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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 JC, Guo M, Zhang W, Lu XY - Mol. Psychiatry (2011)

Bottom Line: Stress and glucocorticoid stress hormones inhibit neurogenesis, whereas antidepressants increase neurogenesis and block stress-induced decrease in neurogenesis.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.Leptin treatment reversed the GR agonist dexamethasone (DEX)-induced reduction of proliferation of cultured neural stem/progenitor cells from adult hippocampus.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.

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-3β (GSK-3β) and β-catenin. While DEX decreased Ser9 phosphorylation and increased Tyr216 phosphorylation of GSK-3β, leptin increased Ser9 phosphorylation and attenuated the effects of DEX at both Ser9 and Tyr216 phosphorylation sites of GSK-3β. Moreover, leptin increased total level and nuclear translocation of β-catenin, a primary substrate of GSK-3β and a key regulator in controlling hippocampal neural progenitor cell proliferation, and reversed the inhibitory effects of DEX on β-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-3β/β-catenin signaling pathway.

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Effect of leptin on dexamethasone-induced suppression of adult hippocampal neural stem/progenitor cell proliferation. A. Colocalization of LepRb mRNA and GR protein in nestin-positive cells in the dentate gyrus of adult hippocampus. Left image, LepRb mRNA in situ hybridization (green); middle image, GR immunostaining (red); right image, nestin immunostaining (blue). White arrows indicate triple-labeled cells for LepRb, GR and nestin. Scale bars = 10 μm. GCL, granular layer; SGZ, subgranular zone. B. Top panel, immunohistochemical staining showing the expression of GR (red) in nestin (blue)-positive hippocampal neural stem/progenitor cells in cultures. Bottom panel, colocalization of LepRb mRNA (green) and GR (red) in nestin (blue) positive cells. C. Adult hippocampal neural stem/progenitor cells were treated with 10 μM dexamethasone (DEX), 1 nM leptin, or a combination of DEX (10 μM) and various doses of leptin (0.1, 1.0 or 3.0 nM). BrdU (10 μM) was added to label proliferating cells and was detected by immunohistochemistry. Top panel, quantitative data demonstrating the effects of leptin and DEX on the number of BrdU-labeled cells. Bottom panel, representative images showing BrdU-labeled cells under different treatment conditions. Data are presented as mean ± SEM. **P < 0.01 compared to vehicle treatment; ++P < 0.01 compared to the DEX treatment.
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Figure 4: Effect of leptin on dexamethasone-induced suppression of adult hippocampal neural stem/progenitor cell proliferation. A. Colocalization of LepRb mRNA and GR protein in nestin-positive cells in the dentate gyrus of adult hippocampus. Left image, LepRb mRNA in situ hybridization (green); middle image, GR immunostaining (red); right image, nestin immunostaining (blue). White arrows indicate triple-labeled cells for LepRb, GR and nestin. Scale bars = 10 μm. GCL, granular layer; SGZ, subgranular zone. B. Top panel, immunohistochemical staining showing the expression of GR (red) in nestin (blue)-positive hippocampal neural stem/progenitor cells in cultures. Bottom panel, colocalization of LepRb mRNA (green) and GR (red) in nestin (blue) positive cells. C. Adult hippocampal neural stem/progenitor cells were treated with 10 μM dexamethasone (DEX), 1 nM leptin, or a combination of DEX (10 μM) and various doses of leptin (0.1, 1.0 or 3.0 nM). BrdU (10 μM) was added to label proliferating cells and was detected by immunohistochemistry. Top panel, quantitative data demonstrating the effects of leptin and DEX on the number of BrdU-labeled cells. Bottom panel, representative images showing BrdU-labeled cells under different treatment conditions. Data are presented as mean ± SEM. **P < 0.01 compared to vehicle treatment; ++P < 0.01 compared to the DEX treatment.

Mentions: Stress-induced glucocorticoid surge activates GR, which is believed to mediate the suppressive effects of stress on neurogenesis 89. Both GR and LepRb have been reported to be expressed in the dentate gyrus 90, 91. To determine whether these two receptors coexist in neural progenitor cells, we employed a triple-labeling detection method to demonstrate the colocalization of LepRb, GR and nestin, a marker of undifferentiated neural stem/progenitor cells, in the dentate gyrus. As shown in Figure 4A, LepRb and GR were distributed in the entire dentate gyrus, whereas nestin-positive cells were restricted to the subgranular zone. Colocalization of LepRb and GR was observed in nestin-positive cells in the subgranular zone of the dentate gyrus (Figure 4A). In vitro studies demonstrated that GR was expressed in almost all nestin-positive cells (Figure 4B). The co-existence of LepRb, GR and nestin were confirmed in cultured hippocampal neural stem/progenitor cells (Figure 4B). These observations provide the biological basis for a possible mechanism by which leptin antagonizes the effect of glucocorticoid stress hormones on hippocampal neurogenesis.


