Immunization with a low dose of zymosan A confers resistance to depression-like behavior and neuroinflammatory responses in chronically stressed mice.

Stimulation of the innate immune system prior to stress exposure is a possible strategy to prevent depression under stressful conditions. Based on the innate immune system stimulating activities of zymosan A, we hypothesize that zymosan A may prevent the development of chronic stress-induced depression-like behavior. Our results showed that a single injection of zymosan A 1 day before stress exposure at a dose of 2 or 4 mg/kg, but not at a dose of 1 mg/kg, prevented the development of depression-like behaviors in mice treated with chronic social defeat stress (CSDS). The prophylactic effect of a single zymosan A injection (2 mg/kg) on CSDS-induced depression-like behaviors disappeared when the time interval between zymosan A and stress exposure was extended from 1 day or 5 days to 10 days, which was rescued by a second zymosan A injection 10 days after the first zymosan A injection and 4 days (4×, once daily) of zymosan A injections 10 days before stress exposure. Further analysis showed that a single zymosan A injection (2 mg/kg) 1 day before stress exposure could prevent the CSDS-induced increase in pro-inflammatory cytokines in the hippocampus and prefrontal cortex. Inhibition of the innate immune system by pretreatment with minocycline (40 mg/kg) abolished the preventive effect of zymosan A on CSDS-induced depression-like behaviors and CSDS-induced increase in pro-inflammatory cytokines in the brain. These results suggest that activation of the innate immune system triggered by zymosan A prevents the depression-like behaviors and neuroinflammatory responses in the brain induced by chronic stress.

The cost of "snubbing": the effect of parental phubbing on filial piety behavior in children and adolescents.

Background: Although numerous studies have used Chinese samples to examine the consequences of parental phubbing, these studies focused on children's mental health and peer interaction. No research to date has directly explored the association between parental phubbing and child-parent interaction. Since parental phubbing is a way how parents interact with their children (parent-child), it might be associated with the way how children interact with their parents (child-parent), such as filial piety behavior, which prescribes how children behave toward their parents and remains one of the goals of parents in educating their children in modern Chinese society. Based on social exchange theory and social gender theory, this study investigated the impact of parental phubbing on filial piety behavior and tested its mediation of perceived parental rejection, its moderation of gender among children and adolescents. Methods: This study was conducted using a questionnaire method. A total of 753 students from Grade 4 to 9 (Mage = 12.28 years, SD = 1.81 years) was surveyed using the Parental Phubbing Scale, Perceived Parental Rejection Questionnaire, and the revised Dual Filial Piety Scale. Results: First, parental phubbing was negatively correlated with reciprocal filial piety (RFP) behavior, but not correlated with authoritarian filial piety (AFP) behavior. Second, perceived parental rejection played a mediating role between parental phubbing and RFP behavior. Third, this direct effect was moderated by gender, in that it was stronger for boys than for girls. Conclusion: These findings suggest that there are intergenerational costs of phubbing, such as reducing children and adolescents' RFP behavior. The present study is the first to combine parent-child interaction in the digital media era (parental phubbing) with traditional Chinese child-parent interaction (RFP behavior), which expands the research topic on the influence of parental phubbing on children and adolescents' psychological development.

Microglia-Dependent Reversal of Depression-Like Behaviors in Chronically Stressed Mice by Administration of a Specific Immuno-stimulant ß-Glucan.

In recent years, the decline of microglia in the hippocampus has been shown to play a role in the development of depression, and its reversal shows marked antidepressant-like effects. ß-glucan is a polysaccharide from Saccharomyces cerevisiae and has numerous beneficial effects on the nervous system, including improving axon regeneration and cognition. Considering its immuno-stimulatory activities in cultured microglia and brain tissues, we hypothesize that ß-glucan may be a potential candidate to correct the functional deficiency of microglia and thereby alleviate depression-like behaviors in chronically stressed animals. An expected, our results showed that a single injection of ß-glucan 5 h before behavioral tests at a dose of 10 or 20 mg/kg, but not at a dose of 5 mg/kg, reversed the depression-like behavior induced by chronic stress in mice in the tail suspension test, forced swimming test, and sucrose preference test. The effect of ß-glucan (20 mg/kg) also showed time-dependent properties that were statistically significant 5 and 8, but not 3, hours after drug injection and persisted for at least 7 days. Fourteen days after ß-glucan injection, no antidepressant-like effect was observed anymore. However, this effect was overcome by a second ß-glucan injection (20 mg/kg) 14 days after the first ß-glucan injection. Stimulation of microglia appeared to mediate the antidepressant-like effect of ß-glucan, because both inhibition of microglia and their depletion prevented the antidepressant-like effect of ß-glucan. Based on these effects of ß-glucan, ß-glucan administration could be developed as a new strategy for the treatment of depression.

