A Neural Circuit For Feeding Affected By Pain

Pain is one of the most common clinical symptoms,affecting up to 30%of the population.Pain can generate a series of complications.For example,pain,as an evolutionarily conserved signal of threat,poses a substantial competition to feeding behavior.Patients with chronic pain usually have symptoms of anorexia,which may affect pain recovery,even cause negative emotions,forming a vicious circle.However,the neural circuit mechanism underlying this symptom is still unclear.Due to the complexity and heterogeneity of the mechanism of pain,the current analgesic drugs and treatments are far from meeting the needs of patients.Therefore,fully analyzing the neural circuit mechanism of pain affecting food intake can not only provide a new theoretical basis for in-depth understanding of pain,but also provide new ideas for pain management.It also has potential scientific significance and clinical value.The anterior cingulate cortex(ACC)is the advanced brain region encoding pain perception and emotion.Past studies have shown that ACC receives a large amount of sensory information input from the thalamus and plays an important role in the processing and integration of nociceptive information.In addition,the connection between ACC and nucleus accumbens is involved in the regulation of pain-induced aversion,and optogenetic inhibition of the ACC was significantly alleviate pain-induced anxiety.These studies suggest that ACC may be involved in the regulation of pain related complications.In this paper,we will explore the neural circuit mechanism of ACC participating in the regulation of food intake under pain conditions by using viral tracing,in vitro electrophysiology,in vivo multi-channel recording,in vivo optical fiber recording,in vivo two-photon calcium imaging,and chemogenetic comprehensively.This study is based on mice pain models induced by complete Freund’s adjuvant and nerve ligation.Through continuous feeding monitoring,feeding pattern analysis and free feeding behavior test,we found that the food consumption of these pain model mice is significantly reduced.Subsequently,by immunofluorescence staining we found that the expression of c-Fos in ACC of pain model mice was significantly increased,and these c-Fos signals were mainly co-located with glutamate antibody.Through two-photon calcium imaging,in vivo optical fiber recording and in vivo multi-channel recording,we found that the calcium activity and firing rate of glutamate(GluACC)neurons in ACC of pain model mice was significantly enhanced.Inhibition of GluACC neurons using chemogenetic could significantly relieve allodynia and increase food consumption in pain model mice.Subsequently,we found that GluACC neurons projected to many brain regions through anterograde virus tracing,including the lateral hypothalamus area(LHA),known as "feeding center",suggesting that there is a neural pathway between ACC and LHA that may participate in the regulation feeding under pain condition.Combined with retrograde viral tracing,in vitro electrophysiological recording and in vivo multi-channel recording,we found that there was an excitatory functional connection between ACC and LHA glutamate(GluLHA)neurons.In addition,the increased activity of GluACC neurons excited GluLHA neurons,and inhibition of the GluACC→GluLHA circuit using chemogenetic could significantly alleviate the pain-induced suppression of food intake in pain model mice.Using similar experimental techniques,we found that the downstream of the GluACC→GluLHA circuit was exported to the pro-opiomelanocortin(POMC)neurons in the arcuate nucleus(Arc),and the structural connection of the GluACC→GluLHA→POMCArc neural circuit was identified by the three-stage circuit tracing.The functional connection of GluACC→GluLHA→POMCArc neural circuit was verified by photogenetics combined with in vitro electrophysiological recording.We found that inhibition of GluCC→GluLHA→POMCArc neural circuit using chemogenetic could alleviate the suppression of food intake in pain model mice.And activation of the GluACC→GluLHA→POMCArc neural circuit using chemogenetic could simulate the effect of pain-induced supression of food intake in normal mice.We have proved that the GluACC→GluLHA→POMCArc neural circuit plays a suffcient and necessary role in regulating anorexia under pain condition.In summary,this paper identities the structure of a GluACC→GluLHA→POMCArc neural circuit.Under pain condition,the activity of GIuACC neurons increased,which excited the GluLHA neurons in the "feeding center",and then increased the activity of POMCArc neurons related to appetite regulation,which eventually led to food intake inhibition.The results of this paper enrich the theoretical system of pain,and also provide new ideas for the multi-system regulation of pain.