A Central Amygdala Input To The Parafascicular Nucleus Controls Comorbid Pain In Depression

There are over 100 million patients who have comorbidities such as pain and depression or anxiety worldwide.The proper treatment for CP represents a major challenge and research focus in the field,as the underlying mechanisms of comorbid pain in depression(CP)are poorly understood.Depression symptoms occur with an estimated prevalence of up to 52%in patients with chronic pain,in addition,pain symptoms occur with an estimated prevalence of up to 65%in patients with major depression.Furthermore,CP symptoms can worsen depressed mood,and are associated with poor responses to both depression and pain treatment,creating a cycle of depression and pain that is often difficult to break(patients do not respond well to more than two treatment).Therefore,studying the mechanism of pain-emotional disorder comorbidity provide a new approach for clinically treatment,which is meaningful.Chronic pain varies in etiology,with different conditions exhibiting distinct profiles of pain symptomatology.Alterations in serotonergic and noradrenergic systems are considered the common pathological roots of depression and chronic pain,and they share a clinical pattern of persistence beyond the precipitant.However,approximately one-third of depression patients do not respond well to treatment by targeting these systems.Notably,the acute use of serotonin-selective serotonin reuptake inhibitors(SSRIs)produces early adverse events in some patients,which may exacerbate pain symptoms.Together,the current evidence indicates that the neuroanatomical and molecular substrates that underlie CP may be different from those that underlie other various somatic pain syndromes,which could be beyond the serotonergic and noradrenergic systems.The amygdaloid complex is well-known to be relevant to fear learning,anxiety,reward,and pain.Even the PFC and IC have been reported to interact with the amygdala in processing cognition,emotion,and pain.This raises the possibility that the amygdala could be an important site for processing the depressive symptoms associated with pain.The central nucleus of the amygdala(CeA),referred to as the "nociceptive amygdala,"serves as the main output nucleus for amygdala functions.Highly processed,polymodal information reaches the CeA indirectly from the thalamus and cortical areas or direct nociceptive inputs from the spinal cord and brainstem.Imaging studies have shown significant alterations in the activity of the CeA in chronic pain.Furthermore,the CeA forms widespread connections with forebrain areas and the brainstem,which has been implicated in mediating fear and mood disorders.These studies suggest that the CeA is a probable convergent point of chronic pain and depression.However,the cause-and-effect relationship between the adaptation of CeA circuits and the pathology of CP is unknown.In this study,using virus tracing method,we found that GABAergic neurons in CeA projected to glutamatergic neurons in parafascicular nucleus(PF),which is a subnucleus of thalamus.Through electrophysiology in vitro,immunofluorescence and in vivo multi-channel recording technology,we determined an inhibitory functional connection between CeA and PF.With the same experimental strategy,we found the PF project to the secondary somatosensory cortex(S2),and then confirmed the connection and function of GABACeA→GluPF→S2 pathway through triple tracing.We established the model of depression and pain comorbid in mice with chronic restraint stress.We explored the activity changes of GABACeA neurons and GluPF neurons in CP mice using whole cell recording,and detect the GABA concentration in PF by microdialysis combined with high performance liquid chromatography.In addition,manipulated the activity of GABACeA→GluPF→S2 pathway combining optogenetic and chemogenetic,we found that this pathway is essential for CP regulation in mice.The advantage of studying the neural circuit of a disorder seems to reveal convergent points of drug action and pathologically relevant behavioral consequences.Combining viral tracing,optogenetic,and electrophysiological methods in mice,we define a pathway,whereby GABAergic neurons from the central nucleus of the amygdala(GABACeA)project to glutamatergic neurons in the parafascicular nucleus(GluPF).These GluPF neurons relay directly to neurons in the S2,a well-known area involved in pain signal processing.Collectively,we describe an inhibition GABACeA→GluPF→S2 pathway,the alteration of which is both necessary and sufficient for manifesting CP.