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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 chronic unpredictable stress (CUS)-induced depression-like behaviors. A. Schematic representation of the experimental procedure for CUS and treatments in rats. CUS rats were exposed to one stressor per day for 21 days, and then received 14 days of leptin or vehicle injections during which CUS continued. B. Open field test. Exploratory activity (total distance traveled and movement velocity) and freezing time were evaluated for a 5 min test session. C. Sucrose preference test. Sucrose preference is expressed as a ratio of sucrose solution: water intake measured within the 12 h dark cycle. D. Forced swim test. Time spent for immobility, swimming and climbing was scored for a 5 min test session. E. Body weight was measured before and after leptin treatment. The arrow indicates the beginning of leptin or vehicle administration. Results are expressed as mean ± SEM (n = 5–8 per group). **P < 0.01, ***P < 0.001, compared to handling control group.
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Figure 1: Effect of chronic leptin treatment on chronic unpredictable stress (CUS)-induced depression-like behaviors. A. Schematic representation of the experimental procedure for CUS and treatments in rats. CUS rats were exposed to one stressor per day for 21 days, and then received 14 days of leptin or vehicle injections during which CUS continued. B. Open field test. Exploratory activity (total distance traveled and movement velocity) and freezing time were evaluated for a 5 min test session. C. Sucrose preference test. Sucrose preference is expressed as a ratio of sucrose solution: water intake measured within the 12 h dark cycle. D. Forced swim test. Time spent for immobility, swimming and climbing was scored for a 5 min test session. E. Body weight was measured before and after leptin treatment. The arrow indicates the beginning of leptin or vehicle administration. Results are expressed as mean ± SEM (n = 5–8 per group). **P < 0.01, ***P < 0.001, compared to handling control group.

Mentions: Using the CUS model established above, the effects of leptin on the stress-induced suppression of adult hippocampal neurogenesis and behavioral deficits were examined. Rats were first exposed to the CUS procedure for 21 days followed by 14 days of leptin treatment (1 mg/kg) or vehicle daily, during which CUS exposure continued (Supplementary Table 1) (Figure 1A). For behavioral tests, ANOVA indicated there were significant differences among three treatments in their effect on open field behaviors: Exploratory activity (F(2,17) = 20.11, P < 0.001), moving velocity (F(2,17) = 7.89, P < 0.005) and freezing time (F(2,17) = 7.88, P < 0.005). Post hoc tests revealed vehicle-treated CUS rats exhibited a significant decrease in exploration (P < 0.0001) and moving velocity (P < 0.0001) and an increase in freezing (P < 0.0001) compared to the vehicle-treated control rats, but leptin treatment had no significant effect on any open field measure (P > 0.5) (Figure 1B). ANOVA showed a main effect of treatment on sucrose preference (F(2, 13) = 7.19, P < 0.01). Post hoc tests indicated that vehicle-treated CUS rats had a significantly lower preference for sucrose solution than the vehicle-treated control rats (P < 0.05), and leptin treatment reversed the CUS-induced decrease in sucrose preference (P = 0.01) (Figure 1C). In the forced swim test, ANOVA revealed main effects of treatment on immobility (F(2, 26) = 8.78, P = 0.001), swimming (F(2, 26) = 10.74, P < 0.0005) and climbing (F(2, 26) = 4.01, P < 0.05). Post hoc tests demonstrated leptin treatment significantly decreased immobility time (P < 0.001) and increased swimming activity in CUS rats (P < 0.0001) (Figure 1D). Reversal of CUS-induced ‘behavioral despair’ and ’anhedonia’ by chronic leptin treatment confirmed the antidepressant potential of leptin. In addition, the effects of CUS and leptin on body weight were monitored (Figure 1E). ANOVA with repeated measures indicated that the CUS exposure significantly decreased body weight gain prior to leptin or vehicle treatment (F(2,46)= 8.789, P < 0.0001). After rats received leptin or vehicle administration, ANOVA showed a main effect of treatment on body weight gain (F(2, 170) = 7.90, P < 0.005). Post hoc tests revealed a significant decrease in body weight gain in vehicle-treated CUS rats compared to vehicle-treated control rats. Leptin treatment further decreased body weight gain in CUS rats compared to vehicle treatment (P < 0.01).


