title: Inflammation-induced lethargy is mediated by suppression of orexin neuron activity.
abstract: 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.
authors.affiliation: Neuroscience Graduate Program, Oregon Health & Science University, Portland, Oregon 97239, USA.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Grossberg
authors.forename: XinXia
authors.initials: X
authors.lastname: Zhu
authors.forename: Gina M
authors.initials: GM
authors.lastname: Leinninger
authors.forename: Peter R
authors.initials: PR
authors.lastname: Levasseur
authors.forename: Theodore P
authors.initials: TP
authors.lastname: Braun
authors.forename: Martin G
authors.initials: MG
authors.lastname: Myers
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Marks
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003623:Dark Adaptation / Q000187:drug effects; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005508:Food Deprivation; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000150:complications*; D007276:Injections, Intraventricular / Q000379:methods; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000494:pharmacology; D020547:Lateral Ventricles / Q000187:drug effects / Q000502:physiology; D053609:Lethargy / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D000072000:NF-KappaB Inhibitor alpha; D009368:Neoplasm Transplantation / Q000379:methods; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism* / Q000494:pharmacology; D009496:Neurotensin / Q000235:genetics; D000068797:Orexins; D017440:Photoperiod; D011134:Polysaccharides / Q000009:adverse effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D018043:Receptors, Corticotropin / Q000037:antagonists & inhibitors; D053702:Receptors, Interleukin-11 / Q000235:genetics / Q000378:metabolism; D053606:Receptors, OSM-LIF / Q000235:genetics / Q000378:metabolism
chemical_list: D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; C000606205:Nfkbia protein, mouse; C000606206:Nfkbia protein, rat; D000068797:Orexins; D011134:Polysaccharides; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D018043:Receptors, Corticotropin; D053702:Receptors, Interleukin-11; D053606:Receptors, OSM-LIF; D000072000:NF-KappaB Inhibitor alpha; D049452:Green Fluorescent Proteins; C103272:SHU 9119; D009496:Neurotensin; D009074:Melanocyte-Stimulating Hormones