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.

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.

ß-glucan, a specific immuno-stimulant, produces rapid antidepressant effects by stimulating ERK1/2-dependent synthesis of BDNF in the hippocampus.

A decline in microglia in the dentate gyrus of the hippocampus has recently been described as an important mechanism for the progression of depression. Reversal of this decline by innate immune system stimulants may represent a novel strategy to ameliorate the depressive phenotype in chronically stressed animals. ß-glucan is a polysaccharide from Saccharomyces cerevisiae. It can efficiently stimulate microglia without inducing the production of pro-inflammatory cytokines. Therefore, ß-glucan could be an ideal drug to ameliorate depressive phenotypes. In the present study, we found that a single injection of ß-glucan reversed depression-like behaviors in mice induced by chronic unpredictable stress (CUS) in a dose-dependent manner, which was accompanied by a reversal of the CUS-induced decrease in brain-derived neurotrophic factor (BDNF) protein levels in the dentate gyrus. The crucial role of BDNF signaling in the antidepressant effect of ß-glucan was demonstrated by experiments showing that infusion of an anti-BDNF antibody into dentate gyrus, construction of BDNF-Val68Met allele knock-in mice, or treatment with the BDNF receptor antagonist K252a abolished the antidepressant effect of ß-glucan. The increased BDNF signaling induced by ß-glucan was mediated by extracellular signal-regulated kinase1/2 (ERK1/2)-mediated BDNF synthesis, and inhibition of ERK1/2 by SL327 was able to abolish the antidepressant effect of ß-glucan. Moreover, inhibition or depletion of microglia by minocycline or PLX3397 abolished the reversal effect of ß-glucan on CUS-induced depression-like behaviors and CUS-induced impairment of ERK1/2-BDNF signaling. These results suggest that ß-glucan exhibits antidepressant effects by stimulating microglia-mediated activation of ERK1/2 and synthesis of BDNF in the hippocampus.

Visible-Light-Induced Defluorinative α-C(sp3)-H Alkylation for the Synthesis of gem-Difluoroallylated α-Trifluoromethylamines.

Herein, we describe a novel and efficient photoredox catalytic Cα radical addition/defluoroalkylation coupling reaction between α-trifluoromethyl alkenes and N-trifluoroethyl hydroxylamine. A series of gem-difluoroallylated α-trifluoromethylamines were synthesized by the Cα radical addition enabled by a 1,2-H shift of the in situ-generated N-trifluoroethyl radical. Notably, this protocol is distinguished by its mild conditions, easy operation, and excellent functional group tolerability.

Microglial stimulation triggered by intranasal lipopolysaccharide administration produces antidepressant-like effect through ERK1/2-mediated BDNF synthesis in the hippocampus.

We recently reported that reversing the chronic stress-induced decline of microglia in the dentate gyrus (DG) of the hippocampus by intraperitoneal injection of a low dose of lipopolysaccharide (LPS) ameliorated depression-like behavior in chronically stressed mice. In this study, we found that a single intranasal administration of LPS dose-dependently improved depression-like behavior in mice treated with chronic unpredictable stress (CUS), as evidenced by the reduction of immobility time in the tail suspension test (TST) and forced swimming test (FST) and by the increase of sucrose uptake in the sucrose preference test (SPT). The antidepressant effects of intranasal administration of LPS could be abolished by inhibition of brain-derived neurotrophic factor (BDNF) signaling by infusion of an anti-BDNF antibody, by knock-in of the mutant BDNF Val68Met allele, or by the BDNF receptor antagonist K252a. In addition, intranasal administration of LPS was found to exert antidepressant effects in a BDNF-dependent manner via promotion of BDNF synthesis mediated by extracellular signal-regulated kinase 1/2 (ERK1/2) signaling but not protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling in DG. Inhibition of microglia by minocycline or depletion of microglia by PLX3397 was able to abolish the reversal effect of intranasal LPS administration on CUS-induced depression-like behaviors as well as the CUS-induced decrease in phospho-ERK1/2 and BDNF protein levels in DG. These results demonstrate that stimulation of hippocampal microglia by intranasal LPS administration can induce antidepressant effects via ERK1/2-dependent synthesis of BDNF protein, providing hope for the development of new strategies for the treatment of depression.

Zymosan A produces a rapid and sustained antidepressant effect in chronically stressed mice by stimulating hippocampal microglia.