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 chronic unpredictable stress (CUS)-induced depression-like behaviors. A. Schematic representation of the experimental procedure for CUS and treatments in rats. CUS rats were exposed to one stressor per day for 21 days, and then received 14 days of leptin or vehicle injections during which CUS continued. B. Open field test. Exploratory activity (total distance traveled and movement velocity) and freezing time were evaluated for a 5 min test session. C. Sucrose preference test. Sucrose preference is expressed as a ratio of sucrose solution: water intake measured within the 12 h dark cycle. D. Forced swim test. Time spent for immobility, swimming and climbing was scored for a 5 min test session. E. Body weight was measured before and after leptin treatment. The arrow indicates the beginning of leptin or vehicle administration. Results are expressed as mean ± SEM (n = 5–8 per group). **P < 0.01, ***P < 0.001, compared to handling control group.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3368076&req=5

Figure 1: Effect of chronic leptin treatment on chronic unpredictable stress (CUS)-induced depression-like behaviors. A. Schematic representation of the experimental procedure for CUS and treatments in rats. CUS rats were exposed to one stressor per day for 21 days, and then received 14 days of leptin or vehicle injections during which CUS continued. B. Open field test. Exploratory activity (total distance traveled and movement velocity) and freezing time were evaluated for a 5 min test session. C. Sucrose preference test. Sucrose preference is expressed as a ratio of sucrose solution: water intake measured within the 12 h dark cycle. D. Forced swim test. Time spent for immobility, swimming and climbing was scored for a 5 min test session. E. Body weight was measured before and after leptin treatment. The arrow indicates the beginning of leptin or vehicle administration. Results are expressed as mean ± SEM (n = 5–8 per group). **P < 0.01, ***P < 0.001, compared to handling control group.
Mentions: Using the CUS model established above, the effects of leptin on the stress-induced suppression of adult hippocampal neurogenesis and behavioral deficits were examined. Rats were first exposed to the CUS procedure for 21 days followed by 14 days of leptin treatment (1 mg/kg) or vehicle daily, during which CUS exposure continued (Supplementary Table 1) (Figure 1A). For behavioral tests, ANOVA indicated there were significant differences among three treatments in their effect on open field behaviors: Exploratory activity (F(2,17) = 20.11, P < 0.001), moving velocity (F(2,17) = 7.89, P < 0.005) and freezing time (F(2,17) = 7.88, P < 0.005). Post hoc tests revealed vehicle-treated CUS rats exhibited a significant decrease in exploration (P < 0.0001) and moving velocity (P < 0.0001) and an increase in freezing (P < 0.0001) compared to the vehicle-treated control rats, but leptin treatment had no significant effect on any open field measure (P > 0.5) (Figure 1B). ANOVA showed a main effect of treatment on sucrose preference (F(2, 13) = 7.19, P < 0.01). Post hoc tests indicated that vehicle-treated CUS rats had a significantly lower preference for sucrose solution than the vehicle-treated control rats (P < 0.05), and leptin treatment reversed the CUS-induced decrease in sucrose preference (P = 0.01) (Figure 1C). In the forced swim test, ANOVA revealed main effects of treatment on immobility (F(2, 26) = 8.78, P = 0.001), swimming (F(2, 26) = 10.74, P < 0.0005) and climbing (F(2, 26) = 4.01, P < 0.05). Post hoc tests demonstrated leptin treatment significantly decreased immobility time (P < 0.001) and increased swimming activity in CUS rats (P < 0.0001) (Figure 1D). Reversal of CUS-induced ‘behavioral despair’ and ’anhedonia’ by chronic leptin treatment confirmed the antidepressant potential of leptin. In addition, the effects of CUS and leptin on body weight were monitored (Figure 1E). ANOVA with repeated measures indicated that the CUS exposure significantly decreased body weight gain prior to leptin or vehicle treatment (F(2,46)= 8.789, P < 0.0001). After rats received leptin or vehicle administration, ANOVA showed a main effect of treatment on body weight gain (F(2, 170) = 7.90, P < 0.005). Post hoc tests revealed a significant decrease in body weight gain in vehicle-treated CUS rats compared to vehicle-treated control rats. Leptin treatment further decreased body weight gain in CUS rats compared to vehicle treatment (P < 0.01).

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