Transient forebrain over-expression of CRF induces plasma corticosterone and mild behavioural changes in adult conditional CRF transgenic mice

• Published in: Pharmacology, biochemistry and behavior Vol. 93; no. 1; pp. 17 - 24
• Main Authors: Vicentini, Elena, Arban, Roberto, Angelici, Ornella, Maraia, Gabriella, Perico, MariaElisa, Mugnaini, Manolo, Ugolini, Annarosa, Large, Charles, Domenici, Enrico, Gerrard, Philip, Bortner, Donna, Mansuy, Isabelle M., Mangiarini, Laura, Merlo-Pich, Emilio
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Inc 01.07.2009; Elsevier
• Subjects: Adult and adolescent clinical studies; Animals; Anxiety; Anxiety - etiology; Anxiety - genetics; Anxiety - physiopathology; Base Sequence; Behavior, Animal - drug effects; Behavior, Animal - physiology; Biological and medical sciences; Corticosterone - blood; Corticotropin-Releasing Hormone - genetics; Corticotropin-Releasing Hormone - physiology; CRF; Depression; Dexamethasone - pharmacology; Disease Models, Animal; DNA Primers - genetics; Doxycycline; Female; Gene Expression; HPA axis; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mood disorders; Mood Disorders - etiology; Mood Disorders - genetics; Mood Disorders - physiopathology; Prosencephalon - physiology; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Rats; RNA, Messenger - genetics; RNA, Messenger - metabolism; Stress, Physiological - genetics; Stress, Physiological - physiology; Synaptic Transmission - genetics; Synaptic Transmission - physiology; Transgenic mice; Depression; HPA axis; Anxiety; CRF; Transgenic mice; Doxycycline; Biological fluid; Hypothalamohypophysoadrenal axis; Corticosterone; Central nervous system; Corticotropin releasing factor; Transgenic animal; Gene overexpression; Glucocorticoid; Blood plasma; Adult; Protein synthesis inhibitor; Hormone releasing factor; Human; Mood disorder; Steroid hormone; Tetracycline derivatives; Rodentia; Behavior change; Prosencephalon; Hypothalamic hormone; Vertebrata; Mammalia; Mouse; Adrenal hormone
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2009.03.015

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