title: Cingulate Overexpression of Mitogen-Activated Protein Kinase Phosphatase-1 as a Key Factor for Depression.
abstract: Depression is frequently associated with chronic pain or chronic stress. Among cortical areas, the anterior cingulate cortex (ACC, areas 24a and 24b) appears to be important for mood disorders and constitutes a neuroanatomical substrate for investigating the underlying molecular mechanisms. The current work aimed at identifying ACC molecular factors subserving depression.
  
  
  
  Anxiodepressive-like behaviors in C57BL/6J male mice were induced by neuropathic pain, unpredictable chronic mild stress, and optogenetic ACC stimulation and were evaluated using novelty suppressed feeding, splash, and forced swim tests. ACC molecular changes in chronic pain-induced depression were uncovered through whole-genome expression analysis. Further mechanistic insights were provided by chromatin immunoprecipitation, Western blot, and immunostaining. The causal link between molecular changes and depression was studied using knockout, pharmacological antagonism, and local viral-mediated gene knockdown.
  
  
  
  Under chronic pain-induced depression, gene expression changes in the ACC highlighted the overexpression of a regulator of the mitogen-activated protein kinase pathway, mitogen-activated protein kinase phosphatase-1 (MKP-1). This upregulation is associated with the presence of transcriptionally active chromatin marks (acetylation) at its proximal promoter region as well as increased cyclic adenosine monophosphate response element-mediated transcriptional activity and phosphorylation of cyclic adenosine monophosphate response element binding protein and activating transcription factor. MKP-1 overexpression is also observed with unpredictable chronic mild stress and repeated ACC optogenetic stimulation and is reversed by fluoxetine. A knockout, an antagonist, or a local silencing of MKP-1 attenuates depressive-like behaviors, pointing to an important role of this phosphatase in depression.
  
  
  
  These data point to ACC MKP-1 as a key factor in the pathophysiology of depression and a potential target for treatment development.
authors.affiliation: Institute of Cellular and Integrative Neuroscience, National Centre for Scientific Research, Strasbourg; University of Strasbourg, Strasbourg.
authors.forename: Florent
authors.initials: F
authors.lastname: Barthas
authors.affiliation: Institute of Cellular and Integrative Neuroscience, National Centre for Scientific Research, Strasbourg; University of Strasbourg, Strasbourg.
authors.forename: Muris
authors.initials: M
authors.lastname: Humo
authors.affiliation: Institute of Pharmacology and Toxicology, University of Freiburg, and BIOSS Centre for Biological Signalling Studies, Freiburg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gilsbach
authors.affiliation: Institute of Cellular and Integrative Neuroscience, National Centre for Scientific Research, Strasbourg.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Waltisperger
authors.affiliation: Institute of Cellular and Integrative Neuroscience, National Centre for Scientific Research, Strasbourg; University of Strasbourg, Strasbourg.
authors.forename: Meltem
authors.initials: M
authors.lastname: Karatas
authors.affiliation: University François Rabelais, French Institute of Health and Medical Research, Tours, France.
authors.forename: Samuel
authors.initials: S
authors.lastname: Leman
authors.affiliation: Institute of Pharmacology and Toxicology, University of Freiburg, and BIOSS Centre for Biological Signalling Studies, Freiburg, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Hein
authors.affiliation: University François Rabelais, French Institute of Health and Medical Research, Tours, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Belzung
authors.affiliation: Laboratory of Cognitive and Adaptive Neuroscience, National Centre for Scientific Research, Strasbourg.
authors.forename: Anne-Laurence
authors.initials: AL
authors.lastname: Boutillier
authors.affiliation: Institute of Cellular and Integrative Neuroscience, National Centre for Scientific Research, Strasbourg.
authors.forename: Michel
authors.initials: M
authors.lastname: Barrot
authors.affiliation: Institute of Cellular and Integrative Neuroscience, National Centre for Scientific Research, Strasbourg. Electronic address: yalcin@inci-cnrs.unistra.fr.
authors.forename: Ipek
authors.initials: I
authors.lastname: Yalcin
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D059350:Chronic Pain / Q000201:enzymology; D003866:Depressive Disorder / Q000188:drug therapy / Q000201:enzymology*; D004195:Disease Models, Animal; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005473:Fluoxetine / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006179:Gyrus Cinguli / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D013315:Stress, Psychological / Q000188:drug therapy / Q000201:enzymology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018687:Antidepressive Agents, Second-Generation; D016760:Proto-Oncogene Proteins c-fos; D005473:Fluoxetine; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse
keywords: Anterior cingulate cortex; Chronic pain; Chronic stress; Depression; MAPK; MKP-1