Dopaminergic neurons in the ventral periaqueductal gray projecting to the dorsal lateral septum regulate comorbid pain and anxiety

The comorbidity of pain and anxiety is one of the most prevalent mental health disorders globally. However, its underlying etiological mechanisms remain incompletely understood. This study revealed that the dorsal lateral septum (LSD) and its associated neural circuits play key roles in pain and/or anxiety regulation. Using chemical genetic techniques, we found that the specific inhibition of LSD GABAergic neurons significantly alleviated pain responses and anxiety-like behaviors. Conversely, the specific activation of LSD GABAergic neurons induced hyperalgesia and anxiety-like behaviors in mice. Furthermore, our study showed that dopaminergic neurons in the ventral periaqueductal gray (vPAG) play a crucial role in regulating pain and anxiety comorbidity through their projections to the LSD. This regulatory mechanism depends on the release of dopamine and its binding to the D2 receptor of LSD. In summary, this study highlights the critical role of LSD GABAergic neurons and their associated neural circuits in the comorbidity of pain and anxiety, thereby providing a new theoretical foundation and research direction for developing potential therapeutic strategies. • Chemogenetic activation/inhibition of LSD GABAergic neurons modulates mechanical pain sensitization and anxiety-like behaviors. • vPAG dopaminergic neurons project to LSD GABAergic neurons, mediating their effects via D2 receptors. • Chemogenetic modulation of vPAG-to-LSD dopaminergic projections alters mechanical pain sensitization and anxiety-like behaviors by releasing dopamine and interacting with D2 receptors in LSD.