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Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms mediating these effects are poorly understood. Here we identify the glucocorticoid receptor (GR) target gene, serum- and glucocorticoid-inducible kinase 1 (SGK1), as one such mechanism. Using a human hippocampal progenitor cell line, we found that a small molecule inhibitor for SGK1, GSK650394, counteracted the cortisol-induced reduction in neurogenesis. Moreover, gene expression and pathway analysis showed that inhibition of the neurogenic Hedgehog pathway by cortisol was SGK1-dependent. SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation. Experiments combining the inhibitor for SGK1, GSK650394, with the GR antagonist, RU486, demonstrated that SGK1 was involved in the cortisol-induced reduction in progenitor proliferation both downstream of GR, by regulating relevant target genes, and upstream of GR, by increasing GR function. Corroborating the relevance of these findings in clinical and rodent settings, we also observed a significant increase of SGK1 mRNA in peripheral blood of drug-free depressed patients, as well as in the hippocampus of rats subjected to either unpredictable chronic mild stress or prenatal stress. Our findings identify SGK1 as a mediator for the effects of cortisol on neurogenesis and GR function, with particular relevance to stress and depression.

Telomerase, the DNA polymerase responsible for maintaining telomere length, has previously been implicated in depression and the response to antidepressant drugs. In this study, we aimed to compare telomerase activity in peripheral blood mononuclear cells between patients with severe depression recruited as part of the KEEP-WELL Trial (Ketamine for Depression Relapse Prevention Following ECT; NCT02414932) and age- and sex-matched healthy volunteers both at baseline/pre-ECT and at follow-up 1 month later for controls or in patients after a course of ECT. We found no differences in telomerase activity between patients with depression (n = 20) compared to healthy controls (n = 33) at baseline/pre-ECT, or between patients treated with ECT compared to controls at follow-up. In patients, telomerase activity was not associated with mood, as assessed by the 24-item Hamilton Rating Scale for Depression, or the duration of the current depressive episode. Additionally, we found no significant relationship between telomerase activity and exposure to recent or childhood adversity in either the patient or control groups. Overall, our results suggest that telomerase activity is not associated with depression, the therapeutic response to ECT, or exposure to adversity.

Major depressive disorder is a chronic debilitating mental illness. Its pathophysiology at cellular and molecular levels is incompletely understood. Increasing evidence supports a pivotal role of the mitogen-activated protein kinase (MAPK), in particular the extracellular signal-regulated kinase (ERK) subclass of MAPKs, in the pathogenesis, symptomatology, and treatment of depression. In humans and various chronic animal models of depression, the ERK signaling was significantly downregulated in the prefrontal cortex and hippocampus, two core areas implicated in depression. Inhibiting the ERK pathway in these areas caused depression-like behavior. A variety of antidepressants produced their behavioral effects in part via normalizing the downregulated ERK activity. In addition to ERK, the brain-derived neurotrophic factor (BDNF), an immediate upstream regulator of ERK, the cAMP response element-binding protein (CREB), a transcription factor downstream to ERK, and the MAPK phosphatase (MKP) are equally vulnerable to depression. While BDNF and CREB were reduced in their activity in the prefrontal cortex and hippocampus of depressed animals, MKP activity was enhanced in parallel. Chronic antidepressant treatment readily reversed these neurochemical changes. Thus, ERK signaling in the depression-implicated brain regions was disrupted during the development of depression, which contributes to the long-lasting and transcription-dependent neuroadaptations critical for enduring depression-like behavior and the therapeutic effect of antidepressants.

Depression alters the structure and function of brain reward circuitry. Preclinical evidence suggests that medium spiny neurons (MSNs) in the nucleus accumbens (NAc) undergo structural plasticity; however, the molecular mechanism and behavioral significance is poorly understood. Here we report that atrophy of D1, but not D2 receptor containing MSNs is strongly associated with social avoidance in mice subject to social defeat stress. D1-MSN atrophy is caused by cell-type specific upregulation of the GTPase RhoA and its effector Rho-kinase. Pharmacologic and genetic reduction of activated RhoA prevents depressive outcomes to stress by preventing loss of D1-MSN dendritic arbor. Pharmacologic and genetic promotion of activated RhoA enhances depressive outcomes by reducing D1-MSN dendritic arbor and is sufficient to promote depressive-like behaviors in the absence of stress. Chronic treatment with Rho-kinase inhibitor Y-27632 after chronic social defeat stress reverses depression-like behaviors by restoring D1-MSN dendritic complexity. Taken together, our data indicate functional roles for RhoA and Rho-kinase in mediating depression-like behaviors via dendritic remodeling of NAc D1-MSNs and may prove a useful target for new depression therapeutics.

