IL-1ra treatment prevents chronic social defeat stress-induced depression-like behaviors and glutamatergic dysfunction via the upregulation of CREB-BDNF.

BACKGROUND: Proinflammatory cytokines IL-1ß has been proposed to be a key mediator in the pathophysiology of mood-related disorders. However, the IL-1 receptor antagonist (IL-1ra) is a natural antagonist of IL-1 and plays a key role in the regulation of IL-1-mediated inflammation, the effects of IL-1ra in stress-induced depression has not been well elucidated. METHODS: Chronic social defeat stress (CSDS) and lipopolysaccharide (LPS) were used to investigate the effects of IL-1ra. ELISA kit and qPCR were used to detect IL-1ra levels. Golgi staining and electrophysiological recordings were used to investigate glutamatergic neurotransmission in the hippocampus. Immunofluorescence and western blotting were used to analyze CREB-BDNF pathway and synaptic proteins. RESULTS: Serum levels of IL-1ra increased significantly in two animal models of depression, and there was a significant correlation between serum IL-1ra levels and depression-like behaviors. Both CSDS and LPS induced the imbalance of IL-1ra and IL-1ß in the hippocampus. Furthermore, chronic intracerebroventricular (i.c.v.) infusion of IL-1ra not only blocked CSDS-induced depression-like behaviors, but also alleviated CSDS-induced decrease in dendritic spine density and impairments in AMPARs-mediated neurotransmission. Finally, IL-1ra treatment produces antidepressant-like effects through the activation of CREB-BDNF in the hippocampus. LIMITATION: Further studies need to investigate the effect of IL-1ra in the periphery in CSDS-induced depression. CONCLUSION: Our study suggests that the imbalance of IL-1ra and IL-1ß reduces the expression of the CREB-BDNF pathway in the hippocampus, which dysregulates AMPARs-mediated neurotransmission, ultimately leading to depression-like behaviors. IL-1ra could be a new potential candidate for the treatment of mood disorders.

Beyond direct neighbourhood effects: higher-order interactions improve modelling and predicting tree survival and growth.

It is known that biotic interactions are the key to species coexistence and maintenance of species diversity. Traditional studies focus overwhelmingly on pairwise interactions between organisms, ignoring complex higher-order interactions (HOIs). In this study, we present a novel method of calculating individual-level HOIs for trees, and use this method to test the importance of size- and distance-dependent individual-level HOIs to tree performance in a 25-ha temperate forest dynamic plot. We found that full HOI-inclusive models improved our ability to model and predict the survival and growth of trees, providing empirical evidence that HOIs strongly influence tree performance in this temperate forest. Specifically, assessed HOIs mitigate the competitive direct effects of neighbours on survival and growth of focal trees. Our study lays a foundation for future investigations of the prevalence and relative importance of HOIs in global forests and their impact on species diversity.

B cells induced by Schistosoma japonicum infection display diverse regulatory phenotypes and modulate CD4+ T cell response.

BACKGROUND: The increased activity of regulatory B cells (Breg) is known to be involved in immunosuppression during helminth infection, which is characterized by inducing IL-10-producing Breg cells. However, the current knowledge of B cell subsets differentiation and IL-10-independent immunoregulatory mechanisms of B cells in schistosomiasis is insufficient. METHODS: BALB/c mice were percutaneously infected with cercariae for investigating the profile of B cell subsets during Schistosoma japonicum infection. B cells isolated from the spleen or peritoneal cavity were analyzed for the regulatory phenotype after stimulation with soluble egg antigens (SEA) in vitro. CD4+ T cells were then cocultured with B cells pretreated with or without anti-PD-L1 antibody for investigating the role of B cells from infected mice on regulating CD4+ T cells. Furthermore, the in vivo administration of anti-PD-L1 antibody was conducted to investigate the role of PD-L1 in regulating host immunity during infection. RESULTS: The percentages of peritoneal and splenic B-1a cells, as well as marginal zone B (MZB) cells were decreased at eight and twelve weeks after infection compared to those from uninfected mice. In splenic B cells, TGF-ß expression was increased at eight weeks but declined at twelve weeks of infection, and PD-L1 expression was elevated at both eight and twelve weeks of infection. In addition, SEA stimulation in vitro significantly promoted the expression of IL-10 in peritoneal B cells and CD5 in splenic B cells, and the SEA-stimulated splenic and peritoneal B cells preferentially expressed PD-L1 and TGF-ß. The splenic B cells from infected mice were able to suppress the function of Th1 and Th2 cells in vitro but to expand the expression of Tfh transcription factor Bcl6, which was further enhanced by blocking PD-L1 of B cells before co-cultivation. Moreover, Th2 response and Bcl6 expression in CD4+ T cells were also increased in vivo by blocking PD-L1 after infection, although the hepatic pathology was slightly influenced. CONCLUSIONS: Our findings revealed that S. japonicum infection modulates the differentiation of B cell subsets that have the capability to affect the CD4+ T cell response. This study contributes to a better understanding of B cells immune response during schistosomiasis.

Leptin: a potential anxiolytic by facilitation of fear extinction.

