Brain Response to Endotoxin

Abstract The cellular and systemic responses of the brain to endotoxin [lipopolysaccharide (LPS)] administration are considered in relation to how the central nervous system receives information about the presence of LPS in blood and extracellular fluids (ECFs). In an attempt to provide an answer to the question of “How does the brain know the body is sick?” we review LPS-induced signaling pathways, reaction of the gastrointestinal (GI) tract epithelium and related vagal sensory nerves, related endothelium of local vascular beds in both the GI tract and the brain, as well as the specialized brain vasculature of circumventricular organs (CVOs) and blood vessels in the brain parenchyma. The featured signal pathways activated by low (subseptic) doses of LPS involve cytokines and prostanoids conveying messages to the brain via perivascular and blood vessel component cells and vagal visceral afferents. Activation of the hypothalamic–pituitary–adrenal (HPA) axis, as it represents a key component of the acute-phase reaction to LPS, is the functional endpoint emphasized in the studies presented. Individual animals were instrumented to permit rapid sampling from ECF in the anterior hypothalamus and concomitant peripheral blood sampling at 15-min intervals before and after intravenous LPS administration. Changes in interleukin (IL)-1β and hormones from pituitary [adrenocorticotropin (ACTH)] and adrenal (corticosterone) components of the HPA axis were studied in individual animals. Intrahypothalamic changes in IL-1β and corticotropin-releasing hormone (CRH) within the first half hour after LPS administration implicate hypothalamic mechanisms contributing to HPA axis activation after endotoxin. The importance of hypothalamus in this acute-phase reaction is examined further in another set of experiments involving excitotoxic chemical lesions of cell bodies in the anterior hypothalamic area (AHA) prior to LPS exposure. When viewed together, the results of these studies emphasize the importance of rapid communication of the periphery with the AHA via multiple routes after peripheral exposure to LPS, which allows the activation of all levels of the HPA axis during the acute-phase reaction.