Hippocampal neurogenesis dysfunction linked to depressive-like behaviors in a neuroinflammation induced model of depression.

Our previous work found that triple central lipopolysaccharide (LPS) administration could induce depressive-like behaviors and increased central pro-inflammatory cytokines mRNA, hippocampal cytokine mRNA in particular. Since several neuroinflammation-associated conditions have been reported to impair neurogenesis, in this study, we further investigated whether the neuroinflammation induced depression would be associated with hippocampal neurogenesis dysfunction. An animal model of depression induced by triple central lipopolysaccharide (LPS) administration was used. In the hippocampus, the neuroinflammatory state evoked by LPS was marked by an increased production of pro-inflammatory cytokines, including interleukin-1ß, interleukin-6, and tumor necrosis factor-α. It was found that rats in the neuroinflammatory state exhibited depressive-like behaviors, including reduced saccharin preference and locomotor activity as well as increased immobility time in the tail suspension test and latency to feed in the novelty suppressed feeding test. Adult hippocampal neurogenesis was concomitantly inhibited, including decreased cell proliferation and newborn cell survival. We also demonstrated that the decreased hippocampal neurogenesis in cell proliferation was significantly correlated with the depressive-like phenotypes of decreased saccharine preference and distance travelled, the core and characteristic symptoms of depression, under neuro inflammation state. These findings provide the first evidence that hippocampal neurogenesis dysfunction is correlated with neuroinflammation-induced depression, which suggests that hippocampal neurogenesis might be one of biological mechanisms underlying depression induced by neruoinflammation.

Comparison of stress-induced and LPS-induced depressive-like behaviors and the alterations of central proinflammatory cytokines mRNA in rats.

Although proinflammatory cytokine changes in depression have been studied widely, few investigations have searched for specific and common changes in cytokines. In the present study, two animal models of depression were compared: a chronic stress model using forced swim stress and an immune activation model using repeated central lipopolysaccharide (LPS) infusion. The levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 mRNA were examined in the brain regions of the prefrontal cortex, amygdala, and hippocampus using real-time polymerase chain reaction (RT-PCR). It was found that both chronic swim stress and repeated central LPS infusion induced depressive-like behaviors, including decreased body weight, reduced saccharin preference, and increased immobility time or shortened latency of immobility in the tail suspension test. Central TNF-α mRNA expression was elevated in both models and central IL-6 mRNA expression was unchanged in both models. Central IL-1ß mRNA expression was increased only in the chronic immune activation model. The findings from this study suggest that TNF-α may be a common risk factor for inflammation in depressive disorders.

Effects of aspirin on immobile behavior and endocrine and immune changes in the forced swimming test: comparison to fluoxetine and imipramine.

Aspirin (ASP) is the most commonly used non-steroidal anti-inflammatory drug in the world. Recent clinical and preclinical evidence suggests that ASP may also exert psychoactive effects. It remains unclear whether ASP has antidepressant-like activity, and any molecular mechanisms underlying such activity have yet to be elucidated. Using the forced swimming test (FST), a well-established animal model of depression widely used to screen potential antidepressants in rodents, we investigated the effects of subacute treatment with ASP (0, 6, 12, 25, and 50mg/kg, i.p.) on immobility in the FST, and on FST-induced changes in endocrine and immune parameters in rats, in comparison to the clinical antidepressants imipramine (IMI) and fluoxetine (FLU). Serum levels of corticosterone, pro-inflammatory cytokine interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were determined by enzyme-linked immunosorbent assay. ASP dose-dependently decreased immobility in the FST, without altering the locomotor activity in the open-field test. The inhibitory effects of higher doses (25 and 50mg/kg) of ASP on immobility were similar to that of FLU and IMI at a dose of 10mg/kg. In addition, the levels of corticosterone, IL-6, and TNF-α in peripheral blood were significantly increased after the FST exposure. IMI, but not FLU and ASP at any dose tested, significantly attenuated corticosterone responses in the FST. Both FLU and IMI treatment reduced the increase of IL-6 and TNF-α levels following the FST exposure. ASP dose-dependently decreased FST-induced increase of cytokine levels, as manifested by significantly stronger effects on IL-6 and TNF-α levels at higher doses (25 and 50mg/kg) than the lowest dose of ASP (6 mg/kg). In all, these results indicate that ASP treatment dose-dependently decreased the immobility time and the release of pro-inflammatory cytokines in the FST, suggesting that the anti-inflammatory effects of ASP might be involved in the antidepressant-like effect.

Juvenile stress affects anxiety-like behavior and limbic monoamines in adult rats.

Epidemiological evidence suggests that childhood and adolescent maltreatment is a major risk factor for mood disorders in adulthood. However, the mechanisms underlying the manifestation of mental disorders during adulthood are not well understood. Using a recently developed rat model for assessing chronic variable stress (CVS) during early adolescence (juvenility), we investigated the long-term effects of juvenile CVS on emotional and cognitive function and on monoaminergic activities in the limbic areas. During juvenility (postnatal days 27-33), rats in the stress group were exposed to variable stressors every other day for a week. Four weeks later, anhedonia was tested in the sucrose test, anxiety-like behaviors were assessed in the elevated plus-maze (EPM) and open field (OF) tests, and cortically mediated cognitive function was evaluated during an attentional set-shifting task (AST). After the behavioral tests, the rats were decapitated to determine limbic monoamine and metabolite levels. Adult rats stressed during juvenility exhibited higher anxiety-like behaviors, as evidenced by reduced locomotion and rearing behavior in the OF and fewer entries into the open arms in the EPM. There were no differences between the stressed rats and the controls in depressive-like anhedonia during the sucrose preference test or in cognitive function during the AST test in adulthood. In addition, the previously stressed rats exhibited increased dopamine (DA) and decreased 5-HIAA in the medial prefrontal cortex (mPFC) and decreased noradrenaline in the amygdala compared with controls. Furthermore, DA levels in the mPFC were correlated with adult anxious behaviors in the OF. These results suggest that juvenile stress induces long-term changes in the expression of anxiety-like behaviors and limbic monoaminergic activity in adult rats.