Distribution and expression of CRF receptor 1 and 2 mRNAs in the CRF over-expressing mouse brain

Abstract

Corticotropin-releasing factor (CRF) acts through CRF 1 and CRF 2 receptors (CRF1, CRF2). To test the hypothesis that CRF controls the expression of these receptors in a brain site- and receptor-type specific manner, we studied CRF1 mRNA and CRF2 mRNA expressions in mice with central CRF over-expression (CRF-OE) and using in situ hybridization. CRF1 and CRF2 mRNAs appear to be differentially distributed across the brain. The brain structures expressing the receptors are the same in wild-type (WT) and in CRF-OE mice. We therefore conclude that chronically elevated CRF does not induce or inhibit expression of these receptors in structures that normally do not or do, respectively, show these receptors. However, from counting cell body profiles positive for CRF1 and CRF2 mRNAs, clear differences appear in receptor expression between CRF-OE and WT mice, in a brain-structure-specific fashion. Whereas some structures do not differ, CRF-OE mice exhibit remarkably lower numbers of CRF1 mRNA-positive profiles in the subthalamic nucleus (-38.6%), globus pallidus (-31.5%), dorsal part of the lateral septum (-23.5%), substantia nigra (-22,8%), primary somatosensory cortex (-18.9%) and principal sensory nucleus V (-18.4%). Furthermore, a higher number of CRF2 mRNA-positive profiles are observed in the dorsal raphe nucleus (+32.2%). These data strongly indicate that central CRF over-expression in the mouse brain is associated with down-regulation of CRF1 mRNA and up-regulation of CRF2 mRNA in a brain-structure-specific way. On the basis of these results and the fact that CRF-OE mice reveal a number of physiological and autonomic symptoms that may be related to chronic stress, we suggest that CRF1 in the basal nuclei may be involved in disturbed information processing and that CRF2 in the dorsal raphe nucleus may play a role in mediating stress-induced release of serotonin by CRF.

An Anxiolytic Role for CRF Receptor Type 1 in the Globus Pallidus

“…This result can be interpreted as a stressinduced inhibition of CRFR1 function in the GPe, here proposed to be anxiolytic. Our finding is in accordance with a previous study showing that in a mouse model of central CRF overexpression, which reveals a number of physiological and autonomic symptoms related to chronic stress, CRFR1 mRNA expression is reduced in the globus pallidus (Korosi et al, 2006).…”

“…However, there are some experimental data, as indicated below, suggesting a possible functional stress-related role for CRFR1 in the GPe. In a mouse model of central CRF overexpression, which reveals a number of physiological and autonomic symptoms related to chronic stress, CRFR1 mRNA expression was reduced mainly in the globus pallidus (Korosi et al, 2006). Consistent with this finding, CRF levels were significantly increased in the striatum, the main afferent to the GPe, of 72 h sleep-deprived rats, a model that incorporates multiple stress factors such as isolation, immobility, and general stress (Fadda and Fratta, 1997).…”

“…Antisense and sense (control) RNA probes were generated using mouse CRFR1 cDNA and labeled with DIG-11-UTP using a labeling kit from Roche Molecular Biochemicals. In situ hybridization of CRFR1 mRNA was performed with the free-floating section method, as previously reported (Korosi et al, 2006). CRFR1-positive cell nuclei within the GPe and the reticular thalamic nucleus (Rt) were counted on two representative sections per animal from the lentisiCRFR1 and the control virus group (n ϭ 3 each group).…”

Urocortin-1 and -2 double-deficient mice show robust anxiolytic phenotype and modified serotonergic activity in anxiety circuits

“…In situ hybridization of CRF mRNA was carried out with the free-floating section method, as reported by Korosi et al 38 Adrenal glands from both WT and Ucn1/Ucn2 dKO mice were rapidly dissected and placed in 4% paraformaldehyde overnight. Tissues (WT, n = 4; Ucn1/Ucn2 dKO, n = 5) were dehydrated, embedded in paraffin, sectioned and stained with hematoxylin and eosin according to the standard protocols.…”

Forebrain-Specific CRF Overproduction During Development is Sufficient to Induce Enduring Anxiety and Startle Abnormalities in Adult Mice

“…Interestingly, CRF was recently found to exert anxiolytic actions in the globus pallidus and midbrain dopaminergic neurons in contrast to its major anxiogenic effects in the forebrain (Muller et al, 2003;Refojo et al, 2011;Sztainberg et al, 2011). Lifetime CRFOE was also reported to induce significant CRF receptor expression changes in several forebrain areas including the cortex, septum, globus pallidus, and substantia nigra with additional reduction of urocortin expression (Korosi et al, 2006;Kozicz et al, 2004). These findings may partially explain the different phenotypes between the CRFOE dev , CRFOE life , and CRFOE adult exposure models, with striatal CRF signaling possibly competing with the anxiogenic effects of CRF in other limbic regions.…”