The ventral hippocampus to paraventricular thalamus circuit regulates context-dependent hyperlocomotion through PAC1 receptor signaling in the chronic stress-induced PTSD mouse model

The context-dependent behavior serves as a core behavioral manifestation of intrusive traumatic memory flashbacks in PTSD, its neural circuit and underlying brain regions remain incompletely understood. Although pituitary adenylate cyclase-activating polypeptide (PACAP) has been implicated as a key pathological factor in PTSD pathogenesis, its role in PTSD-like contextual behavioral responses has not yet been elucidated. In this study, we demonstrated that chronic social defeat stress (CSDS) induced locomotor hyperactivity in male mice, but only when they were re-exposed to the stress-associated chamber. Notably, neurons in the paraventricular thalamus (PVT) showed significant activation following the expression of above context-dependent behavior. Chronic optogenetic activation of PVT neurons was sufficient to recapitulate PTSD-like contextual behavior in naïve mice. Furthermore, anterograde and retrograde tracing revealed that the ventral hippocampus (vHip) sends monosynaptic and glutamatergic projections to the PVT. Chronic inhibition of PVT-projecting vHip neurons selectively suppressed PTSD-like context-dependent locomotion hyperactivity without affecting other stress-induced behavioral alterations. In contrast, chronic inhibition of vHip recipient PVT neurons attenuated most CSDS-induced PTSD-like behaviors. Moreover, CSDS led to upregulated expression of the PAC1 receptor in PVT neurons. Local pharmacological blockade of the PAC1 receptor in the PVT during the CSDS paradigm prevented the development of both context-dependent hyperactivity and other PTSD-like behavioral phenotypes. Collectively, our findings identify a vHip-PVT circuit and PVT PACAP/PAC1 signaling in the pathophysiology of PTSD-like contextual behavior and highlight the PVT as a potential therapeutic target for treating PTSD-related context-dependent symptoms.