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Leptin restores adult hippocampal neurogenesis in a chronic unpredictable stress model of depression and reverses glucocorticoid-induced inhibition of GSK-3?/?-catenin signaling.

ABSTRACT: Stress and glucocorticoid stress hormones inhibit neurogenesis, whereas antidepressants increase neurogenesis and block stress-induced decrease in neurogenesis. Our previous studies have shown that leptin, an adipocyte-derived hormone with antidepressant-like properties, promotes baseline neurogenesis in the adult hippocampus. This study aimed to determine whether leptin is able to restore suppression of neurogenesis in a rat chronic unpredictable stress (CUS) model of depression. Chronic treatment with leptin reversed the CUS-induced reduction of hippocampal neurogenesis and depression-like behaviors. Leptin treatment elicited a delayed long-lasting antidepressant-like effect in the forced swim behavioral despair test, and this effect was blocked by ablation of neurogenesis with X-irradiation. The functional isoform of the leptin receptor, LepRb, and the glucocorticoid receptor (GR) were colocalized in hippocampal neural stem/progenitor cells in vivo and in vitro. Leptin treatment reversed the GR agonist dexamethasone (DEX)-induced reduction of proliferation of cultured neural stem/progenitor cells from adult hippocampus. Further mechanistic analysis revealed that leptin and DEX converged on glycogen synthase kinase-3? (GSK-3?) and ?-catenin. While DEX decreased Ser9 phosphorylation and increased Tyr216 phosphorylation of GSK-3?, leptin increased Ser9 phosphorylation and attenuated the effects of DEX at both Ser9 and Tyr216 phosphorylation sites of GSK-3?. Moreover, leptin increased total level and nuclear translocation of ?-catenin, a primary substrate of GSK-3? and a key regulator in controlling hippocampal neural progenitor cell proliferation, and reversed the inhibitory effects of DEX on ?-catenin. Taken together, our results suggest that adult neurogenesis is involved in the delayed long-lasting antidepressant-like behavioral effects of leptin, and leptin treatment counteracts chronic stress and glucocorticoid-induced suppression of hippocampal neurogenesis via activating the GSK-3?/?-catenin signaling pathway.

SUBMITTER: Garza JC

PROVIDER: S-EPMC3368076 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Leptin restores adult hippocampal neurogenesis in a chronic unpredictable stress model of depression and reverses glucocorticoid-induced inhibition of GSK-3β/β-catenin signaling.

Garza J C JC Guo M M Zhang W W Lu X-Y XY

Molecular psychiatry 20111220 8

Stress and glucocorticoid stress hormones inhibit neurogenesis, whereas antidepressants increase neurogenesis and block stress-induced decrease in neurogenesis. Our previous studies have shown that leptin, an adipocyte-derived hormone with antidepressant-like properties, promotes baseline neurogenesis in the adult hippocampus. This study aimed to determine whether leptin is able to restore suppression of neurogenesis in a rat chronic unpredictable stress (CUS) model of depression. Chronic treatm ...[more]

