Affiliations: Cellular Function Imaging Team, Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, Hyogo, Japan | Molecular Dynamics Imaging Unit, Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, Hyogo, Japan
Note: [] Correspondence to: Yosky Kataoka, MD, PhD, Cellular Function Imaging Team, Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Cuo-ku, Kobe, Hyogo 650-0047, Japan. Tel.: +81 78 304 7115; Fax: +81 78 304 7161; E-mail: [email protected]
Abstract: We have developed various animal models of neuroinflammation and fatigue. Here, two types of models using rats are introduced: one is a model of central fatigue obtained by excessive depolarizing stimuli to the central nervous system (CNS); another is that of immunological fatigue obtained by intraperitoneal injection of polyriboinosinic:polyribocytidylic acid (poly I:C), double-stranded RNA, which mimics viral infection. In the central fatigue model, we introduced cortical spreading depression (SD), the propagation of neuronal membrane depolarization throughout the cerebral cortex. Prostaglandins (PG) including PGD2 were produced by COX-2 expression in neurons in the cortex following SD. In such a model, the amount of non-rapid eye movement (non-REM) sleep, but not of REM sleep, subsequently increased for several hours. The increase in non-REM sleep was completely attenuated by application of NS-398, a COX-2 inhibitor, indicating that non-REM sleep was induced by the production of prostaglandins in the brain. This system is thought to relieve excessive brain activity by inducing resting behavior and non-REM sleep. In the immunological fatigue model, intraperitoneal administration of poly I:C, a synthetic double-stranded RNA, induced transient fever and suppression of locomotor activity in rats. We have demonstrated that interleukin (IL)-1β expression was up-regulated in various brain regions, and that intracerebroventricular infusion of IL-1 receptor antagonist significantly attenuated the poly I:C-induced fatigue-like behavior. Pretreatment with minocycline, a potent suppressor of neuroinflammation in CNS, nullified the suppressive effect on locomotor activity by poly I:C injection. The balance of IL-1β and the endogenous antagonist in the brain possibly regulate neuroinflammation and fatigue-like behavior.
