Possible Involvement of the IL-6/JAK2/STAT3 Pathway in the Hypothalamus in Depressive-Like Behavior of Rats Exposed to Chronic Mild Stress.

INTRODUCTION: The interleukin-6/janus kinase 2/signal transducer and activator of transcription 3 (IL-6/JAK2/STAT3) pathway plays an important role in immune function, but little research has focused on this pathway in depression. We sought to examine the relationship between the IL-6/JAK2/STAT3 pathway and depressive-like behavior. METHODS: Using a chronic mild stress (CMS) paradigm, a total of 36 adult male Sprague-Dawley rats were divided into four matched groups: (1) control + vehicle, (2) CMS + vehicle, (3) control + paroxetine, and (4) CMS + paroxetine. We investigated the effects of CMS on depressive-like behavior by using the forced swimming test (FST). Subsequently, the mRNA levels of members of the IL-6/JAK2/STAT3 pathway were assessed by qRT-PCR. RESULTS: We found that rats exposed to CMS displayed a significant increase in immobility time and a decrease in climbing time in the FST. Moreover, mRNA levels of IL-6, JAK2, and STAT3 in the hypothalamus were increased following CMS. We also found that mRNA levels of IL-6, JAK2, and STAT3 were normalized by paroxetine administration, which coincided with normalization of the depressive-like behavior. CONCLUSIONS: The IL-6/JAK2/STAT3 pathway may be activated in depression, and targeting this pathway may provide a novel effective therapeutic approach for the treatment of depression.

Fecal microbiota transplantation from chronic unpredictable mild stress mice donors affects anxiety-like and depression-like behavior in recipient mice via the gut microbiota-inflammation-brain axis.

Recent studies have demonstrated that there are significant changes in the gut microbiota (GM) of humans with depression and animal models of depression and chronic stress. In our present study, we determined whether an alteration in GM is a decisive factor in anxiety-like and depression-like behavior and its impact on brain neurochemistry. An antibiotic cocktail was used to deplete the GM of mice before they were colonized, via fecal microbiota transplantation (FMT), by the GM of control mice or mice that had been exposed to chronic unpredictable mild stress (CUMS donors). The CUMS-donor group of mice and the mice that were colonized by their microbiota (the CUMS-recipient group) both showed higher levels of anxiety- and depression-like behavior compared to the controls. The GM community of the CUMS-donor and CUMS-recipient was distinctively different from the controls, with the CUMS group characterized by a lower relative abundance of Lactobacillus and a higher relative abundance of Akkermansia. Interestingly, FMT affected both behavior and neuroinflammation. Mice given the CUMS microbiota had significant elevations of interferon-γ (IFN-γ) and the tumor necrosis factor-alpha (TNF-α) in the hippocampus, which were accompanied by upregulated indoleamine 2,3-dioxygenase 1 (IDO1) in the hippocampus. These results suggest that GM modulates pro-inflammatory cytokines in the hippocampus through dysfunctional microbiota-gut-brain axis, exacerbating anxiety- and depression-like phenotypes. Key Points Chronic unpredictable mild stress increased anxiety- and depression-like behavior in mice. Mice colonized with gut microbiota (GM) from stressed mice showed similar behaviors. The GM composition of the donor and recipient mice was also comparable. Their relative pattern of two bacteria has been tied to neuroinflammatory activity. The results suggest a link between GM, brain function, and anxiety and depression.

Oral Probiotics Ameliorate the Behavioral Deficits Induced by Chronic Mild Stress in Mice via the Gut Microbiota-Inflammation Axis.

