title: Genetic or pharmacologic disruption of the calcineurin-nuclear factor of activated T-cells axis prevents social stress-induced voiding dysfunction in a murine model.
abstract: OBJECTIVE
  Social stress can suppress the voiding reflex, with resultant diminished voiding frequency and increased volumes. The calcineurin-NFAT (nuclear factor of activated T cells) pathway is important in memory development. It was hypothesized that interruption of the calcineurin-NFAT pathway might prevent social stress-induced voiding dysfunction.
  
  
  METHODS
  Mice were subjected to social stress in an established resident-intruder model for 1 h, followed by 23 h of barrier separation. NFATc3, NFATc4 knockout (KO) and wild-type (WT) mice were studied. At two weeks, voiding patterns were collected; this was followed by sacrifice. Corticotropin-releasing factor (CRF) mRNA expression in Barrington's nucleus (BN) was determined by in-situ hybridization.
  
  
  RESULTS
  Social stress decreased voiding frequency and increased voided volumes in WT strains. At baseline, NFATc3 KO mice showed decreased voids and increased volumes, while the NFATc4 KO mice resisted social stress. However, CRF mRNA increased in WT mice following social stress and was increased at baseline in NFATc3 KO mice. It was found that CRF mRNA did not increase following social stress in NFATc4 KO mice. The administration of CsA to WT mice normalized voiding patterns following social stress, albeit with no effect on CRF mRNA in BN.
  
  
  CONCLUSIONS
  Disrupting the calcineurin-NFAT axis by either genetic or pharmacologic approaches confers resistance to the development of social stress-induced voiding and dysfunction.
authors.affiliation: John W. Duckett Center for Pediatric Urology at The Children's Hospital of Philadelphia, USA; The Perelman School of Medicine at The University of Pennsylvania, USA. Electronic address: loncg3@email.chop.edu.
authors.forename: C J
authors.initials: CJ
authors.lastname: Long
authors.affiliation: John W. Duckett Center for Pediatric Urology at The Children's Hospital of Philadelphia, USA; The Perelman School of Medicine at The University of Pennsylvania, USA. Electronic address: butlers@email.chop.edu.
authors.forename: S
authors.initials: S
authors.lastname: Butler
authors.affiliation: John W. Duckett Center for Pediatric Urology at The Children's Hospital of Philadelphia, USA; The Perelman School of Medicine at The University of Pennsylvania, USA. Electronic address: sliwoski@email.chop.edu.
authors.forename: J
authors.initials: J
authors.lastname: Fesi
authors.affiliation: John W. Duckett Center for Pediatric Urology at The Children's Hospital of Philadelphia, USA; The Perelman School of Medicine at The University of Pennsylvania, USA. Electronic address: charles.frank@emory.edu.
authors.forename: C
authors.initials: C
authors.lastname: Frank
authors.affiliation: John W. Duckett Center for Pediatric Urology at The Children's Hospital of Philadelphia, USA; The Perelman School of Medicine at The University of Pennsylvania, USA. Electronic address: canning@email.chop.edu.
authors.forename: D A
authors.initials: DA
authors.lastname: Canning
authors.affiliation: John W. Duckett Center for Pediatric Urology at The Children's Hospital of Philadelphia, USA. Electronic address: zderic@email.chop.edu.
authors.forename: S A
authors.initials: SA
authors.lastname: Zderic
mesh_terms: D000818:Animals; D065095:Calcineurin Inhibitors / Q000627:therapeutic use*; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D016572:Cyclosporine / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D013315:Stress, Psychological / Q000150:complications*; D014555:Urination Disorders / Q000209:etiology* / Q000517:prevention & control*
chemical_list: D065095:Calcineurin Inhibitors; D050778:NFATC Transcription Factors; C467907:Nfatc4 protein, mouse; D012333:RNA, Messenger; C445503:transcription factor NF-AT c3; D016572:Cyclosporine; D003346:Corticotropin-Releasing Hormone
keywords: Barrington's nucleus; Corticotropin releasing factor; Nuclear factor of activated T-cells; Social stress; Voiding dysfunction