Cannabidiol prevents depressive-like behaviors through the modulation of neural stem cell differentiation

doi:10.1007/s11684-021-0896-8

Front. Med.

2022, Vol. 16

Issue (2) : 227-239 https://doi.org/10.1007/s11684-021-0896-8

RESEARCH ARTICLE

Cannabidiol prevents depressive-like behaviors through the modulation of neural stem cell differentiation

Ming Hou¹, Suji Wang¹, Dandan Yu¹, Xinyi Lu¹, Xiansen Zhao¹, Zhangpeng Chen^1,^2,³(

), Chao Yan^1,^2,^3,⁴(

)

¹. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China
². Institute of Artificial Intelligence Biomedicine, Nanjing University, Nanjing 210023, China
³. Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing 210023, China
⁴. Engineering Research Center of Protein and Peptide Medicine, Ministry of Education, Nanjing 210023, China

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Abstract

Chronic stress impairs radial neural stem cell (rNSC) differentiation and adult hippocampal neurogenesis (AHN), whereas promoting AHN can increase stress resilience against depression. Therefore, investigating the mechanism of neural differentiation and AHN is of great importance for developing antidepressant drugs. The nonpsychoactive phytocannabinoid cannabidiol (CBD) has been shown to be effective against depression. However, whether CBD can modulate rNSC differentiation and hippocampal neurogenesis is unknown. Here, by using the chronic restraint stress (CRS) mouse model, we showed that hippocampal rNSCs mostly differentiated into astrocytes under stress conditions. Moreover, transcriptome analysis revealed that the FoxO signaling pathway was involved in the regulation of this process. The administration of CBD rescued depressive-like symptoms in CRS mice and prevented rNSCs overactivation and differentiation into astrocyte, which was partly mediated by the modulation of the FoxO signaling pathway. These results revealed a previously unknown neural mechanism for neural differentiation and AHN in depression and provided mechanistic insights into the antidepressive effects of CBD.

Keywords cannabidiol depression radial neural stem cells neurogenesis

Corresponding Author(s): Zhangpeng Chen,Chao Yan

About author:

Mingsheng Sun and Mingxiao Yang contributed equally to this work.

Just Accepted Date: 16 September 2021 Online First Date: 22 February 2022 Issue Date: 26 April 2022

Cite this article:

Ming Hou,Suji Wang,Dandan Yu, et al. Cannabidiol prevents depressive-like behaviors through the modulation of neural stem cell differentiation[J]. Front. Med., 2022, 16(2): 227-239.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0896-8
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I2/227

Fig.1 CRS caused depressive-like behaviors and increased proliferation in the hippocampal DG. (A) Schematic of the experimental design. C57BL/6 mice were subjected to restraint stress for 3 h every day for 3 weeks then to behavioral tests. (B) Percentage of preference for sucrose solution in the SPT (n = 8). (C) Comparison of total water consumption between the control and CRS group in the SPT experiment. (D) Immobility time in the FST (n = 8). (E) Serum corticosterone levels in the control and CRS groups (n = 6). (F) Representative confocal microscopy images showing Ki-67-labeled cells in the DG of mice. White arrowheads mark proliferating cells. Scale bar= 50 µm. (G) Quantification of Ki-67-labeled cells (n = 5). *P<0.05, **P<0.01. n.s., no significant difference.

Fig.2 CRS caused abnormal neurogenesis in the hippocampal DG. (A,C) Representative confocal images of nestin-labeled cells in the DG after CRS (A) and the corresponding quantification results (C, n = 6). Scale bar= 100 µm. (B,D) Representative confocal images showing GCL thickness in the DG after CRS (B) and the corresponding quantification results, which were measured as the distance between the hilus and molecular layer (D, n = 5). Scale bar= 50 µm. (E,G) Representative confocal images showing DCX-labeled cells in the DG after CRS (E) and the corresponding quantification results (G, n = 5). Scale bar= 50 µm. (F,H) Representative confocal images showing GFAP-labeled cells in the DG after CRS (F) and the corresponding quantification results (H, n = 5). Scale bar= 50 µm. (I) Transcriptome heatmap analysis showing the differential expression of genes in the control group versus that in the CRS group. (J,K) KEGG pathway enrichment analysis showing the involvement of the FoxO signaling pathway in CRS-induced stress. (L,M) Difference in the expression levels of CDKN1A and SGK1 in the control group versus those in the CRS group. *P<0.05, **P<0.01. n.s., no significant difference.

