Induction of Fos-like immunoreactivity in the rat brain following Pasteurella multocida endotoxin administration

The functional neuroanatomy of the immune system link to the CNS was investigated by assessing neuronal activity with Fos immunohistochemistry following systemic lipopolysaccharide (LPS) administration. Two hours after LPS robust Fos-like immunoreactivity (Fos-IR) was observed in several nuclear groups in the brain including the paraventricular and supraoptic nuclei of the hypothalamus, central nucleus of the amygdala, and nucleus of the solitary tract. A similar but diminished pattern of Fos-IR was present at 6 hours and was absent 24 hours after LPS administration. Investigation of the functional neuroanatomy of the acute phase reaction could prove to be critical in enhancing the ability of individuals to combat insults such as tissue damage and inflammation. The central nervous system (CNS), particularly the hypothalamus, is intimately involved in the coordination of the various aspects of the acute phase reaction (reviewed in 1). Understanding the functional neuroanatomy by which the brain responds to immune system challenges would greatly augment the ability to control the deleterious and enhance the beneficial aspects of the acute phase reaction. In this study we have used lipopolysaccharide (LPS or endotoxin) administration as an experimental model to study immune system activation. LPS is a complex glycolipid and a component of the outer membrane of most Gram-negative bacteria (2). Administration of LPS has been demonstrated to induce the secretion of several proteins including interleukin-1 (IL-1), tumor necrosis factor (TNF), and interleukin-6 (IL-6; reviewed in 3). Further, it has been hypothesized that LPS induction of IL-1 and TNF is the key event in the pathogenesis of Gram-negative bacterial septic shock syndrome (2). Many recent studies have utilized immunohistochemistry for Fos, the product of the immediate early gene c-fos, as a marker of neuronal activation. Fos is a nuclear-binding protein that is expressed at increased levels in activated neurons (4). Although the exact function of Fos in the CNS is still unknown, it is thought that Fos is transcribed after cellular stimulation as a means to convert a stimulus into long-term genetic action (for reviews see 5,6). This study investigated the activation of the CNS by peripherally administered LPS isolated from the bacterium Pasteurella multocida. As a marker of neuronal activation, immunohistochemistry for the Fos protein was performed and image analysis was utilized to quantify the Fos induction in the CNS.