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

INTRODUCTION

Post-traumatic stress disorder (PTSD) develops when acute threat responses fail to resolve, resulting in persistent anxiety, avoidance, and hyperarousal. However, the specific neural circuits and molecular mechanisms governing the transition from acute stress to enduring pathology remain incompletely understood. Objectives This study aimed to determine whether endocannabinoid (eCB) signaling within posterior basolateral amygdala (pBLA) to oval bed nucleus of the stria terminalis (ovBNST) projections constrains the maladaptive transition from social threat to PTSD-like anxiety and defensive states.

METHODS

Using a modified 5-day chronic social defeat stress (CSDS) paradigm, we employed a multimodal experimental strategy that included in vivo fiber photometry, molecular analyses, optogenetic manipulation, pharmacological intervention, and genetic perturbation to interrogate neuronal activity and modulate eCB signaling dynamics in the ovBNST, followed by stress-related behavioral assays. Genetic suppression of 2-arachidonoylglycerol (2-AG) synthesis was employed to evaluate circuit-specific eCB function.

RESULTS

Both acute social defeat and trauma re-experiencing enhanced ovBNST neuronal activity and eCB signaling. CSDS reduced pBLA Cnr1 mRNA expression and ovBNST cannabinoid type-1 receptor (CB1R) protein levels, leading to heightened ovBNST excitability, likely due to diminished presynaptic inhibition of glutamate release from pBLA-ovBNST terminals. Pharmacological inhibition of 2-AG degradation in the ovBNST or optogenetic activation of CB1Rs in pBLA-ovBNST projections reversed CSDS-induced social avoidance and anxiety-like behaviors. In contrast, genetic suppression of 2-AG synthesis exacerbated PTSD-like phenotypes.

CONCLUSION

These findings identify a social threat-responsive pBLA-ovBNST circuit in which eCB signaling modulates glutamatergic transmission to promote resilience against PTSD-like behavioral states. Restoring eCB homeostasis within this pathway may represent a promising therapeutic strategy for PTSD intervention.