Central innate immunization induces tolerance against post-traumatic stress disorder-like behavior and neuroinflammatory responses in male mice.

Post-traumatic stress disorder (PTSD) is a severe psychiatric disorder associated with abnormally elevated neuroinflammatory responses. Suppression of neuroinflammation is considered to be effective in ameliorating PTSD-like behaviors in rodents. Since pre-stimulation of microglia prior to stress exposure can prevent neuroinflammation, we hypothesized that pre-stimulation of microglia may prevent PTSD in animals. The results show that a single injection of a classical immune stimulant, lipopolysaccharide (LPS), at 50, 100 or 500, but not 10 µg/kg, one day before stress exposure, prevented the anxiety- and fear-like behaviors induced by modified single prolonged stress (mSPS). The time-dependent analysis shows that a single injection of LPS (100 µg/kg) either one or five, but not ten, days before stress prevented mSPS-induced anxiety- and fear-like behaviors. A second low-dose LPS injection 10 days after the first injection or a repeated LPS injection (4 × ) 10 days before stress induced tolerance to mSPS. Mechanistic studies show that a single injection of LPS one day before stress stimulation prevented mSPS-induced increases in levels of interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and IL-6 mRNA in the hippocampus and medial prefrontal cortex. Inhibition of microglia by pretreatment with minocycline or depletion of microglia by PLX3397 abolished the preventive effect of low-dose LPS pre-injection on mSPS-induced anxiety- and fear-like behavior and neuroinflammatory responses. These results suggest that pre-stimulation of microglia may prevent the development of PTSD-like behaviors by attenuating the development of neuroinflammatory responses. This could help to develop new strategies to prevent the damaging effects of harmful stress on the brain.

Mobilization of the innate immune response by a specific immunostimulant ß-glucan confers resistance to chronic stress-induced depression-like behavior by preventing neuroinflammatory responses.

Pre-stimulation of the innate immune response is an effective strategy to prevent depression-like phenotypes in animals. However, the use of conventional immunostimulants may cause adverse effects. Therefore, the search for agents that stimulate the innate immune response but do not induce a pro-inflammatory response could be a new research direction for the prevention of depression. ß-glucan is a polysaccharide from Saccharomyces cerevisiae with unique immunomodulatory activity in microglia without eliciting a pro-inflammatory response that could lead to tissue damage. This suggests that ß-glucan may be a suitable drug that can be used to prevent depression-like phenotypes. Our results showed that a single injection of ß-glucan 1 day before stress exposure at a dose of 10 or 20 mg/kg, but notat a dose of 5 mg/kg, prevented depression-like behavior in mice treated with chronic unpredictable stress (CUS). This effect of ß-glucan disappeared when the time interval between ß-glucan and stress was extended from 1 day or 5 days to 10 days, which was rescued by a second injection 10 days after the first injection or by a repeated injection (4×, once daily) 10 days before stress exposure. A single ß-glucan injection (20 mg/kg) 1 day before stress exposure prevented the CUS-induced increase in brain pro-inflammatory cytokines, and inhibition of the innate immune response by minocycline (40 mg/kg) abolished the preventive effect of ß-glucan on CUS-induced depression-like behaviors and neuroinflammatory responses. These results suggest that ß-glucan may prevent chronic stress-induced depression-like phenotypes and neuroinflammatory responses by stimulating the innate immune response.

Obligatory role of microglia-mobilized hippocampal CREB-BDNF signaling in the prophylactic effect of ß-glucan on chronic stress-induced depression-like behaviors in mice.

