shu-9119 and Lethargy

In response to illness, animals subvert normal homeostasis and divert their energy utilization to fight infection. An important and unexplored feature of this response is the suppression of physical activity and foraging behavior in the setting of negative energy balance. Inflammatory signaling in the hypothalamus mediates the febrile and anorectic responses to disease, but the mechanism by which locomotor activity (LMA) is suppressed has not been described. Lateral hypothalamic orexin (Ox) neurons link energy status with LMA, and deficiencies in Ox signaling lead to hypoactivity and hypophagia. In the present work, we examine the effect of endotoxin-induced inflammation on Ox neuron biology and LMA in rats. Our results demonstrate a vital role for diminished Ox signaling in mediating inflammation-induced lethargy. This work defines a specific population of inflammation-sensitive, arousal-associated Ox neurons and identifies a proximal neural target for inflammatory signaling to Ox neurons, while eliminating several others.

Topics: Analysis of Variance; Animals; Dark Adaptation; Disease Models, Animal; Drug Administration Routes; Enzyme-Linked Immunosorbent Assay; Food Deprivation; Gene Expression Regulation; Green Fluorescent Proteins; I-kappa B Proteins; Inflammation; Injections, Intraventricular; Interleukin-1beta; Interleukin-6; Intracellular Signaling Peptides and Proteins; Lateral Ventricles; Lethargy; Male; Melanocyte-Stimulating Hormones; Mice; Mice, Transgenic; Motor Activity; Neoplasm Transplantation; Neurons; Neuropeptides; Neurotensin; NF-KappaB Inhibitor alpha; Orexins; Photoperiod; Polysaccharides; Proto-Oncogene Proteins c-fos; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Receptors, Corticotropin; Receptors, Interleukin-11; Receptors, OSM-LIF; RNA, Messenger