The oval bed nucleus of the stria terminalis endocannabinoid signaling constrains post-traumatic stress disorder-like behaviors.

Zuo H.; Li J.; Li J.; Zhang X.; Zhang B. · Journal of advanced research · 2026

**Background & Methods** This review examined endocannabinoid (eCB) signaling in the oval bed nucleus of the stria terminalis (ovBNST) and its role in PTSD-like behaviors using a modified 5-day chronic social defeat stress (CSDS) paradigm in animal models. The multimodal experimental approach included in vivo fiber photometry, molecular analyses, optogenetic manipulation, pharmacological intervention, genetic perturbation, and behavioral assays to interrogate neuronal activity and modulate eCB signaling dynamics. **Key Findings** • Chronic social defeat stress reduced cannabinoid type-1 receptor (CB1R) protein levels in the ovBNST and decreased posterior basolateral amygdala (pBLA) Cnr1 mRNA expression, resulting in heightened ovBNST excitability and diminished presynaptic inhibition of glutamate release from pBLA-ovBNST terminals. • Pharmacological inhibition of 2-arachidonoylglycerol (2-AG) degradation in the ovBNST and optogenetic activation of CB1Rs in pBLA-ovBNST projections both reversed CSDS-induced social avoidance and anxiety-like behaviors, demonstrating the therapeutic potential of enhancing eCB signaling. • Genetic suppression of 2-AG synthesis exacerbated PTSD-like phenotypes, confirming that endocannabinoid signaling within this circuit is critical for promoting resilience against stress-induced pathology and that restoration of eCB homeostasis may represent a viable therapeutic strategy for PTSD. **Dosage & Administration** Not reported. **Safety & Adverse Effects** Not reported. **Evidence Quality** As a review article published in 2026, this work synthesizes preclinical animal research using rodent models of social defeat stress. The findings are based on controlled laboratory experiments with sophisticated neuroscientific techniques but lack direct clinical evidence in human PTSD populations. Key limitations include the translational gap from animal models to human pathophysiology, reliance on behavioral proxies for PTSD symptoms, and the need for pharmacokinetic and safety data in human subjects before clinical application. The evidence represents a mechanistic advance in understanding eCB signaling in PTSD-like states rather than clinical-grade evidence. Future work should validate these findings in human neuroimaging studies and conduct clinical trials of eCB-enhancing therapies.

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