Gene expression profiles highlight adaptive brain mechanisms in corticotropin releasing factor overexpressing mice.
Corticotropin-releasing factor (CRF) plays an important role in mediating central and peripheral responses to stress. Alterations in CRF system activity have been linked to a number of psychiatric disorders, including anxiety and depression. Aim of this study was to elucidate homeostatic mechanisms induced by lifelong elevated CRF levels in the brain. We therefore profiled gene expression in several brain areas of transgenic mice overexpressing CRF (CRF-OE), a model for chronic stress. Several genes showed altered expression levels in CRF-OE mice when compared to their wild type littermates and were confirmed by quantitative PCR. Differences in gene expression profiles revealed the presence of previously unrecognized homeostatic mechanisms in CRF-OE animals. These included changes in glucocorticoid signaling, as exemplified by changes in 11beta-hydroxysteroid dehydrogenase type 1, FK506 binding protein 5 and serum/glucocorticoid kinase. Alterations in expression of genes involved in myelination (myelin, myelin-associated glycoprotein), cell proliferation and extracellular matrix formation (Edg2, Fgfr2, decorin, brevican) suggest changes in the dynamics of neurogenesis in CRF-OE. Pronounced changes in neurotensin (NT) receptors 1 and 2 mRNA were identified. Overall downregulation of NT receptors in CRF-OE animal was substantiated by receptor binding studies. Pronounced neurotensin receptor downregulation was observed for NT type 1 receptors in limbic brain areas, suggesting that NT could be implicated in some of the effects attributed to CRF overexpression. These data show that lifelong exposure to excessive CRF leads to adaptive changes in the brain which could play a role in some of the behavioral and physiological alterations seen in these animals.
Johnson and Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Pieter J
PJ
Peeters
Frederik L P
FL
Fierens
Ilse
I
van den Wyngaert
Hinrich W
HW
Goehlmann
Sigrid M
SM
Swagemakers
Stefan U
SU
Kass
Xavier
X
Langlois
Shirley
S
Pullan
Mary P
MP
Stenzel-Poore
Thomas
T
Steckler
D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D006706:Homeostasis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009496:Neurotensin / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000502:physiology; D013315:Stress, Psychological
D009496:Neurotensin; D003346:Corticotropin-Releasing Hormone; D002118:Calcium