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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 chronic leptin treatment on cell proliferation and differentiation in the adult hippocampus of rats exposed to chronic unpredictable stress (CUS). A. Timeline of experimental procedures. B. Left panel, quantitative data showing the effects of CUS and leptin treatment on the number of total BrdU-positive cells in the dentate gyrus. Right panel, representative images showing BrdU-positive cells in the dentate gyrus following different treatments. C. Left panel, the number of survived BrdU-labeled cells in the dentate gyrus at 28 days after BrdU labeling. Right panel, percentage of BrdU-positive cells double-labeled for NeuN or GFAP at 28 days after BrdU labeling. D. Confocal images showing colocalization of BrdU with NeuN or GFAP. Scale bars = 10 μm. Con/Veh, handled control rats treated with vehicle (n = 7); CUS/Veh CUS rats treated with vehicle (n = 8); CUS/Lep, CUS rats treated with leptin (n = 5). Data are expressed as mean ± SEM. *P < 0.05 compared to Con/Veh; ##P < 0.01 compared to CUS/Veh; ***P < 0.001 compared to Con/Veh; ##P < 0.01 compared to CUS/Veh; + P = 0.07 compared to CUS/Veh.
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Figure 2: Effect of chronic leptin treatment on cell proliferation and differentiation in the adult hippocampus of rats exposed to chronic unpredictable stress (CUS). A. Timeline of experimental procedures. B. Left panel, quantitative data showing the effects of CUS and leptin treatment on the number of total BrdU-positive cells in the dentate gyrus. Right panel, representative images showing BrdU-positive cells in the dentate gyrus following different treatments. C. Left panel, the number of survived BrdU-labeled cells in the dentate gyrus at 28 days after BrdU labeling. Right panel, percentage of BrdU-positive cells double-labeled for NeuN or GFAP at 28 days after BrdU labeling. D. Confocal images showing colocalization of BrdU with NeuN or GFAP. Scale bars = 10 μm. Con/Veh, handled control rats treated with vehicle (n = 7); CUS/Veh CUS rats treated with vehicle (n = 8); CUS/Lep, CUS rats treated with leptin (n = 5). Data are expressed as mean ± SEM. *P < 0.05 compared to Con/Veh; ##P < 0.01 compared to CUS/Veh; ***P < 0.001 compared to Con/Veh; ##P < 0.01 compared to CUS/Veh; + P = 0.07 compared to CUS/Veh.

Mentions: The effect of leptin on adult hippocampal neurogenesis in CUS rats was assessed by analyzing BrdU labeling (Figure 2A). Cell proliferation was assessed at 2 h after BrdU labeling. ANOVA revealed a main effect of treatment on total number of BrdU-positive cells (F(2,17) = 5.56, P = 0.01). CUS exposure significantly decreased the total number of BrdU-positive cells compared to control (Figure 2B, P < 0.05), and this effect of CUS was significantly reversed by chronic leptin treatment (P < 0.01). The survival of newly proliferated cells in the dentate gyrus was examined 28 days after BrdU administration (Figure 2C). ANOVA indicated a significant effect of treatment on total number of survived BrdU-positive cells (F(2,17) = 17.57, P < 0.0001). The vehicle-treated CUS group exhpibited a significantly lower number of survived BrdU-positive cells than in the vehicle-treated control group (P < 0.01), and CUS-induced decrease in the number of survived BrdU-labeled cells was partially reversed by leptin treatment (P = 0.01) (Figure 2C left panel). The majority of survived BrdU-positive cells exhibited a neuronal phenotype, i.e. co-localizing with NeuN, however, there was no significant effect of treatment on percentage of BrdU-labeled cells that were double-labeled for NeuN (F(2,16) = 1.89, P = 0.184) (Figure 2C right panel and D). A low percentage of survived BrdU-positive cells were co-localized with GFAP (Figure 2C right panel and D). CUS exposure decreased the percentage of BrdU-positive cells differentiated into glia (P < 0.001), and this was reversed by treatment with leptin. Together, this data supports that leptin is capable of reversing the CUS-induced suppression of neurogenesis in the adult hippocampus.


