Somatosensory Cortex Circuit Controls Comorbid Anxiety In Chronic Pain

Chronic pain and anxiety are clinically common diseases,the comorbidity rate of the two disorders is as high as 60%.Chronic pain can lead to an increase in anxiety.Conversely,anxiety can lead to an acceleration in pain duration and intensity.These often lead to a vicious circle of chronic pain and anxiety symptoms.Patients with comorbid anxiety symptoms in pain(CASP)have more difficulties for treatment compared to either of these two clinical disorders.Nowadays,due to the poor knowledge of the neural mechanisms of CASP,this field has become challenging and interesting for scientists to investigate.Many nuclei participate in the central mechanisms of chronic pain and anxiety disorders,such as amygdala,anterior cingulate cortex,medial prefrontal cortex.Selective serotonin reuptake inhibitors(SSRIs),whose potential target is 5-HT system,are first-line drugs used in clinical treatment of anxiety disorders,part of these also have analgesic effects.Therefore,some features of chronic pain and anxiety may be interrelated.However,more than one-third of patients with CASP have no significant response to anxiolytic drugs.This clinical manifestation suggests that the CASP may not be mediated solely by 5-HT systems.However,whether chronic pain induced anxiety disorders are caused by maladaptation due to changes in pain-related neural circuits,are not clear.The primary somatosensory cortex(S1)integrates pain-related information indirectly through thalamus and other cortical areas,or directly receiving noxious stimuli from the spinal cord and brainstem.Furthermore,the SI has direct or indirect connections with many nuclear groups involved in anxiety disorders.Consequently,S1 may be a key brain area that links to CASP.In this study,functional connection between glutamatergic neurons of S1(Glus1)and GABAergic neurons of caudal dorsolateral striatum(cDLS)(GABAcDLS)were found by using virus tracking and patch clamp technique.In the CASP model mice,the patch clamp recording showed an increase in the excitability of Glus1,in vivo microdialysis with the high-performance liquid chromatography showed an escalation in the content of glutamate neurotransmitters in cDLS,resulting in an increase in the excitability of GABAcDLS.Optogenetic and Chemogenetic silence respectively of GluS1 and GABAcDLS can rescue the anxiety-like behaviors in CASP mice.Similarly,optogenetic inhibition of glutamatergic neuronal projection of GluS1-cDLS,the anxiety-like behaviors in CASP mice were significantly attenuated rather than in model mice of other kind of anxiety-like behaviors(acute restraint stress induced anxiety).Our study defines Glus1→GABAcDLS pathway through which CASP is generated.