Fig.3 CBD treatment improved depressive-like behaviors in CRS mice. (A) Schematic of the experimental design and timeline of CBD administration, CRS stimulus, and behavioral tests. (B–D) Percentage of preference for sucrose solution in the SPT (B), total water consumption (C), and immobility time in the FST (D) in the control, CRS, and CBD treatment (5 mg/kg or 10 mg/kg) groups (n = 12–15). (E) Serum corticosterone levels in the control, CRS, and CBD treatment (5 mg/kg or 10 mg/kg) groups (n = 7–8). (F,H) Locomotor distance in the OFT (F), time spent in the open arm in the EPM (G), and representative EPM behavioral trace (H) in the control, CRS, and CBD treatment (5 mg/kg or 10 mg/kg) groups (n = 12–15). (I,J) Representative confocal images showing Ki-67-labeled cells in the DG after CRS (I) and the corresponding quantification results (J, n = 5). Scale bar= 50 µm. *P<0.05, **P<0.01, ***P<0.001. n.s., no significant difference.

Fig.4 CBD treatment prevented abnormal neurogenesis in CRS mice. (A) Representative confocal microscopy images showing nestin-, DCX-, NeuN-, and GFAP-labeled cells in DG in the control, CRS, and CBD treatment (5 mg/kg or 10 mg/kg) groups. Scale bar= 50 µm. (B–E) Quantification of the number of nestin-, DCX-, NeuN-, and GFAP-labeled cells in the control, CRS, and CRS+ CBD groups (n = 5). *P<0.05, **P<0.01. n.s., no significant difference.

Fig.5 CBD treatment affected the differentiation fate of neural stem cells in CRS mice. (A) Schematic of the experimental design and timeline of BrdU administration, CBD administration, and CRS stimulation. (B,D) Representative confocal images showing BrdU-labeled and BrdU/NeuN-colabeled cells in the DG in the control, CRS, and CBD treatment (5 mg/kg or 10 mg/kg) groups (B) and the corresponding quantification results (D, n = 5). Scale bar= 50 µm. (C,E) Representative confocal images showing BrdU-labeled and BrdU/GFAP-colabeled cells in the DG in the control, CRS, and CBD treatment (5 mg/kg or 10 mg/kg) groups (C) and the corresponding quantification results (E, n = 5). Scale bar= 50 µm. *P<0.05, **P<0.01. n.s., no significant difference.

Fig.6 FoxO signaling pathway is involved in the antidepressive effect of CBD in vitro and in vivo. (A) Transcriptome heatmap analysis of genes that were differentially expressed between the CRS alone group versus the 10 mg/kg CBD treatment group. (B,C) KEGG pathway enrichment analysis showing the trends and details of the FoxO signaling pathway in the CRS alone group versus those in the 10 mg/kg CBD treatment group. (D,E) Difference in the expression levels of CDKN1A and SGK1 in the CRS alone group versus those in the 10 mg/kg CBD treatment group. (F,G) Effects of CBD treatment on the mRNA levels of CDKN1A and SGK1 in CRS mice were analyzed by using RT-PCR. (H) Effect of corticosterone (30 μmol/L), CBD (10 μmol/L), and wortmannin (20 μmol/L) on the growth of NE-4C neural stem cells. Cell viability was measured by MTT after treatment with corticosterone, CBD, and wortmannin either alone or in combination. (I,J) Effect of corticosterone, CBD, and wortmannin treatment on the proteins of the FoxO signaling pathway. mTOR and FOXO3A protein levels were analyzed by using Western blot analysis. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. n.s., no significant difference

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