AIMS: Anxiety disorders are characterized by a deficient extinction of fear memory. Evidence is growing that leptin influences numerous neuronal functions. The aims of this study were to investigate the effects and the mechanism of leptin on fear extinction. METHODS AND RESULTS: Leptin (1 mg/kg, i.p) was applied to evaluate the anxiolytic effect in rat behavioral tests. Field potentials recording were used to investigate the changes in synaptic transmission in the thalamic-lateral amygadala (LA) pathway of rat. We found that leptin produced strong anxiolytic effects under basal condition and after acute stress. Systemic administration and intra-LA infusions of leptin facilitated extinction of conditioned fear responses. The antagonist of NMDA receptor, MK-801, blocked the effect of leptin on fear extinction completely. Furthermore, these effects of leptin on fear extinction were accompanied by a reversal of conditioning-induced synaptic potentiation in the LA. Leptin facilitated NMDA receptor-mediated synaptic transmission, and reversed amygdala long-term potentiation (LTP) in a dose-dependent manner in vitro, and this LTP depotentiation effect was mediated by NMDA receptor and MAPK signaling pathway. CONCLUSIONS: These results identify a key role of leptin in dampening fear conditioning-induced synaptic potentiation in the LA through NMDA receptor and indicate a new strategy for treating anxiety disorders.

SKF83959 produces antidepressant effects in a chronic social defeat stress model of depression through BDNF-TrkB pathway.

BACKGROUND: SKF83959 stimulates the phospholipase Cß/inositol phosphate 3 pathway, resulting in the activation of Ca(2+)/calmodulin-dependent kinase IIα, which affects the synthesis of brain-derived neurotrophic factor, a neurotrophic factor critical for the pathophysiology of depression. Previous reports showed that SKF83959 elicited antidepressant activity in the forced swim test and tail suspension test as a novel triple reuptake inhibitor. However, there are no studies showing the effects of SKF83959 in a chronic stress model of depression and the role of phospholipase C/inositol phosphate 3/calmodulin-dependent kinase IIα/brain-derived neurotrophic factor pathway in SKF83959-mediated antidepressant effects. METHODS: In this study, SKF83959 was firstly investigated in the chronic social defeat stress model of depression. The changes in hippocampal neurogenesis, dendrite spine density, and brain-derived neurotrophic factor signaling pathway after chronic social defeat stress and SKF83959 treatment were then investigated. Pharmacological inhibitors and small interfering RNA/short hairpin RNA methods were further used to explore the antidepressive mechanisms of SKF83959. RESULTS: We found that SKF83959 produced antidepressant effects in the chronic social defeat stress model and also restored the chronic social defeat stress-induced decrease in hippocampal brain-derived neurotrophic factor signaling pathway, dendritic spine density, and neurogenesis. By using various inhibitors and siRNA/shRNA methods, we further demonstrated that the hippocampal dopamine D5 receptor, phospholipase C/inositol phosphate 3/ calmodulin-dependent kinase IIα pathway, and brain-derived neurotrophic factor system are all necessary for the SKF83959 effects. CONCLUSION: These results suggest that SKF83959 can be developed as a novel antidepressant and produces antidepressant effects via the hippocampal D5/ phospholipase C/inositol phosphate 3/calmodulin-dependent kinase IIα/brain-derived neurotrophic factor pathway.

The stability of NR2B in the nucleus accumbens controls behavioral and synaptic adaptations to chronic stress.

BACKGROUND: The nucleus accumbens (NAc) is closely correlated with depression. It has been demonstrated that the glutamatergic system in NAc plays an important role in the reward pathway, dysfunction of which would cause anhedonia, a core symptom of depression. We therefore tested whether N-methyl-D-aspartate receptors and the synaptic plasticity in the NAc are regulated by chronic stress and the relevance to depression. METHODS: We applied behavioral tests (n = 12, each group) of social interaction and sucrose preference tests to identify the susceptibility of mice to chronic social defeat stress. We then tested N-methyl-D-aspartate receptor-long-term depression at cortico-accumbal synapse to determine the relationship between the susceptibility and changes in synaptic plasticity (n = 8, each group). We further investigated whether restoration of these changes could produce antidepressant effects (n = 10). RESULTS: We found that chronic stress induced selective downregulation of N-methyl-D-aspartate receptor NR2B subunits in the confined surface membrane pool of NAc neurons. Remarkably, the loss of synaptic NR2B was a long-lived event and further translated to the significant modulation of synaptic plasticity in the form of long-term depression. We further observed that the stress-induced changes were restored by fluoxetine and that resilient mice-those resistant to chronic stress-showed patterns of molecular regulation in the NAc that overlapped dramatically with those seen with fluoxetine treatment. Behaviorally, restoration of NR2B loss prevented the behavioral sensitization of mice to chronic stress. CONCLUSIONS: Our results identify NR2B in the NAc as a key regulator in the modulation of persistent psychomotor plasticity in response to chronic stress.

Aquaporin-4 deficiency impairs synaptic plasticity and associative fear memory in the lateral amygdala: involvement of downregulation of glutamate transporter-1 expression.

Astrocytes are implicated in information processing, signal transmission, and regulation of synaptic plasticity. Aquaporin-4 (AQP4) is the major water channel in adult brain and is primarily expressed in astrocytes. A growing body of evidence indicates that AQP4 is a potential molecular target for the regulation of astrocytic function. However, little is known about the role of AQP4 in synaptic plasticity in the amygdala. Therefore, we evaluated long-term potentiation (LTP) in the lateral amygdala (LA) and associative fear memory of AQP4 knockout (KO) and wild-type mice. We found that AQP4 deficiency impaired LTP in the thalamo-LA pathway and associative fear memory. Furthermore, AQP4 deficiency significantly downregulated glutamate transporter-1 (GLT-1) expression and selectively increased NMDA receptor (NMDAR)-mediated EPSCs in the LA. However, low concentration of NMDAR antagonist reversed the impairment of LTP in KO mice. Upregulating GLT-1 expression by chronic treatment with ceftriaxone also reversed the impairment of LTP and fear memory in KO mice. These findings imply a role for AQP4 in synaptic plasticity and associative fear memory in the amygdala by regulating GLT-1 expression.