In recent years, a burgeoning body of research has revealed links between depression and the gut microbiota, leading to the therapeutic use of probiotics for stress-related disorders. In this study, we explored the potential antidepressant efficacy of a multi-strain probiotics treatment (Lactobacillus helveticus R0052, Lactobacillus plantarum R1012, and Bifidobacterium longum R0175) in a chronic mild stress (CMS) mouse model of depression and determined its probable mechanism of action. Our findings revealed that mice subjected to CMS exhibited anxiety- and depressive-like behaviors in the sucrose preference test, elevated plus maze, and forced swim test, along with increased interferon-γ, tumor necrosis factor-α, and indoleamine 2,3-dioxygenase-1 levels in the hippocampus. Moreover, the microbiota distinctly changed from the non-stress group and was characterized by highly diverse bacterial communities associated with significant reductions in Lactobacillus species. Probiotics attenuated CMS-induced anxiety- and depressive-like behaviors, significantly increased Lactobacillus abundance, and reversed the CMS-induced immune changes in the hippocampus. Thus, the possible mechanism involved in the antidepressant-like activity of probiotics is correlated with Lactobacillus species via the gut microbiota-inflammation-brain axis.

Alpha7 nAChR Agonists for Cognitive Deficit and Negative Symptoms in Schizophrenia: A Meta-analysis of Randomized Double-blind Controlled Trials.

BACKGROUND: Previous clinical trials of α7-nicotinic acetylcholine receptor agonists (α7-nAChR agonists) showed mixed results in treating the cognitive and negative symptoms of schizophrenia. AIMS: To assess the efficacy and safety of α7-nAChR agonists in treating the cognitive and negative symptoms in schizophrenia. METHODS: A literature search was conducted to identify randomized double-blind placebo-controlled trials for schizophrenia published before May 26, 2017, by searching PubMed, Embase, ClinicalTrials.gov, the Cochrane Library and the Chinese language databases CNKI, Wanfang, and VIP Data. The effects of α7-nAChR agonists were evaluated for overall cognitive function and negative symptoms by calculating standard mean difference (SMDs) between active drugs and placebo added to antipsychotics. RESULTS: 8 studies with low bias were included. We found no statistically significant effects of α7 nAChR agonists on the overall cognitive function (SMD=-0.10[-0.46, 0.25], I2 =88%) and negative symptoms (SMD=0.13 [-0.04, 0.30], I2 =64%) in patients with schizophrenia. Sensitivity analysis showed these results to be firm. And this drug is generally safe and well tolerated with no significant difference from placebo based on adverse events (RR=1.02, [0.85, 1.23]) and dropouts (RR=1.04, [0.61, 1.78]) data. Evidence based on outcomes from the meta-analysis was rated as 'moderate' as per the GRADE guidelines. CONCLUSION: α7-nAChR agonists may not be effective in reversing overall cognitive impairments and negative symptoms in patients with schizophrenia as adjunctive therapies.

Adolescent escitalopram prevents the effects of maternal separation on depression- and anxiety-like behaviours and regulates the levels of inflammatory cytokines in adult male mice.

There is little research on the effects of adolescent administration of antidepressants on behavioural function and inflammation in early-life stressed adult mice. Using maternal separation (MS), a paradigm of early adversity, we investigated the effects of adolescent (PND 33-54) escitalopram (ES; 10mg/kg) exposure on depression- and anxiety-like behaviours and the levels of inflammatory cytokines (interleukin [IL]-1ß, tumor necrosis factor [TNF]-α, and IL-10) in the ventral hippocampus (HPV), prefrontal cortex (PFC), and serum in adult (PND 61) male offspring mice. The results showed that MS has no effect on locomotor activity, but increased depression-like behaviours in the saccharin preference test and increased anxiety-like behaviours in the social preference and elevated plus maze tests. MS increased the levels of IL-1ß in the HPV, PFC, and serum, while decreasing the level of IL-10 in the HPV. Furthermore, adolescent ES treatment inhibited these depression- and anxiety-like behaviours, decreased the levels of IL-1ß, and increased the level of IL-10 in the HPV. The results also showed that there are no effects of chronic escitalopram administration on normal behaviour in control mice. Taken together, the current data provide experimental evidence that MS increases depression and anxiety levels in adult male offspring. Additionally, the findings support the idea that early pharmacological intervention with ES may be an effective treatment for reducing the behavioral abnormalities induced by early adversity and regulating the underlying inflammatory mechanisms involved.

