Abstract
Chronic cerebral hypoperfusion (CCH) is a primary contributor to cognitive decline in the elderly. Enriched environment (EE) is proved to improve cognitive function. However, mechanisms involved remain unclear. The purpose of the study was exploring the mechanisms of EE in alleviating cognitive deficit in rats with CCH. To create a rat model of CCH, 2-vessel occlusion (2-VO) surgery was performed. All rats lived in standard or enriched environments for 4 weeks. Cognitive function was assessed using the novel object recognition test and Morris water maze test. The protein levels of glutamatergic synapses, neurotoxic reactive astrocytes, reactive microglia, and JAK2-STAT3 signaling pathway were measured using Western blot. The mRNA levels of synaptic regulatory factors, C1q, TNF-α, and IL-1α were identified using quantitative PCR. Immunofluorescence was used to detect glutamatergic synapses, neurotoxic reactive astrocytes, and reactive microglia, as well as the expression of p-STAT3 in astrocytes in the hippocampus. The results demonstrated that the EE mitigated cognitive impairment in rats with CCH and enhanced glutamatergic synaptogenesis. EE also inhibited the activation of neurotoxic reactive astrocytes. Moreover, EE downregulated microglial activation, levels of C1q, TNF-α and IL-1α and phosphorylation of JAK2 and STAT3. Our results suggest that inhibition of neurotoxic reactive astrocytes may be one of the mechanisms by which EE promotes glutamatergic synaptogenesis and improves cognitive function in rats with CCH. The downregulation of reactive microglia and JAK2-STAT3 signaling pathway may be involved in this process.
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The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Abbreviations
- CCH:
-
Chronic cerebral hypoperfusion
- VD:
-
Vascular dementia
- 2-VO:
-
2-vessel occlusion
- C1q:
-
Complement component 1q
- TNF-α:
-
Tumor necrosis factor alpha
- IL-1α:
-
Interleukin 1 alpha
- Gpc4:
-
Glypicans 4
- Gpc6:
-
Glypicans 6
- Thbs1:
-
Thrombospondin 1
- Thbs2:
-
Thrombospondin 2
- Sparc:
-
Secreted protein acidic enriched in cysteine
- EE:
-
Enriched environment
- JAK2:
-
Janus kinase 2
- STAT3:
-
Signal transducer and activator of transcription 3
- NOR:
-
Novel object recognition
- MWM:
-
Morris water maze
- RT-qPCR:
-
Real time-quantitative polymerase chain reaction
- SDS-PAGE:
-
Sodium dodecyl sulfate-polyacrylamide gel
- ECL:
-
Enhanced chemiluminescence
- PSD95:
-
Postsynaptic density protein 95
- VGLUT1:
-
Vesicular glutamate transporter 1
- C3:
-
Complement protein 3
- GFAP:
-
Glial fibrillary acidic protein
- Iba1:
-
Ionized calcium binding adaptor molecule 1
- GAPDH:
-
Glyceraldehyde-3-phosphate dehydrogenase
- ANOVA:
-
Analysis of variance
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Acknowledgements
The authors thank all the teachers and colleagues from Wuhan University and the Department of Neurorehabilitation, Zhongnan Hospital of Wuhan University.
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This work was supported by grants from the National Natural Science Foundation of China (No.82102670).
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Bin Fan: conceptualization, methodology, investigation, visualization, writing - original draft. Junbin Lin: conceptualization, Investigation, Data Curation, Formal analysis. Qihang Luo: investigation, visualization. Weijing Liao: resources; supervision, writing - review & editing. Chizi Hao: funding acquisition, validation, writing - review & editing. All authors have read and approved the final manuscript.
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Fan, B., Lin, J., Luo, Q. et al. Enriched Environment Inhibits Neurotoxic Reactive Astrocytes via JAK2-STAT3 to Promote Glutamatergic Synaptogenesis and Cognitive Improvement in Chronic Cerebral Hypoperfusion Rats. Neurotox Res 42, 22 (2024). https://doi.org/10.1007/s12640-024-00704-4
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DOI: https://doi.org/10.1007/s12640-024-00704-4