Abstract: Objective: Physical exercise is known to improve the cognitive function decline and emotional disorders induced by chronic sleep deprivation (CSD) . Therefore, the aim of this study was to examine the effects of 8 weeks treadmill exercise on CSD induced spatial memory and anxiety-like behavior by measuring hippocampus inflammatory biomarkers levels (IL-6 and TNF-α) and hippocampus DG (dentate gyrus) BDNF and TrkB expression levels. Methods: 44 rats were randomly allocated into either a sedentary control group (SG) , an exercise group (EX) , a chronic sleep deprived group (CSD) , or a CSD+exercise group (CSD+E) . The sleep deprivation was induced by using modified multiple platform method (18 h/day, for 8 weeks) in CSD and CSD+E groups. Simultaneously, the rats in EX and CSD+E groups were conducted treadmill exercise training for 8 weeks (1 h/day, 6 d/week) . Thereafter, the anxiety-related behavior was assessed with the elevated-plus maze (EPM) , and the spatial learning and memory were assessed by using the eight arm maze test (ERM) . Additionally, the hippocampus inflammatory biomarkers (IL-6 and TNF-α) and hippocampus DG BDNF and TrkB expression levels were measured. Results: 1) Compared to the sedentary control rats, the latency of memory error was shorted in CSD rats, the numbers of achieving training standard and total memory errors were significantly increased (P<0.01, respectively) ; in addition, the correct numbers before the first error was decreased (P<0.05) in the ERM test. In the EPM test, the time and entries of open arm was significantly decreased in CSD rats by comparing with SG group, and the anxiety index was increased (P<0.01, respectively) ; the TNF-α and IL-6 concentrations in hippocampus were increased (P<0.01) , and the expression levels of BNDF and TrkB in hippocampus DG were decreased (P<0.01) . 2) 8 week treadmill exercise training was significantly attenuated anxiety-related behavior and prevented spatial learning and memory impairment; the levels of IL-6 and TNF-α in hippocampus were decreased; moreover, the expression levels of BDNF and TrkB in hippocampus DG were significantly increased after exercise training. Conclusions: Moderate-intensity treadmill exercise improved the learning and memory ability and attenuate anxiety like behavior in the CSD rats. The possible mechanisms might be related to the exercise preventing proinflammatory responses in hippocampus, and increasing BDNF and TrkB expression in hippocampus DG and improving the nerve protective effect via BDNF/TrkB pathway.