Our previous studies have reported that pre-stimulation of microglia before stress stimulation is a possible strategy to prevent depression-like phenotypes; however, the molecular mechanisms underlying this effect are still unclear. Here, we used ß-glucan, a polysaccharide from Saccharomyces cerevisiae with immunomodulatory activities that cannot elicit pro-inflammatory responses in microglia, to address this issue. Our results showed that a single injection of ß-glucan one day before stress exposure dose-dependently prevented the depression-like behaviors triggered by chronic unpredictable stress (CUS), which peaked at 20 mg/kg and prevented the impairment of hippocampal brain-derived neurotrophic factor (BDNF) signaling, a pathological process critical for the progression of depression-like phenotypes. Inhibition of BDNF signaling by infusion of an anti-BDNF antibody into the hippocampus, knock-in of the mutant BDNF Val68Met allele, or blockade of the BDNF receptor in the hippocampus abolished the preventive effect of ß-glucan on CUS-induced depression-like behaviors. Further analysis showed that cAMP-response element binding protein (CREB)-mediated increase of BDNF expression in the hippocampus was essential for the prevention of depression-like phenotypes by ß-glucan. Pretreatment with minocycline or PLX3397 before ß-glucan injection to suppress microglia abolished the preventive effect of ß-glucan on impaired CREB-BDNF signaling in the hippocampus and depression-like behaviors in CUS mice. These results suggest that an increase in hippocampal BDNF following CREB activation triggered by ß-glucan-induced microglia stimulation and subsequent TrkB signaling mediates the preventive effect of ß-glucan on depression. ß-Glucan may be a more suitable immunostimulant for the prevention of depression due to its inability to promote pro-inflammatory responses in microglia.

Scream Sound-induced Chronic Psychological Stress Results in Diminished Ovarian Reserve in Adult Female Rat.

It is well established that chronic psychological stress (PS) induces female reproductive dysfunction. However, the studies on the consequences of chronic PS exposure precisely targeting ovarian reserve are lacking. In the present study, we employed a chronic scream sound-induced PS model to investigate the potential effect of pure psychosocial stressors on ovary reserve. Female rats were subjected to scream sound stress, white noise, or background for 3 weeks. Animals were euthanized by cervical dislocation after stress for collection of blood or ovaries. Sex hormones were analyzed by enzyme-linked immunosorbent assay. The follicle number was examined by histopathology. Granulosa cell apoptosis of the ovaries was examined by in situ cell death detection kit. Finally, rats were mated with proven fertile male rats to study fertility parameters. Female rats exposed to scream sound were presented with reduced weight gain and sucrose preference, while immobility time in forced swim test and serum corticosterone concentration were significantly increased. Scream sound stress sequentially decreased plasma anti-Müllerian hormone and estradiol concentration, induced primordial and preantral follicles loss, augmented granulosa cell apoptosis in ovarian growing follicles, and eventually decreased litter sizes. Based on these results, we suggest that chronic PS induced loss of ovarian reserve by accelerated primordial follicle activation and destruction of growing follicles, which results in follicle depletion and decreased fertility.

Innate immune stimulation prevents the development of anxiety-like behaviors in chronically stressed mice.

Anxiety is a common psychological disease which can induce severe social burdens. Searching methods that prevent the onset of anxiety is of great significance for ameliorating the social and individual problems induced by this type of disease. In this study, we investigated how innate immune pre-stimulation influences the anxiety-like behaviors in chronically stressed mice. Our results showed that a single injection of an innate immune stimulant lipopolysaccharide (LPS) at the dose of 50, 100, and 500 µg/kg 1 day before stress exposure prevented chronic social defeat stress (CSDS)-induced anxiety-like behaviors in mice. A single injection of LPS (100 µg/kg) 5 days before stress exposure produced similar preventive effects on CSDS-induced anxiety-like behaviors, while similar effects were not observed at the condition of 10-days interval between LPS injection and stress exposure. A second LPS injection 10 days after the first LPS injection or a 4 × LPS injection 10 days before stress exposure also prevented CSDS-induced anxiety-like behaviors. Moreover, a single injection of LPS (100 µg/kg) 1 day before stress exposure prevented the production of pro-inflammatory cytokines in the hippocampus and prefrontal cortex of CSDS mice. Suppression of innate immune stimulation by minocycline pretreatment simultaneously abrogated the preventive effect of LPS pre-injection (100 µg/kg) on CSDS-induced anxiety-like behaviors and pro-inflammatory cytokine production in the brain. Our results demonstrated that the pre-stimulation of the innate immune system can prevent the development of anxiety-like behaviors and the progression of the neuroinflammatory responses in the brain in chronically stressed mice.