title: The anterior cingulate cortex is a critical hub for pain-induced depression.
abstract: BACKGROUND
  Besides chronic stress, chronic pain is a prevalent determinant for depression. Changes induced in specific brain regions by sustained pain may alter the processing of affective information, thus resulting in anxiodepressive disorders. Here, we compared the role of the anterior cingulate cortex (ACC) and the posterior insular cortex in the anxiodepressive, sensory, and affective aspects of chronic pain.
  
  
  METHODS
  Neuropathic pain was induced by cuffing the right sciatic nerve of C57BL/6J mice. Lesions were performed by local injection of ibotenic acid and chronic activation of the ACC by optogenetic stimulation. Anxiodepressive-related behaviors were evaluated through the novelty suppressed feeding, marble burying, splash, and forced swimming tests. Mechanical thresholds were determined using von Frey filaments, and the relief of spontaneous pain was determined by using place conditioning.
  
  
  RESULTS
  The ACC lesion prevented the anxiodepressive consequences of chronic pain without affecting the sensory mechanical allodynia. Conversely, the tonic or spontaneous pain and the anxiodepressive consequences of pain remained present after posterior insular cortex lesion, even though the mechanical allodynia was suppressed. Furthermore, optogenetic stimulation of the ACC was sufficient to induce anxiety and depressive-like behaviors in naïve animals.
  
  
  CONCLUSIONS
  Our results show that, at cortical level, the sensory component of chronic pain remains functionally segregated from its affective and anxiodepressive components. Spontaneous tonic pain and evoked allodynia can be experimentally dissociated. Furthermore, the ACC appears as a critical hub for mood disorders, including for the anxiodepressive consequences of chronic pain, and thus constitutes an important target for divulging the underlying mechanism.
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique; Université de Strasbourg, Strasbourg, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Barthas
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique; Université de Strasbourg, Strasbourg, France.
authors.forename: Jim
authors.initials: J
authors.lastname: Sellmeijer
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Hugel
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Waltisperger
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique.
authors.forename: Michel
authors.initials: M
authors.lastname: Barrot
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique. Electronic address: yalcin@inci-cnrs.unistra.fr.
authors.forename: Ipek
authors.initials: I
authors.lastname: Yalcin
mesh_terms: D000818:Animals; D001007:Anxiety / Q000503:physiopathology; D002540:Cerebral Cortex / Q000503:physiopathology*; D059350:Chronic Pain / Q000503:physiopathology*; D003213:Conditioning, Psychological / Q000502:physiology; D003866:Depressive Disorder / Q000503:physiopathology*; D004195:Disease Models, Animal; D006179:Gyrus Cinguli / Q000503:physiopathology*; D006930:Hyperalgesia / Q000503:physiopathology; D007051:Ibotenic Acid; D007150:Immunohistochemistry; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009437:Neuralgia / Q000503:physiopathology*; D062308:Optogenetics; D017288:Pain Threshold / Q000502:physiology; D018408:Patch-Clamp Techniques; D012584:Sciatic Nerve / Q000293:injuries
chemical_list: D007051:Ibotenic Acid
keywords: Anterior cingulate cortex; Anxiety; Behavior; Depression; Insular cortex; Neuropathic pain; Optogenetics