Investigation of the impact of preconditioning with lipopolysaccharide on inflammation-induced gene expression in the brain and depression-like behavior in male mice.

Although several recent studies have suggested that neuroinflammation plays a role in depression, both medication and neuroinflammatory preventive strategies have been poorly investigated. Recent studies have indicated that preconditioning with lipopolysaccharide (LPS) reduces the damage that occurs following ischemic stroke and brain trauma. However, to date, the effects of LPS preconditioning on psychiatric symptoms have not been reported. Thus, we assessed gene expression and behavioral changes affected by preconditioning with low-dose (LD) LPS in male mice with systemic inflammation induced by administration of high-dose (HD) LPS. mRNA expression analyses of cytokine-, glial-, and oxidative stress-associated genes revealed that majority of these genes responded to HD LPS. Differential gene expression in the presence and absence of LD LPS preconditioning, identified a subset of genes that may contribute to the mechanism of LPS preconditioning in the brain. Notably, LPS preconditioning attenuated an increase in expression of the astrocyte marker Gfap caused by systemic inflammation, suggesting that astrocytes have a key role in endotoxin tolerance in the brain induced by LPS preconditioning. As increased astrocyte in the brain of patients with depression is suggested to contribute to the pathophysiology of major depression, LPS preconditioning might be applicable to the prevention and treatment of depression. Unfortunately, in this study, LPS preconditioning did not show a reversal effect on behavior decline due to high-dose LPS-induced systemic inflammation. Alternative aspects of behavioral changes should be assessed to identify behavioral components that are affected by LPS preconditioning. Nonetheless, the findings in the present study indicate the possibility of the mechanism of endotoxin tolerance induction in the brain via astrocyte regulation by LPS preconditioning. Since there has been reported pharmacological significance of astrocytes in psychiatric disorders, regulation of endotoxin tolerance might be a key method to control psychiatric symptoms.

Differential effects of voluntary wheel running and toy rotation on the mRNA expression of neurotrophic factors and FKBP5 in a post-traumatic stress disorder rat model with the shuttle-box task.

Life-threatening experiences can result in the development of post-traumatic stress disorder. We have developed an animal model for post-traumatic stress disorder (PTSD) using a shuttle box in rats. In this paradigm, the rats were exposed to inescapable foot-shock stress (IS) in a shuttle box, and then an avoidance/escape task was performed in the same box 2 weeks after IS. A previous study using this paradigm revealed that environmental enrichment (EE) ameliorated avoidance/numbing-like behaviors, but not hyperarousal-like behaviors, and EE also elevated hippocampal brain-derived neurotrophic factor (BDNF) expression. However, the differential effects of EE components, i.e., running wheel (RW) or toy rotation, on PTSD-like behaviors has remained unclear. In this experiment, we demonstrated that RW, toy rotation, and EE (containing RW and toy rotation) ameliorated avoidance/numbing-like behaviors, induced learning of avoidance responses, and improved depressive-like behaviors in traumatized rats. The RW increased the hippocampal mRNA expression of neurotrophic factors, especially BDNF and glial-cell derived neurotrophic factor. Toy rotation influenced FK506 binding protein 5 mRNA expression, which is believed to be a regulator of the hypothalamic-pituitary-adrenal (HPA)-axis system, in the hippocampus and amygdala. This is the first report to elucidate the differential mechanistic effects of RW and toy rotation. The former appears to exert its effects via neurotrophic factors, while the latter exerts its effects via the HPA axis. Further studies will lead to a better understanding of the influence of environmental factors on PTSD.