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 JC, Guo M, Zhang W, Lu XY - Mol. Psychiatry (2011)

Effect of leptin on dexamethasone-induced suppression of adult hippocampal neural stem/progenitor cell proliferation. A. Colocalization of LepRb mRNA and GR protein in nestin-positive cells in the dentate gyrus of adult hippocampus. Left image, LepRb mRNA in situ hybridization (green); middle image, GR immunostaining (red); right image, nestin immunostaining (blue). White arrows indicate triple-labeled cells for LepRb, GR and nestin. Scale bars = 10 μm. GCL, granular layer; SGZ, subgranular zone. B. Top panel, immunohistochemical staining showing the expression of GR (red) in nestin (blue)-positive hippocampal neural stem/progenitor cells in cultures. Bottom panel, colocalization of LepRb mRNA (green) and GR (red) in nestin (blue) positive cells. C. Adult hippocampal neural stem/progenitor cells were treated with 10 μM dexamethasone (DEX), 1 nM leptin, or a combination of DEX (10 μM) and various doses of leptin (0.1, 1.0 or 3.0 nM). BrdU (10 μM) was added to label proliferating cells and was detected by immunohistochemistry. Top panel, quantitative data demonstrating the effects of leptin and DEX on the number of BrdU-labeled cells. Bottom panel, representative images showing BrdU-labeled cells under different treatment conditions. Data are presented as mean ± SEM. **P < 0.01 compared to vehicle treatment; ++P < 0.01 compared to the DEX treatment.
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Related In: Results  -  Collection

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Figure 4: Effect of leptin on dexamethasone-induced suppression of adult hippocampal neural stem/progenitor cell proliferation. A. Colocalization of LepRb mRNA and GR protein in nestin-positive cells in the dentate gyrus of adult hippocampus. Left image, LepRb mRNA in situ hybridization (green); middle image, GR immunostaining (red); right image, nestin immunostaining (blue). White arrows indicate triple-labeled cells for LepRb, GR and nestin. Scale bars = 10 μm. GCL, granular layer; SGZ, subgranular zone. B. Top panel, immunohistochemical staining showing the expression of GR (red) in nestin (blue)-positive hippocampal neural stem/progenitor cells in cultures. Bottom panel, colocalization of LepRb mRNA (green) and GR (red) in nestin (blue) positive cells. C. Adult hippocampal neural stem/progenitor cells were treated with 10 μM dexamethasone (DEX), 1 nM leptin, or a combination of DEX (10 μM) and various doses of leptin (0.1, 1.0 or 3.0 nM). BrdU (10 μM) was added to label proliferating cells and was detected by immunohistochemistry. Top panel, quantitative data demonstrating the effects of leptin and DEX on the number of BrdU-labeled cells. Bottom panel, representative images showing BrdU-labeled cells under different treatment conditions. Data are presented as mean ± SEM. **P < 0.01 compared to vehicle treatment; ++P < 0.01 compared to the DEX treatment.
Mentions: Stress-induced glucocorticoid surge activates GR, which is believed to mediate the suppressive effects of stress on neurogenesis 89. Both GR and LepRb have been reported to be expressed in the dentate gyrus 90, 91. To determine whether these two receptors coexist in neural progenitor cells, we employed a triple-labeling detection method to demonstrate the colocalization of LepRb, GR and nestin, a marker of undifferentiated neural stem/progenitor cells, in the dentate gyrus. As shown in Figure 4A, LepRb and GR were distributed in the entire dentate gyrus, whereas nestin-positive cells were restricted to the subgranular zone. Colocalization of LepRb and GR was observed in nestin-positive cells in the subgranular zone of the dentate gyrus (Figure 4A). In vitro studies demonstrated that GR was expressed in almost all nestin-positive cells (Figure 4B). The co-existence of LepRb, GR and nestin were confirmed in cultured hippocampal neural stem/progenitor cells (Figure 4B). These observations provide the biological basis for a possible mechanism by which leptin antagonizes the effect of glucocorticoid stress hormones on hippocampal neurogenesis.

Bottom Line: Stress and glucocorticoid stress hormones inhibit neurogenesis, whereas antidepressants increase neurogenesis and block stress-induced decrease in neurogenesis.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.Leptin treatment reversed the GR agonist dexamethasone (DEX)-induced reduction of proliferation of cultured neural stem/progenitor cells from adult hippocampus.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.

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-3β (GSK-3β) and β-catenin. While DEX decreased Ser9 phosphorylation and increased Tyr216 phosphorylation of GSK-3β, leptin increased Ser9 phosphorylation and attenuated the effects of DEX at both Ser9 and Tyr216 phosphorylation sites of GSK-3β. Moreover, leptin increased total level and nuclear translocation of β-catenin, a primary substrate of GSK-3β and a key regulator in controlling hippocampal neural progenitor cell proliferation, and reversed the inhibitory effects of DEX on β-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-3β/β-catenin signaling pathway.

Show MeSH
Related in: MedlinePlus