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

Abstract

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.

A septo-hypothalamic-medullary circuit directs stress-induced analgesia

“…Indeed, in our experiments, we observed that the LS-centric SIA circuitry is effective in suppressing hyperalgesia in mice with chronic inflammatory pain. Interestingly, contrary to our findings, a recent study have shown that the LS neurons promote both pain and anxiety 80 . The contradiction may be because the authors have primarily tested for mechanical sensitivity while we have focused on the thermal thresholds.…”

“…The role of dLS neurons in chronic pain is unclear. Interestingly, a recent study has shown that the dLS neurons promote both pain and anxiety (Wang et al, 2023). This is contrary to our data which shows that dLS activation has analgesic effects.…”

Whole‐brain monosynaptic inputs to lateral periaqueductal gray glutamatergic neurons in mice

“…For example, increased signals from the anterior cingulate cortex to the DL/LPAG are critical for fear avoidance in chronic pain disability 39 . The hypothalamus, especially the LH, is also involved in pain perception and promotion 57,58 . The lateral septum‐LH circuit is critical for pain modulation, 57 and activation of the orexin system facilitates pain control 59 .…”

“…39 The hypothalamus, especially the LH, is also involved in pain perception and promotion. 57,58 The lateral septum-LH circuit is critical for pain modulation, 57 and activation of the orexin system facilitates pain control. 59 In addition, Siemian et al 60 demonstrated that the LH parvalbumin-positive (LH PV ) glutamatergic neurons have a potential role as a target for analgesia, in which the LH PV neurons-VLPAG axonal projections play a vital role.…”

Developmental origin and local signals cooperate to determine septal astrocyte identity

“…The septal area, situated in the ventral forebrain, governs a diverse array of behaviors related to memory, movement, mood and motivational processes (Kesner et al, 2021; Menon, Suss, Oliveira, Neumann, & Bludau, 2022; Mocellin & Mikulovic, 2021; Wirtshafter & Wilson, 2021). These multifaceted functions of the septum are thought to be mediated by diverse septal neuron cell types, which establish circuit connections with a wide range of brain regions, most notably the hippocampus and hypothalamic area nuclei (Muller & Remy, 2018; Sun et al, 2014; D. Wang et al, 2023). Over the past several years, there has been significant progress in delineating the roles of genetically defined septal neuron types (Magno et al, 2022; Turrero Garcia et al, 2021).…”