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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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Involvement of hippocampal neurogenesis in mediating the antidepressant-like efficacy of leptin. A. Ablation of hippocampal neurogenesis by X-irradiation. Top panel, timeline of experimental procedures. Bottom-left panel, representative photomicrographs showing BrdU-labeled cells 28 days after X-irradiation or sham exposure. Bottom-right panel, number of BrdU-labeled cells at 28 days after exposure to the sham procedure or X-irradiation. ***P < 0.001. B. Top panel, experimental design. Rats received leptin (1 mg/kg, i.p.) or vehicle injection for 14 consecutive days beginning 28 days after exposure to the sham procedure or X-irradiation. The forced swim test was performed 14 days after the cessation of leptin treatment. Bottom panel, quantitative data showing the effects of X-irradiation and leptin treatment on forced swim behaviors. Data are presented as mean ± SEM (n = 5–6/group). *P < 0.05 compared to the sham-vehicle group, ##P < 0.01 compared to the sham-leptin group. C. Antidepressant-like behavioral effects of leptin treatment. Top panel, experimental design. Rats received leptin (1 mg/kg, i.p.) or vehicle (saline) injection for 14 consecutive days beginning 28 days after exposure to the sham procedure, followed by the forced swim test. Bottom panel, effects of leptin treatment on immobility, swimming and climbing. Data are presented as mean ± SEM (n = 5–6/group). *P < 0.05, **P < 0.01 compared to vehicle-treated controls.
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Figure 3: Involvement of hippocampal neurogenesis in mediating the antidepressant-like efficacy of leptin. A. Ablation of hippocampal neurogenesis by X-irradiation. Top panel, timeline of experimental procedures. Bottom-left panel, representative photomicrographs showing BrdU-labeled cells 28 days after X-irradiation or sham exposure. Bottom-right panel, number of BrdU-labeled cells at 28 days after exposure to the sham procedure or X-irradiation. ***P < 0.001. B. Top panel, experimental design. Rats received leptin (1 mg/kg, i.p.) or vehicle injection for 14 consecutive days beginning 28 days after exposure to the sham procedure or X-irradiation. The forced swim test was performed 14 days after the cessation of leptin treatment. Bottom panel, quantitative data showing the effects of X-irradiation and leptin treatment on forced swim behaviors. Data are presented as mean ± SEM (n = 5–6/group). *P < 0.05 compared to the sham-vehicle group, ##P < 0.01 compared to the sham-leptin group. C. Antidepressant-like behavioral effects of leptin treatment. Top panel, experimental design. Rats received leptin (1 mg/kg, i.p.) or vehicle (saline) injection for 14 consecutive days beginning 28 days after exposure to the sham procedure, followed by the forced swim test. Bottom panel, effects of leptin treatment on immobility, swimming and climbing. Data are presented as mean ± SEM (n = 5–6/group). *P < 0.05, **P < 0.01 compared to vehicle-treated controls.

Mentions: To test the involvement of leptin-induced hippocampal neurogenesis in mediating the antidepressant-like effects of leptin, animals were first exposed to a sham procedure or X-irradiation (10 Gy/day for 2 consecutive days) to induce ablation of hippocampal neurogenesis 81, 82. At 28 days after exposure to the sham procedure or X-irradiation, one set of animals was injected with BrdU to examine the effectiveness of X-irradiation in blocking neurogenesis. As reported in previous studies 81, 82, we found that X-irradiation at this dose greatly reduced BrdU-labeled cells in the dentate gyrus (Figure 3A), which confirmed ablation of 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)

Involvement of hippocampal neurogenesis in mediating the antidepressant-like efficacy of leptin. A. Ablation of hippocampal neurogenesis by X-irradiation. Top panel, timeline of experimental procedures. Bottom-left panel, representative photomicrographs showing BrdU-labeled cells 28 days after X-irradiation or sham exposure. Bottom-right panel, number of BrdU-labeled cells at 28 days after exposure to the sham procedure or X-irradiation. ***P < 0.001. B. Top panel, experimental design. Rats received leptin (1 mg/kg, i.p.) or vehicle injection for 14 consecutive days beginning 28 days after exposure to the sham procedure or X-irradiation. The forced swim test was performed 14 days after the cessation of leptin treatment. Bottom panel, quantitative data showing the effects of X-irradiation and leptin treatment on forced swim behaviors. Data are presented as mean ± SEM (n = 5–6/group). *P < 0.05 compared to the sham-vehicle group, ##P < 0.01 compared to the sham-leptin group. C. Antidepressant-like behavioral effects of leptin treatment. Top panel, experimental design. Rats received leptin (1 mg/kg, i.p.) or vehicle (saline) injection for 14 consecutive days beginning 28 days after exposure to the sham procedure, followed by the forced swim test. Bottom panel, effects of leptin treatment on immobility, swimming and climbing. Data are presented as mean ± SEM (n = 5–6/group). *P < 0.05, **P < 0.01 compared to vehicle-treated controls.
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Related In: Results  -  Collection

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Figure 3: Involvement of hippocampal neurogenesis in mediating the antidepressant-like efficacy of leptin. A. Ablation of hippocampal neurogenesis by X-irradiation. Top panel, timeline of experimental procedures. Bottom-left panel, representative photomicrographs showing BrdU-labeled cells 28 days after X-irradiation or sham exposure. Bottom-right panel, number of BrdU-labeled cells at 28 days after exposure to the sham procedure or X-irradiation. ***P < 0.001. B. Top panel, experimental design. Rats received leptin (1 mg/kg, i.p.) or vehicle injection for 14 consecutive days beginning 28 days after exposure to the sham procedure or X-irradiation. The forced swim test was performed 14 days after the cessation of leptin treatment. Bottom panel, quantitative data showing the effects of X-irradiation and leptin treatment on forced swim behaviors. Data are presented as mean ± SEM (n = 5–6/group). *P < 0.05 compared to the sham-vehicle group, ##P < 0.01 compared to the sham-leptin group. C. Antidepressant-like behavioral effects of leptin treatment. Top panel, experimental design. Rats received leptin (1 mg/kg, i.p.) or vehicle (saline) injection for 14 consecutive days beginning 28 days after exposure to the sham procedure, followed by the forced swim test. Bottom panel, effects of leptin treatment on immobility, swimming and climbing. Data are presented as mean ± SEM (n = 5–6/group). *P < 0.05, **P < 0.01 compared to vehicle-treated controls.
Mentions: To test the involvement of leptin-induced hippocampal neurogenesis in mediating the antidepressant-like effects of leptin, animals were first exposed to a sham procedure or X-irradiation (10 Gy/day for 2 consecutive days) to induce ablation of hippocampal neurogenesis 81, 82. At 28 days after exposure to the sham procedure or X-irradiation, one set of animals was injected with BrdU to examine the effectiveness of X-irradiation in blocking neurogenesis. As reported in previous studies 81, 82, we found that X-irradiation at this dose greatly reduced BrdU-labeled cells in the dentate gyrus (Figure 3A), which confirmed ablation of 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