The Roles Of Glutamatergic Neurons Within Different ACC Subregions In Pain Perception And Modulation

Objective:Anterior cingulate cortex (ACC) is closely associated with pain, not only participates in pain sensation, but also is involved in pain modulation. The roles of glutamatergic neurons within different subregions of ACC have not been elucidated yet. Conventional activation by electrical or chemical stimulation can activate both excitatory glutamatergic neurons and inhibitory GABA-ergic neurons without selectivity, hence cannot be used to specifically evaluate the roles of glutamatergic neurons in pain modulation. This study aimed to reveal the roles of glutamatergic neurons in rACC and cACC in pain perception and pain modulation by using the method of optogenetics.Method and Result:[1] Glutamatergic neurons in rACC and cACC were able to express photosensitive protein ChR2 after injecting AAV-EF1a-DIO-hChR2 (E132A)-EYFP virus into rACC and cACC, respectively, in Camkâ…¡a-Cre transgenic mice, and could be activated by blue light with light intensity dependence. [2] Peripheral noxious mechanical stimulation activated glutamatergic neurons in bilateral rACC. [3] Peripheral noxious mechanical stimulation activated most glutamatergic neurons in the ipsilateral cACC and inhibited most glutamatergic neurons in the contralateral. [4] Selective opto-activation of glutamatergic neurons in the rACC changed neither thresholds of pain-like behaviors induced by mechanical and heat stimuli, nor the pain responses induced by formalin. [5] Selective activation of glutamatergic neurons in the cACC by light decreased the pain sensitivity of mice to bilateral mechanical stimulation and contralateral stimulation of formalin. [6] In Vgat-ChR2-eYFP mice, selective activation of GABA neurons in the cACC increased the bilateral sensitivity of mice to mechanical pain.Conclusion:Glutamatergic neurons in both rACC and cACC are capable of responding to input of sensory information and probably participate in the formation of pain sensation. Glutamatergic neurons in the rACC cannot modulate pain behaviors. But glutamatergic neurons in the cACC play important roles in pain modulation, suggesting that cACC may be a potential target for pain relief.