Cellular Mechanisms Underlying Persistent Pain And Emotional Dysfunction In The Cortex

Pain as the most common symptom of an underlying clinical disease,is a major health issue all over the world,which affects up to≈ 30%of the world’s population.Chronic pain is often accompanied by mood disorders such as anxiety and depression affecting the patient’s quality of life.Persistent tissue injury and inflammatory can induce persistent pain and long-term plastic changes along sensory conduction pathways.Although many researchers have extensively studied altered nociceptive signaling and neural circuit plasticity at the spinal cord level,clinical effective treatments to alleviate chronic pain are still insufficient.Human brain imaging studies have unmasked the functional and structural changes of neurons and microglia in the multiple cortical areas are correlated with the occurrence,development,and maintenance of chronic pain.However,the activity changes and interaction patterns of neurons and microglia in these cortical areas during the development of chronic pain,and their functional significance are still poorly understood.To explore possible cell and molecular mechanisms that lead to cortical plasticity in chronic pain,we firstly employed a well-established chronic constriction injury(CCI)of the sciatic nerve induced neuropathic pain model in mice.We found that the CCI mice and their female offspring displayed significant pain sensitization.In these mice,methyl-CpG binding protein 2(MeCP2)expression was increased in the pyramidal neurons of primary somatosensory cortex(S1),correlating with increased neuronal activity.Optical inhibition of the activity of pyramidal neurons in the S1 can significantly alleviate the hyperalgesia in mice.Downregulation of S1 pyramidal neuronal MeCP2 by AAV-mediated RNAi could decrease pain sensitization and neuronal activity.RNA-seq and ChIP-qPCR analysis showed that the expression of a wide range of genes was changed in S1 pyramidal neurons,some of which were regulated by MeCP2.In addition,we found fore limb amputation could cause the secondary pain in ipsilateral hind limb,accompanied by increased neuronal and microglial activity(Microglia,the resident macrophages of the central nervous system)in hindlimb region of the primary somatosensory cortex(S1HL).Chemical activation of pyramidal neurons in forelimb region of the primary somatosensory cortex(S1FL)could imitate these effects of fore limb amputation.Pharmacological inhibition of microglia could relieve secondary hyperalgesia of hind limb and reverse activity of pyramidal neurons in the S1HL.The above studies have shown that the activation of cortical microglia or inflammatory environment can affect neuronal activity and induce persistent pain in the state of tissue injury.Based on these findings,we continue to study the cellular patterns of microglia-neuron interactions and their functional significance.Using lipopolysaccharide(LPS)injection to produce inflammation,we investigated the mechanism by which neuronal structure and functional plasticity in the anterior cingulate cortex(ACC)regulated by microglia contributes to depressive symptoms(Mice with persistent pain display significantly depression-like behavior).Then,we constructed a mouse model of early life inflammation through intraperitoneal injection of LPS on postnatal day 14(P14).We found that early life inflammation could induce depressive-like behaviors at an adolescent period(P45),accompanied by the activation of microglia and decreased pyramidal neuronal activity in the ACC.Chemical activation of pyramidal neurons in the ACC could rescue the depressive-like behavior of adolescent LPS mice.Pharmacological inhibition of microglia could relieve depression-like behaviors of LPS mice on P45 and increase activity of pyramidal neurons in the ACC.Taken together,tissue injury and inflammatory can induce maladaptive plastic changes in the cortical areas and reciprocal interactions between microglia and neurons,which may subsequently contribute to persistent pain and mood disorder.All these findings provide a deeper understanding and new theoretical insights into the development of chronic pain and related mood disorders from the perspective of microglia.