Sex-specific effects of prenatal chronic mild stress on adult spatial learning capacity and regional glutamate receptor expression profiles.

Both animal experiments and clinical studies have demonstrated that prenatal stress can cause cognitive disorders in offspring. To explore the scope of these deficits and identify potential underlying mechanisms, we examined the spatial learning and memory performance and glutamate receptor (GluR) expression patterns of adult rats exposed to prenatal chronic mild stress (PCMS). Principal component analysis (PCA) was employed to reveal the interrelationships among spatial learning indices and GluR expression changes. Female PCMS-exposed offspring exhibited markedly impaired spatial learning and memory in the Morris water maze (MWM) task compared to control females, while PCMS-exposed males showed better initial spatial learning in the MWM compared to control males. PCMS also altered basal and post-MWM glutamate receptor expression patterns, but these effects differed markedly between sexes. Male PCMS-exposed offspring exhibited elevated basal expression of NR1, mGluR5, and mGluR2/3 in the prefrontal cortex (PFC), whereas females showed no basal expression changes. Following MWM training, PCMS-exposed males expressed higher NR1 in the PFC and mammillary body (MB), higher mGluR2/3 in PFC, and lower NR2B in the hippocampus (HIP), PFC, and MB compared to unstressed MWM-trained males. Female PCMS-exposed offspring showed strongly reduced NR1 in MB and NR2B in the HIP, PFC, and MB, and increased mGluR2/3 in PFC compared to unstressed MWM-trained females. This is the first report suggesting that NMDA subunits in the MB are involved in spatial learning. Additionally, PCA further suggests that the NR1-NR2B form is the most important for spatial memory formation. These results reveal long-term sex-specific effects of PCMS on spatial learning and memory performance in adulthood and implicate GluR expression changes within HIP, PFC, and MB as possible molecular mechanisms underlying cognitive dysfunction in offspring exposed to prenatal stress.

Duloxetine prevents the effects of prenatal stress on depressive-like and anxiety-like behavior and hippocampal expression of pro-inflammatory cytokines in adult male offspring rats.

Stress during pregnancy may cause neurodevelopmental and psychiatric disorders. However, the mechanisms are largely unknown. Currently, pro-inflammatory cytokines have been identified as a risk factor for depression and anxiety disorder. Unfortunately, there is very little research on the long-term effects of prenatal stress on the neuroinflammatory system of offspring. Moreover, the relationship between antidepressant treatment and cytokines in the central nervous system, especially in the hippocampus, an important emotion modulation center, is unclear. Therefore, the aim of this study was to determine the effects of prenatal chronic mild stress during development on affective-like behaviors and hippocampal cytokines in adult offspring, and to verify whether antidepressant (duloxetine) administration from early adulthood could prevent the harmful consequences. To do so, prenatally stressed and non-stressed Sprague-Dawley rats were treated with either duloxetine (10mg/kg/day) or vehicle from postnatal day 60 for 21days. Adult offspring were divided into four groups: 1) prenatal stress+duloxetine treatment, 2) prenatal stress+vehicle, 3) duloxetine treatment alone, and 4) vehicle alone. Adult offspring were assessed for anxiety-like behavior using the open field test and depression-like behavior using the forced swim test. Brains were analyzed for pro-inflammatory cytokine markers in the hippocampus via real-time PCR. Results demonstrate that prenatal stress-induced anxiety- and depression-like behaviors are associated with an increase in hippocampal inflammatory mediators, and duloxetine administration prevents the increased hippocampal pro-inflammatory cytokine interleukin-6 and anxiety- and depression-like behavior in prenatally stressed adult offspring. This research provides important evidence on the long-term effect of PNS exposure during development in a model of maternal adversity to study the pathogenesis of depression and its therapeutic interventions.