Lateral septum-lateral hypothalamus circuit dysfunction in comorbid pain and anxiety

Di Wang, Xiangyu Pan, Yu Zhou, Zifeng Wu, Kunpeng Ren, Hanyu Liu, Chaoli Huang, Yumei Yu, Teng He, Xiao Zhang, Ling Yang, Hongxing Zhang, Ming Hu Han, Cunming Liu, Jun Li Cao, Chun Yang

Research output: Contribution to journalArticlepeer-review


Pain and anxiety comorbidities are a common health problem, but the neural mechanisms underlying comorbidity remain unclear. We propose that comorbidity implies that similar brain regions and neural circuits, with the lateral septum (LS) as a major candidate, process pain and anxiety. From results of behavioral and neurophysiological experiments combined with selective LS manipulation in mice, we find that LS GABAergic neurons were critical for both pain and anxiety. Selective activation of LS GABAergic neurons induced hyperalgesia and anxiety-like behaviors. In contrast, selective inhibition of LS GABAergic neurons reduced nocifensive withdrawal responses and anxiety-like behaviors. This was found in two mouse models, one for chronic inflammatory pain (induced by complete Freund’s adjuvant) and one for anxiety (induced by chronic restraint stress). Additionally, using TetTag chemogenetics to functionally mark LS neurons, we found that activation of LS neurons by acute pain stimulation could induce anxiety-like behaviors and vice versa. Furthermore, we show that LS GABAergic projection to the lateral hypothalamus (LH) plays an important role in the regulation of pain and anxiety comorbidities. Our study revealed that LS GABAergic neurons, and especially the LSGABAergic-LH circuit, are a critical to the modulation of pain and anxiety comorbidities.

Original languageEnglish
Pages (from-to)1090-1100
Number of pages11
JournalMolecular Psychiatry
Issue number3
StatePublished - Mar 2023
Externally publishedYes


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