title: Microglial activation, increased TNF and SERT expression in the prefrontal cortex define stress-altered behaviour in mice susceptible to anhedonia.
abstract: A chronic stress paradigm comprising exposure to predation, tail suspension and restraint induces a depressive syndrome in C57BL/6J mice that occurs in some, but not all, animals. Here, we sought to extend our behavioural studies to investigate how susceptibility (sucrose preference<65%) or resilience (sucrose preference>65%) to stress-induced anhedonia affects the 5HT system and the expression of inflammation-related genes. All chronically stressed animals, displayed increased level of anxiety, but susceptible mice exhibited an increased propensity to float in the forced swim test and demonstrate hyperactivity under stressful lighting conditions. These changes were not present in resilient or acutely stressed animals. Compared to resilient animals, susceptible mice showed elevated expression of tumour necrosis factor alpha (TNF) and the 5-HT transporter (SERT) in the pre-frontal area. Enhanced expression of 5HT(2A) and COX-1 in the pre-frontal area was observed in all stressed animals. In turn, indoleamine-2,3-dioxygenase (IDO) was significantly unregulated in the raphe of susceptible animals. At the cellular level, increased numbers of Iba-1-positive microglial cells were also present in the prefrontal area of susceptible animals compared to resilient animals. Consequently, the susceptible animals display a unique molecular profile when compared to resilient, but anxious, animals. Unexpectedly, this altered profile provides a rationale for exploring anti-inflammatory, and possibly, TNF-targeted therapy for major depression.
authors.affiliation: Department of Pharmacology, Oxford University, Mansfield Road, Oxford, UK.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Couch
authors.affiliation: Department of Pharmacology, Oxford University, Mansfield Road, Oxford, UK. Electronic address: daniel.anthony@pharm.ox.ac.uk.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Anthony
authors.affiliation: Department of Molecular Cell Biology, Max-Planck Institute of Biophysical Chemistry, Göttingen, Germany; Institute of Normal Physiology and Pathophysiology, Russian Academy of Medical Sciences, Moscow, Russia.
authors.forename: Oleg
authors.initials: O
authors.lastname: Dolgov
authors.affiliation: Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow, Russia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Revischin
authors.affiliation: pHLOGISTIX LLC, Lenexa, KS, USA.
authors.forename: Barry
authors.initials: B
authors.lastname: Festoff
authors.affiliation: Department of Physiology, Medical Faculty, New University of Lisbon, Campo Martires da Patria, Lisbon, Portugal.
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Santos
authors.affiliation: Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands.
authors.forename: Harry W
authors.initials: HW
authors.lastname: Steinbusch
authors.affiliation: Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Strekalova
mesh_terms: D059445:Anhedonia / Q000502:physiology*; D000818:Animals; D001007:Anxiety / Q000523:psychology; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis; D017931:DNA Primers; D003863:Depression / Q000523:psychology; D005518:Food Preferences; D007150:Immunohistochemistry; D008262:Macrophage Activation / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology*; D017397:Prefrontal Cortex / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D050486:Serotonin Plasma Membrane Transport Proteins / Q000096:biosynthesis*; D013315:Stress, Psychological / Q000276:immunology* / Q000378:metabolism*; D013395:Sucrose / Q000494:pharmacology; D013550:Swimming / Q000523:psychology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D016207:Cytokines; D017931:DNA Primers; D050486:Serotonin Plasma Membrane Transport Proteins; D014409:Tumor Necrosis Factor-alpha; D013395:Sucrose