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Updated: Oct 2, 2025
Chemogenetic Regulation in Reprogrammed Stem Cell-derived Precursor Cells in Treating Neurodegenerative Diseases
Published on: May 2, 2025
Cannabidiol prevents depressive-like behaviors through the modulation of neural stem cell differentiation
Ming Hou1, Suji Wang1, Dandan Yu1
1State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China.
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.
Insights
Chronic stress negatively impacts neural stem cell differentiation and neurogenesis in the hippocampus. Cannabidiol (CBD) treatment reversed these effects and depressive symptoms by modulating the FoxO signaling pathway.
Area of Science:
- Neuroscience
- Stem Cell Biology
- Pharmacology
Background:
- Chronic stress impairs adult hippocampal neurogenesis (AHN), a process crucial for stress resilience and depression treatment.
- Radial neural stem cells (rNSCs) in the hippocampus are affected by stress, differentiating into astrocytes.
- Cannabidiol (CBD), a nonpsychoactive phytocannabinoid, shows antidepressant potential, but its effect on neurogenesis is unclear.
Purpose of the Study:
- To investigate the impact of chronic stress on hippocampal rNSC differentiation.
- To explore the role of the FoxO signaling pathway in stress-induced neurogenesis changes.
- To determine if CBD can modulate rNSC differentiation and AHN and elucidate its antidepressive mechanisms.
Main Methods:
- Utilized a chronic restraint stress (CRS) mouse model.
- Performed transcriptome analysis to identify key regulatory pathways.
- Administered CBD to CRS mice and assessed depressive-like behaviors and hippocampal rNSC differentiation.
Main Results:
- Under stress, hippocampal rNSCs predominantly differentiated into astrocytes.
- Transcriptome analysis implicated the FoxO signaling pathway in this process.
- CBD administration alleviated depressive-like symptoms in CRS mice, preventing excessive rNSC differentiation into astrocytes, partly via FoxO pathway modulation.
Conclusions:
- Chronic stress promotes hippocampal rNSC differentiation into astrocytes, contributing to depression.
- CBD exerts antidepressive effects by modulating the FoxO signaling pathway and normalizing rNSC differentiation and AHN.
- This study reveals a novel neural mechanism underlying depression and the therapeutic action of CBD.
