Transient forebrain over-expression of CRF induces plasma corticosterone and mild behavioural changes in adult conditional CRF transgenic mice.
BACKGROUND
Converging findings support a role for extra-hypothalamic CRF in the mediation of the stress response. The influence of CRF in the amygdala is well established, while less is known of its role in other areas of the forebrain where CRF and CRF(1) receptors are also expressed. In the present study CRF was genetically induced to allow forebrain-restricted expression in a temporally-defined manner at any time during the mouse lifespan. This mouse model may offer the possibility to establish a model of the pathogenesis of recurrent episodes of depression.


METHODS
Mice were engineered to carry both the rtTA transcription factor driven by the CamKII alpha promoter and the doxycycline-regulated operator (tetO) upstream of the CRF coding sequence. Molecular, biochemical and behavioural characterisation of this mouse is described.


RESULTS
Following a three-week period of transcriptional induction, double transgenic mice showed approximately 2-fold increased expression of CRF mRNA in the hippocampus and cortex, but not hypothalamus. These changes were associated with 2-fold increase in morning corticosterone levels, although responses to the dexamethasone suppression test or acute stress were unaffected. In contrast, induced mice displayed modestly altered behaviour in the Light and Dark test and Forced Swim test.


CONCLUSIONS
Transient induction of CRF expression in mouse forebrain was associated with endocrine and mild anxiety-like behavioural changes consistent with enhanced central CRF neurotransmission. This mouse allows the implementation of regimens with longer or repeated periods of induction which may model the initial stages of the pathology underlying recurrent depressive disorders.
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline S.p.A. Medicines Research Centre, Via Fleming 4, 37135 Verona, Italy. elena.a.vicentini@gsk.com
Elena
E
Vicentini
Roberto
R
Arban
Ornella
O
Angelici
Gabriella
G
Maraia
MariaElisa
M
Perico
Manolo
M
Mugnaini
Annarosa
A
Ugolini
Charles
C
Large
Enrico
E
Domenici
Philip
P
Gerrard
Donna
D
Bortner
Isabelle M
IM
Mansuy
Laura
L
Mangiarini
Emilio
E
Merlo-Pich
D000818:Animals; D001007:Anxiety / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D001483:Base Sequence; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D003345:Corticosterone / Q000097:blood*; D003346:Corticotropin-Releasing Hormone / Q000235:genetics* / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019964:Mood Disorders / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D016548:Prosencephalon / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013312:Stress, Physiological / Q000235:genetics / Q000502:physiology; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology
D017931:DNA Primers; D012333:RNA, Messenger; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone