Insula-amygdala and insula-thalamus pathways are involved in comorbid chronic pain and depression-like behavior in mice

The comorbidity of chronic pain and depression poses tremendous challenges for the treatment of either one because they exacerbate each other with unknown mechanisms. As the posterior insular cortex (PIC) integrates multiple somatosensory and emotional information and is implicated in either chronic pain or depression, we hypothesize that the PIC and its projections may contribute to the pathophysiology of comorbid chronic pain and depression. We show that PIC neurons were readily activated by mechanical, thermal, aversive, and stressful and appetitive stimulation in naïve and neuropathic pain male mice subjected to spared nerve injury (SNI). Optogenetic activation of PIC neurons induced hyperalgesia and conditioned place aversion in naïve mice, whereas inhibition of these neurons led to analgesia, conditioned place preference (CPP), and antidepressant effect in both naïve and SNI mice. Combining neuronal tracing, optogenetics, and electrophysiological techniques, we found that the monosynaptic glutamatergic projections from the PIC to the basolateral amygdala (BLA) and the ventromedial nucleus in the thalamus (VM) mimicked PIC neurons in pain modulation in naïve mice; in SNI mice, both projections were enhanced accompanied by hyperactivity of PIC, BLA and VM neurons, and inhibition of these projections led to analgesia, CPP, and antidepressant-like effect. The present study suggests that potentiation of the PIC-BLA and PIC-VM projections may be important pathophysiological bases for hyperalgesia and depression-like behavior in neuropathic pain, and reversing the potentiation may be a promising therapeutic strategy for comorbid chronic pain and depression.Significance Statement Treatment of chronic pain is quite challenging because of the involvement of central sensitization and emotional disorders. It is keenly demanding to search for brain circuits commonly or separately contributing to hyperalgesia and emotional dysfunction in chronic pain. The PIC is involved in both pain and emotional processing. But, the relationship between the malfunction in the PIC and the comorbidity of chronic pain and depression has not been elucidated. Here, we demonstrate that in chronic pain, PIC neurons became hyperactive, and their projections to the BLA and the VM of the thalamus were augmented; these alterations may confer hyperalgesia and depression-like behaviors in chronic pain. Therefore, these pathways may be potential therapeutic targets for comorbid chronic pain and depression.