Recent studies had reported that compounds that stimulate microglia could be developed as potential drugs for the treatment of depression due to their reversal effect on depression-like behaviors in chronically stressed mice. Zymosan A is a cell wall preparation of Saccharomyces cerevisiae composed of ß-glucans. Based on its immuno-stimulatory activities, we hypothesized that zymosan A might have a therapeutic effect on depression. Our results showed that a single injection of zymosan A 5 h before behavioral tests at a dose of 1 or 2 mg/kg, but not at a dose of 0.5 mg/kg, reversed chronic unpredictable stress (CUS)-induced depression-like behaviors in mice in the tail suspension test, forced swimming test, and sucrose preference test. Time-dependent analysis showed that the antidepressant effect of zymosan A (2 mg/kg) in CUS mice became statistically significant at 5 and 8 h, but not at 3 h, and persisted for at least 7 days. Fourteen days after a single injection of zymosan A, no antidepressant effect was observed anymore. However, the disappeared antidepressant effect of zymosan A was restored by a second zymosan A injection (2 mg/kg, 5 h) 14 days after the first zymosan A injection. Stimulation of microglia was essential for the antidepressant effect of zymosan A because pre-inhibition of microglia by minocycline or pre-depletion of microglia by PLX3397 prevented the antidepressant effect of zymosan A. Based on these effects of zymosan A, zymosan A administration could be developed as a new strategy for the treatment of depression.

Intranasal administration of lipopolysaccharide reverses chronic stress-induced depression-like behavior in mice by microglial stimulation.

We recently reported that intraperitoneal injection of a low dose of lipopolysaccharide (LPS) reversed depression-like behavior in mice induced by chronic stress by stimulating microglia in the hippocampus. In this study, we found that a single intranasal administration of LPS at a dose of 5 or 10 µg/mouse, but not at a dose of 1 µg/mouse, rapidly reversed depression-like behavior in mice stimulated with chronic unpredictable stress (CUS). In the time-dependent experiment, a single intranasal administration of LPS (10 µg/mouse) reversed CUS-induced depression-like behavior in mice 5 and 8 h but not 3 h after drug administration. The antidepressant effect of a single intranasal LPS administration (10 µg/mouse) lasted at least 10 days and disappeared 14 days after administration. Fourteen days after the first intranasal LPS administration, a second intranasal LPS administration (10 µg/mouse) still reversed the increased immobility time in TST and FST and the decreased sucrose uptake in SPT in CUS mice, which again exhibited depression-like behaviors 5 h after LPS administration. The antidepressant effect of intranasal LPS administration was dependent on microglial activation, because inhibition of microglia by pretreatment with minocycline (40 mg/kg) or depletion of microglia by pretreatment with PLX3397 (290 mg/kg) prevented the antidepressant effect of intranasal LPS administration in CUS mice. These results suggest that stimulation of the microglia-mediated innate immune response by intranasal administration of LPS can produce rapid and sustained antidepressant effects in animals under chronic stress conditions.

Intranasal Monophosphoryl Lipid a Administration Ameliorates depression-like Behavior in Chronically Stressed Mice Through Stimulation of Microglia.

We and others have reported that systematic stimulation of the central innate immune system by a low dose of lipopolysaccharide (LPS) can improve depression-like behavior in chronically stressed animals. However, it is unclear whether similar stimulation by intranasal administration could improve depression-like behavior in animals. We investigated this question using monophosphoryl lipid A (MPL), a derivative of LPS that lacks the adverse effects of LPS but is still immuno-stimulatory. We found that a single intranasal administration of MPL at a dose of 10 or 20 µg/mouse, but not at a dose of 5 µg/mouse, ameliorated chronic unpredictable stress (CUS)-induced depression-like behavior in mice, as evidenced by the decrease in immobility time in tail suspension test and forced swimming test and the increase in sucrose intake in sucrose preference test. In the time-dependent analysis, the antidepressant-like effect of a single intranasal MPL administration (20 µg/mouse) was observed 5 and 8 h but not 3 h after drug administration and persisted for at least 7 days. Fourteen days after the first intranasal MPL administration, a second intranasal MPL administration (20 µg/mouse) still showed an antidepressant-like effect. The innate immune response mediated by microglia might mediate the antidepressant-like effect of intranasal MPL administration, because both inhibition of microglial activation by pretreatment with minocycline and depletion of microglia by pretreatment with PLX3397 prevented the antidepressant-like effect of intranasal MPL administration. These results suggest that intranasal administration of MPL can produce significant antidepressant-like effects in animals under chronic stress conditions via stimulation of microglia.