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Oxytocin enhances oligodendrocyte development and improves social deficits in autistic rats
Min Wen1,2,3,4, Shuang Zheng1,2,4, Hongbo Luo5
1State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Medical University, Guiyang, Guizhou, China.
Insights
Oxytocin treatment improved social behaviors and reduced anxiety in a rat model of autism spectrum disorder (ASD). This therapeutic effect is linked to oxytocin promoting oligodendrocyte development via the PI3K/AKT pathway.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Autism spectrum disorder (ASD) is a complex neurodevelopmental condition influenced by genetic and environmental factors.
- In utero exposure to environmental stressors, such as valproic acid (VPA), is increasingly linked to ASD pathogenesis.
- Investigating therapeutic interventions for ASD is crucial for improving patient outcomes.
Purpose of the Study:
- To evaluate the therapeutic potential of oxytocin in a VPA-induced rat model of ASD.
- To elucidate the molecular mechanisms underlying oxytocin's effects in this model.
- To assess oxytocin's impact on social behaviors, stereotyped behaviors, and anxiety.
Main Methods:
- A rat model of ASD was generated by exposing pregnant rats to VPA.
- VPA-exposed offspring received daily intranasal oxytocin treatment from postnatal day 21 to 42.
- Behavioral assessments and amygdala RNA sequencing were performed, followed by bioinformatics analysis, transmission electron microscopy, and qPCR.
Main Results:
- Oxytocin administration significantly improved social deficits, reduced repetitive behaviors, and decreased anxiety-like responses in VPA-exposed rats.
- Transcriptomic analysis revealed suppressed oligodendrocyte development and differentiation in the VPA group, associated with the PI3K/AKT pathway.
- Oxytocin treatment promoted oligodendrocyte development and differentiation, improving myelination deficits.
Conclusions:
- Oxytocin demonstrates significant therapeutic potential for ASD, particularly in improving social interaction deficits.
- The mechanism involves oxytocin's activation of the PI3K/AKT pathway, promoting oligodendrocyte development and differentiation.
- Findings highlight oxytocin as a promising therapeutic agent for ASD, addressing underlying neurodevelopmental abnormalities.
Purpose:
Autism spectrum disorder (ASD) is a neurodevelopmental condition with complex etiological factors, including genetic predisposition and environmental influences. In particular, exposure to environmental stressors in utero has increasingly been implicated in disrupting fetal neurodevelopment and potentially contributing to the pathogenesis of ASD in offspring. The aim of this study was to investigate the therapeutic potential of oxytocin and to elucidate its underlying molecular mechanisms in a valproic acid (VPA) exposure-induced rat model of ASD.
Methods:
To generate the ASD offspring model, pregnant rats received intraperitoneal injections of VPA on embryonic day 12.5 (E12.5). A control group was administered saline instead. Only male offspring were included in subsequent experiments. On postnatal day 21 (P21), VPA-exposed offspring were randomly divided into: (1) VPA group (ASD model) and (2) VPA+OT (oxytocin inhaled daily, 400 ug/kg, P21-42) group. Behavioral assessments (social behaviors, stereotyped behaviors, anxiety-like behaviors) and amygdala RNA sequencing were compared across control group, VPA group, and VPA+OT group. Both threshold and threshold-free bioinformatics analysis methods were employed to identify the potential therapeutic mechanisms of oxytocin. The findings were further validated using transmission electron microscopy and qPCR.
Results:
Intranasal oxytocin administration significantly ameliorated social deficits, repetitive behaviors, and anxiety-like responses in ASD model rats. Transcriptomic profiling revealed substantial neurodevelopmental abnormalities in VPA group. Consistent results from GSEA enrichment analysis, dynamic gene expression pattern analysis and WGCNA showed significant suppression of oligodendrocyte development and differentiation in the VPA group. Pathway analysis indicated that this functional inhibition was associated with the PI3K/AKT signaling pathway. Oxytocin may promote oligodendrocyte development and differentiation by activating the PI3K/AKT pathway, thereby ameliorating social deficits. Further validation by transmission electron microscopy and qPCR confirmed that oxytocin treatment improved myelination deficits in the ASD rat model.
Conclusions:
Our findings demonstrate that oxytocin significantly improve social interaction deficits in the VPA-induced autism model, which may be related to its activation of the PI3K/AKT pathway to promote oligodendrocyte development and differentiation.
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