Emerging evidence suggests that the enhanced activity of lateral habenula (LHb) is involved in depressive disorders. This abnormal potentiation of LHb neurons was shown to originate from presynaptic alterations; however, the mechanisms underlying this presynaptic enhancement and physiological consequences are yet to be elucidated. Previously, we reported that presynaptic transmission in the LHb is temporally rhythmic, showing greater activity in the afternoon than in the morning. Here, we used a learned helpless rodent model of depression to show that exposure to a stressor or incubation with the stress hormone, corticosterone, abolished the presynaptic temporal variation in the LHb. In addition, selective inhibition of mitogen-activated protein kinase (MAPK) kinase (MAPKK, MEK) activity in the LHb restored the presynaptic alteration even after stress exposure. Moreover, we observed a slight increase in phosphorylated synapsin I after stress exposure. Finally, we found that a blockade of MAPK signaling before stress exposure successfully prevented the depression-like behaviors, including behavioral despair and helplessness, in an acute learned helpless animal model of depression. Our study delineates the cellular and molecular mechanisms responsible for the abnormal presynaptic enhancement of the LHb in depression, which may mediate depressive behaviors.

DICER1 is an enzyme that generates mature microRNAs (miRNAs), which regulate gene expression post-transcriptionally in brain and other tissues and is involved in synaptic maturation and plasticity. Here, through genome-wide differential gene expression survey of post-traumatic stress disorder (PTSD) with comorbid depression (PTSD&Dep), we find that blood DICER1 expression is significantly reduced in cases versus controls, and replicate this in two independent cohorts. Our follow-up studies find that lower blood DICER1 expression is significantly associated with increased amygdala activation to fearful stimuli, a neural correlate for PTSD. Additionally, a genetic variant in the 3′ un-translated region of DICER1 , rs10144436, is significantly associated with DICER1 expression and with PTSD&Dep, and the latter is replicated in an independent cohort. Furthermore, genome-wide differential expression survey of miRNAs in blood in PTSD&Dep reveals miRNAs to be significantly downregulated in cases versus controls. Together, our novel data suggest DICER1 plays a role in molecular mechanisms of PTSD&Dep through the DICER1 and the miRNA regulation pathway. DICER1 is required for the maturation of miRNAs which regulate expression of thousands of genes. Here the authors show significantly reduced levels of DICER1 in individuals having post-traumatic stress disorder and comorbid depression suggestive of a role in the molecular mechanism of the condition.

Current antidepressants in clinical use always take weeks or even months to exert full therapeutic effects, and sometimes have serious side effects. Thus, it is very necessary to develop novel antidepressants with better efficacy and fewer adverse effects. The present study focused on investigating the antidepressant potential of matrine and its possible mechanisms of action. The forced swim test, tail suspension test, and chronic unpredictable mild stress model of depression were used to reveal the antidepressant-like effects of matrine on mice. Western blotting, immunohistochemistry, and lentivirus were further used together to explore the antidepressant mechanism of matrine. It was found that matrine exhibited significant antidepressant actions in the forced swim test and tail suspension test without affecting the locomotor activity of mice. Chronic matrine administration fully reversed the chronic unpredictable mild stress-induced depressive-like symptoms in forced swim test, tail suspension test, and sucrose preference test. After that, western blotting analysis revealed that chronic matrine treatment restored the decreasing effects of chronic unpredictable mild stress on the PI3K/Akt/mammalian target of rapamycin signaling in hippocampus, but not prefrontal cortex. Furthermore, pharmacological and genetic blockade of the PI3K/Akt/mammalian target of rapamycin signaling in hippocampus abolished the antidepressant actions of matrine on mice. Taken together, matrine produces antidepressant-like effects on mice via promoting the hippocampal PI3K/Akt/ mammalian target of rapamycin signaling.

