• Elena Vicentini, Roberto Arban, Ornella Angelici, Gabriella Maraia, MariaElisa Perico, Manolo Mugnaini, Annarosa Ugolini, Charles Large, Enrico Domenici, Philip Gerrard, Donna Bortner, Isabelle M Mansuy, Laura Mangiarini, and Emilio Merlo-Pich.
• 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
• Pharmacol. Biochem. Behav. 2009 Jul 1; 93 (1): 17-24.

BackgroundConverging 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.MethodsMice 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.ResultsFollowing 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.ConclusionsTransient 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.

45 keywords...

hide…