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Studies of germ-free (GF) mice demonstrate that gut microbiota can influence behaviour by modulating neurochemical pathways in the brain, and that bacterial colonization normalizes behavioural deficits in GF-mice. Since disrupted GABAergic and glutamatergic signaling are reported in mood disorders, this study investigated the effect of gut microbiota manipulations on EIB-relevant gene expression in the brain.
GF Swiss-Webster mice were colonized with E. coli JM83, complex microbiota (specific-pathogen-free; SPF), or no microbiota, and compared with controls (n=6/group). 21 synaptic genes representing GABAergic, glutamatergic, BDNF, and astrocytic functions were measured in the hippocampus, amygdala, and prefrontal cortex using quantitative PCR. Gene co-expression analysis was used to identify gene modules related to colonization status, and compared by permutation analysis. Gene expression profiles were compared to existing post-mortem cohorts of depressed subjects (n=28 cases vs 28 controls).
Region-specific alterations in gene expression were observed in GF-mice compared to controls. 58% of all genes (14/24) altered in GF-mice were normalized following SPF-colonization. GF-mice displayed disorganization of gene co-expression networks in all three brain regions (hippocampus, p=0.0003; amygdala, p=0.0012; mPFC, p=0.0069), which was restored by SPF colonization in hippocampus (p v.s. GF=0.0003, p v.s. control=0.60). The hippocampal gene expression profile in GF-mice was significantly correlated with that in human depression (ρ=0.51, p=0.027), and this correlation was not observed after colonization.
Together, we show that the absence of gut microbiota disrupts the expression of EIB-relevant genes in mice, and colonization restores EIB-relevant expression, in ways that are relevant to human depression.
Together, we show that the absence of gut microbiota disrupts the expression of EIB-relevant genes in mice, and colonization restores EIB-relevant expression, in ways that are relevant to human depression.Prior work has established bivariate associations between suicidal thoughts and behaviors, trauma exposure and sleep disturbance broadly. Specifically, this study tested whether fear of sleep and sleep quality mediated the association between trauma exposure and suicide attempt. Participants (N = 100) were adolescents admitted to an inpatient psychiatric program for suicidality. Trauma exposure history was retrieved from admission notes and participants completed self-report surveys assessing sleep quality, fear of sleep and number of suicide attempts within the previous month. Structural equation modelling was used to investigate the relationships between childhood trauma, fear of sleep, sleep quality, and suicide attempt. Path analysis was used to investigate the indirect effects from trauma exposure to suicide attempt through fear of sleep, and sleep quality. Path analysis revealed a significant indirect effect from trauma exposure to suicide attempt through fear of sleep and sleep quality. Our findings suggest that a significant portion of the association between trauma exposure and suicide attempts in adolescence may be explained by the negative impact of trauma exposure on sleep. Fear of sleep may increase the risk of a suicide attempt by negatively impacting sleep quality. Future studies should investigate whether interventions targeting sleep and fear of sleep reduce the association between trauma and suicide attempt.Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine and promotes neurogenesis and neuroprotection in brains. ISO-1 MIF inhibitor In addition, MIF has been identified as a potential marker of schizophrenia (SCZ). Our recent study also showed that serum MIF level is higher in SCZ and positively correlated with antipsychotic doses, and that MIF promoter polymorphisms are associated with SCZ. Here, we investigated the effects of antipsychotics such as clozapine on MIF expression in primary cultured astrocytes derived from neonatal mouse forebrain. MIF mRNA expression was estimated with quantitative reverse-transcription polymerase chain reaction. MIF protein concentration was measured with enzyme-linked immunosorbent assay. The histone acetylation of MIF promoter was examined with chromatin immunoprecipitation assay. As a result, common antipsychotics, especially clozapine, increased MIF mRNA expression in a dose-dependent manner. Clozapine increased MIF mRNA expression and protein concentration in a time-dependent manner. Moreover, clozapine increased the acetylation of histone H3 at lysine 27 residues (H3K27) in MIF promoter. In conclusion, we provide novel evidence that antipsychotics such as clozapine increases MIF expression via the acetylation of H3K27 in astrocytes, and that MIF may have a potential role for astrocytes in the action mechanisms of antipsychotics.Drug use disorders (DUD) are associated with psychiatric illness and increased risks of suicide. We examined health care utilization prior to suicide in adults with DUD, which may reveal opportunities to prevent suicide in this high-risk population. A national cohort study was conducted of all 6,947,191 adults in Sweden, including 166,682 (2.4%) with DUD, who were followed up for suicide during 2002-2015. A nested case-control design examined health care utilization among persons with DUD who died by suicide and 101 age- and sex-matched controls from the general population. In 86.7 million person-years of follow-up, 15,662 (0.2%) persons died by suicide, including 1946 (1.2%) persons with DUD. Unadjusted and adjusted relative risks of suicide associated with DUD were 11.03 (95% CI, 10.62-11.46) and 2.84 (2.68-3.00), respectively. 30.4% and 52.3% of DUD cases who died by suicide had a health care encounter within 2 weeks or 3 months before the index date, respectively, compared with 5.9% and 24.3% of controls (unadjusted prevalence ratio and difference, less then 2 weeks 5.20 [95% CI, 4.76-5.67] and 24.6 percentage points [22.5-26.6]; less then 3 months 2.15 [2.05-2.26] and 27.9 [25.6-30.2]). However, after adjusting for psychiatric comorbidities, these differences were much attenuated. Among DUD cases, 72.5% of last encounters within 2 weeks before suicide were in outpatient clinics, mostly for non-psychiatric diagnoses. In this large national cohort, suicide among adults with DUD was often shortly preceded by outpatient clinic encounters. Clinical encounters in these settings are important opportunities to identify suicidality and intervene accordingly in patients with DUD.