = 16.0, P < 0.001). Fig. 1 shows examples of the fluorescence from sections of brain stem in the region of the dorsal motor nucleus of the vagus from subdiaphragmatically
Discussion
The results of the present study confirm the observations of very many studies indicating that ip injection of IL-1β and LPS into mice and rats decrease milk intake, food intake, and body weight [17]. Such injections also decrease activity in an open field [20]. They also activate the HPA axis, elevating plasma concentrations of ACTH and corticosterone [2], [6], [10]. IL-1β and LPS both increase the activity of noradrenergic and serotonergic neurons, as well as increasing brain concentrations
Acknowledgements
We thank Charles Dempsey for technical assistance with the neurochemical assays. We thank Dr. Lisa Goehler (University of Virginia) for the generous gift of FluoroGold and assistance in implementing this procedure. This work was supported by a grant from the National Institutes of Health (NS35370).
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