PMID: 22182938

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Project description:Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. We, therefore, investigated the molecular signaling pathways mediating the effects of cortisol on proliferation, neuronal differentiation, and astrogliogenesis, in an immortalized human hippocampal progenitor cell line. In addition, we examined the molecular signaling pathways activated in the hippocampus of prenatally stressed rats, characterized by persistently elevated glucocorticoid levels in adulthood. In human hippocampal progenitor cells, we found that low concentrations of cortisol (100 nM) increased proliferation (+16%), decreased neurogenesis into microtubule-associated protein 2 (MAP2)-positive neurons (-24%) and doublecortin (Dcx)-positive neuroblasts (-21%), and increased differentiation into S100?-positive astrocytes (+23%). These effects were dependent on the mineralocorticoid receptor (MR) as they were abolished by the MR antagonist, spironolactone, and mimicked by the MR-agonist, aldosterone. In contrast, high concentrations of cortisol (100 ?M) decreased proliferation (-17%) and neuronal differentiation into MAP2-positive neurons (-22%) and into Dcx-positive neuroblasts (-27%), without regulating astrogliogenesis. These effects were dependent on the glucocorticoid receptor (GR), blocked by the GR antagonist RU486, and mimicked by the GR-agonist, dexamethasone. Gene expression microarray and pathway analysis showed that the low concentration of cortisol enhances Notch/Hes-signaling, the high concentration inhibits TGF?-SMAD2/3-signaling, and both concentrations inhibit Hedgehog signaling. Mechanistically, we show that reduced Hedgehog signaling indeed critically contributes to the cortisol-induced reduction in neuronal differentiation. Accordingly, TGF?-SMAD2/3 and Hedgehog signaling were also inhibited in the hippocampus of adult prenatally stressed rats with high glucocorticoid levels. In conclusion, our data demonstrate novel molecular signaling pathways that are regulated by glucocorticoids in vitro, in human hippocampal progenitor cells, and by stress in vivo, in the rat hippocampus.

Project description:The depression-like behavior phenotype, neurogenesis in the dentate gyrus and miR-124 expression in the hippocampus are the focus of current research on the pathogenesis of depression and antidepressant therapy. The present study aimed to clarify the dynamic changes of depression-like behavior, dentate gyrus neurogenesis and hippocampal miR-124 expression during depression induced by chronic stress to reveal pathological features at different stages of depression and to further provide insight into depression treatment. Chronic unpredictable mild stress depression models were established by exposing Sprague-Dawley rats to various mild stressors, including white noise, thermal swimming, stroboscopic illumination, soiled cages, pairing with three other stressed animals, cold swimming, tail pinch, restraint and water and food deprivation. Chronic unpredictable mild stress model rats underwent dynamic observation from 1 to 8 weeks and were compared with a control group (normal feeding without any stressors). To observe changes in the depression-like behavior phenotype during chronic unpredictable mild stress-induced depression, a sucrose preference test was used to evaluate the degree of anhedonia. An open-field test was used to evaluate locomotor activity and anxiety status. Compared with the control group, chronic unpredictable mild stress rats lost weight but did not have a depression-like behavioral phenotype at 1-4 weeks. Chronic unpredictable mild stress rats presented decreased sucrose preference and locomotor activity at 5-8 weeks. In addition, chronic unpredictable mild stress rats did not have significant anxiety-like behavior during 1-8 weeks of modeling. To observe neurogenesis dysfunctions and changes in neuronal number in the dentate gyrus during chronic unpredictable mild stress-induced depression, markers (DCX and DCX/BrdU) of neural proliferation and differentiation and the neuronal marker NeuN were assessed by immunofluorescence. Compared with the control group, neurogenesis and the neuronal number in the dentate gyrus did not change from 2 to 6 weeks; however, neural proliferation and differentiation in the dentate gyrus decreased, and the number of neurons decreased until the eighth week in the chronic unpredictable mild stress group. Real-time quantitative reverse transcription polymerase chain reaction assays and fluorescence in situ hybridization were used to measure the expression of hippocampal miR-124 during chronic unpredictable mild stress-induced depression. The results showed that the expression of hippocampal miR-124 was unchanged during the first 4 weeks but increased from 5 to 6 weeks and decreased from 7 to 8 weeks compared with the control group. These findings indicate that during chronic unpredictable mild stress-induced depression, the behavioral phenotype, miR-124 expression in the hippocampus, neurogenesis in the dentate gyrus and neuronal numbers showed dynamic changes, which suggested that various pathological changes occur at different stages of depression. All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Guangzhou University of Chinese Medicine of China in March 2015.

Dataset Information

Leptin restores adult hippocampal neurogenesis in a chronic unpredictable stress model of depression and reverses glucocorticoid-induced inhibition of GSK-3?/?-catenin signaling.

Publications

Leptin restores adult hippocampal neurogenesis in a chronic unpredictable stress model of depression and reverses glucocorticoid-induced inhibition of GSK-3β/β-catenin signaling.

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