Abstract INTRODUCTION: Patients with tuberculosis (TB) may have depression as a comorbidity, which may be associated with poor treatment outcomes. Increased production of pro-inflammatory cytokines activating enzyme indoleamine 2,3-dioxygenase (IDO) has been reported in TB. We studied the association of IDO activity and comorbid depression in TB patients. MATERIALS AND METHODS: Newly diagnosed, treatment-naïve TB patients were evaluated for symptoms of depression using the Patient Health Questionnaire (PHQ)-9 scale. A PHQ-9 score of ≥5 was taken as an indicator for depression. Patients were further categorized into two groups based on their PHQ-9 scores, Group-I with a PHQ-9 score of <5 and Group-II with a PHQ-9 score ≥5. The serum kynurenine (KYN) and tryptophan (TRP) levels were determined using liquid chromatography-mass spectrometry (LC-MS) and the KYN/TRP ratio was taken as a measure for IDO activity. RESULTS: A total of 106 TB patients and 106 healthy controls were enrolled in this study. Over 73.5% of TB patients had PHQ-9 scores of above 5 with an average score of 7.09 ± 2.83, a significant difference (P < 0.05) as compared to the average PHQ-9 scores of healthy controls (2.93 ± 1.20). Group-II TB patients had lower serum TRP 539.55 ± 194.31 ng/mL versus 1109.45 ± 186.04 ng/mL (P < 0.01) in Group-I; higher serum KYN 425.81 ± 65.51 ng/mL versus 250.06 ± 40.28 ng/mL (P < 0.01) and higher K/T ratio 0.906 ± 0.56 versus 0.251 ± 0.052 (P < 0.01). There was a significant linear correlation between PHQ-9 and serum KYN (r: 0.969; P: <0.01; R2: 0.909); serum TRP (r: 0.841; P: <0.01; R2: 0.745); and KYN/TRP ratio (r: 0.745; P < 0.01; R2: 0.618). CONCLUSION: These findings suggest that in TB patients, induction of IDO activity may be relevant to the development of comorbid depression.

Gene expression changes that occur in the brains of people with depression could lead to the development of new therapies. Now, Ronald Duman and his colleagues report that the phosphatase Mkp-1 is upregulated in the postmortem hippocampus of individuals with depression, and altering the expression of this protein in rats and mice can regulate depressive behaviors and their resistance to stress. The lifetime prevalence (∼16%) 1 and the economic burden ($100 billion annually) 2 , 3 associated with major depressive disorder (MDD) make it one of the most common and debilitating neurobiological illnesses. To date, the exact cellular and molecular mechanisms underlying the pathophysiology of MDD have not been identified. Here we use whole-genome expression profiling of postmortem tissue and show significantly increased expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1, encoded by DUSP1 , but hereafter called MKP-1 ) in the hippocampal subfields of subjects with MDD compared to matched controls. MKP-1, also known as dual-specificity phosphatase-1 (DUSP1), is a member of a family of proteins that dephosphorylate both threonine and tyrosine residues and thereby serves as a key negative regulator of the MAPK cascade 4 , a major signaling pathway involved in neuronal plasticity, function and survival 5 , 6 . We tested the role of altered MKP-1 expression in rat and mouse models of depression and found that increased hippocampal MKP-1 expression, as a result of stress or viral-mediated gene transfer, causes depressive behaviors. Conversely, chronic antidepressant treatment normalizes stress-induced MKP-1 expression and behavior, and mice lacking MKP-1 are resilient to stress. These postmortem and preclinical studies identify MKP-1 as a key factor in MDD pathophysiology and as a new target for therapeutic interventions.

Major depressive disorder (MDD) results from repeated and constant exposure to stress over prolonged periods. The highly variable response to stress and the low heritability suggests that MDD has a strong epigenetic basis. Studies show global dysregulation of histone modifications in both susceptible and resilient animals after chronic stress suggesting involvement of epigenetics in stress response in the brain. Given that the hippocampus and dentate gyrus (DG) show epigenetic changes in neurogenesis in Rodent models of stress that is known to be highly affected in MDD, we hypothesized that epigenetic changes might be involved in the advent of depressive phenotype during the progressive stress paradigm. To study the stress progression into the depression-like phenotype at the molecular level, we designed a novel progressive social defeat stress (PSDS) paradigm based on the popular chronic social defeat stress (CSDS) paradigm but involving only 5 days of defeat stress. Our molecular studies revealed consistent downregulation of H3K9me2 marks in the hippocampus and DG after the 4th day of stress while H3K27me2 showed an early upregulation in the hippocampus and a late downregulation after the 5th day of stress in the DG. In parallel, an early increase in phf8 and phf2 in hippocampus and DG, respectively, was observed. These findings of variable changes like repressive histone methylation marks and expression of corresponding demethylase genes after different durations of defeat stress, led to better understanding of the important role epigenetics play in stress progression into depression at molecular level in establishing resilient and susceptible phenotypes.