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 chronic leptin treatment on cell proliferation and differentiation in the adult hippocampus of rats exposed to chronic unpredictable stress (CUS). A. Timeline of experimental procedures. B. Left panel, quantitative data showing the effects of CUS and leptin treatment on the number of total BrdU-positive cells in the dentate gyrus. Right panel, representative images showing BrdU-positive cells in the dentate gyrus following different treatments. C. Left panel, the number of survived BrdU-labeled cells in the dentate gyrus at 28 days after BrdU labeling. Right panel, percentage of BrdU-positive cells double-labeled for NeuN or GFAP at 28 days after BrdU labeling. D. Confocal images showing colocalization of BrdU with NeuN or GFAP. Scale bars = 10 μm. Con/Veh, handled control rats treated with vehicle (n = 7); CUS/Veh CUS rats treated with vehicle (n = 8); CUS/Lep, CUS rats treated with leptin (n = 5). Data are expressed as mean ± SEM. *P < 0.05 compared to Con/Veh; ##P < 0.01 compared to CUS/Veh; ***P < 0.001 compared to Con/Veh; ##P < 0.01 compared to CUS/Veh; + P = 0.07 compared to CUS/Veh.
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Related In: Results  -  Collection

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Figure 2: Effect of chronic leptin treatment on cell proliferation and differentiation in the adult hippocampus of rats exposed to chronic unpredictable stress (CUS). A. Timeline of experimental procedures. B. Left panel, quantitative data showing the effects of CUS and leptin treatment on the number of total BrdU-positive cells in the dentate gyrus. Right panel, representative images showing BrdU-positive cells in the dentate gyrus following different treatments. C. Left panel, the number of survived BrdU-labeled cells in the dentate gyrus at 28 days after BrdU labeling. Right panel, percentage of BrdU-positive cells double-labeled for NeuN or GFAP at 28 days after BrdU labeling. D. Confocal images showing colocalization of BrdU with NeuN or GFAP. Scale bars = 10 μm. Con/Veh, handled control rats treated with vehicle (n = 7); CUS/Veh CUS rats treated with vehicle (n = 8); CUS/Lep, CUS rats treated with leptin (n = 5). Data are expressed as mean ± SEM. *P < 0.05 compared to Con/Veh; ##P < 0.01 compared to CUS/Veh; ***P < 0.001 compared to Con/Veh; ##P < 0.01 compared to CUS/Veh; + P = 0.07 compared to CUS/Veh.
Mentions: The effect of leptin on adult hippocampal neurogenesis in CUS rats was assessed by analyzing BrdU labeling (Figure 2A). Cell proliferation was assessed at 2 h after BrdU labeling. ANOVA revealed a main effect of treatment on total number of BrdU-positive cells (F(2,17) = 5.56, P = 0.01). CUS exposure significantly decreased the total number of BrdU-positive cells compared to control (Figure 2B, P < 0.05), and this effect of CUS was significantly reversed by chronic leptin treatment (P < 0.01). The survival of newly proliferated cells in the dentate gyrus was examined 28 days after BrdU administration (Figure 2C). ANOVA indicated a significant effect of treatment on total number of survived BrdU-positive cells (F(2,17) = 17.57, P < 0.0001). The vehicle-treated CUS group exhpibited a significantly lower number of survived BrdU-positive cells than in the vehicle-treated control group (P < 0.01), and CUS-induced decrease in the number of survived BrdU-labeled cells was partially reversed by leptin treatment (P = 0.01) (Figure 2C left panel). The majority of survived BrdU-positive cells exhibited a neuronal phenotype, i.e. co-localizing with NeuN, however, there was no significant effect of treatment on percentage of BrdU-labeled cells that were double-labeled for NeuN (F(2,16) = 1.89, P = 0.184) (Figure 2C right panel and D). A low percentage of survived BrdU-positive cells were co-localized with GFAP (Figure 2C right panel and D). CUS exposure decreased the percentage of BrdU-positive cells differentiated into glia (P < 0.001), and this was reversed by treatment with leptin. Together, this data supports that leptin is capable of reversing the CUS-induced suppression of neurogenesis in the adult hippocampus.

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