ABSTRACT
A long-standing paradigm posits that hypothalamic corticotropin-releasing hormone (CRH) regulates neuroendocrine functions such as adrenal glucocorticoid release, whereas extra-hypothalamic CRH has a key role in stressor-triggered behaviors. Here we report that hypothalamus-specific Crh knockout mice (Sim1CrhKO mice, created by crossing Crhflox with Sim1Cre mice) have absent Crh mRNA and peptide mainly in the paraventricular nucleus of the hypothalamus (PVH) but preserved Crh expression in other brain regions including amygdala and cerebral cortex. As expected, Sim1CrhKO mice exhibit adrenal atrophy as well as decreased basal, diurnal and stressor-stimulated plasma corticosterone secretion and basal plasma adrenocorticotropic hormone, but surprisingly, have a profound anxiolytic phenotype when evaluated using multiple stressors including open-field, elevated plus maze, holeboard, light-dark box and novel object recognition task. Restoring plasma corticosterone did not reverse the anxiolytic phenotype of Sim1CrhKO mice. Crh-Cre driver mice revealed that PVHCrh fibers project abundantly to cingulate cortex and the nucleus accumbens shell, and moderately to medial amygdala, locus coeruleus and solitary tract, consistent with the existence of PVHCrh-dependent behavioral pathways. Although previous, nonselective attenuation of CRH production or action, genetically in mice and pharmacologically in humans, respectively, has not produced the anticipated anxiolytic effects, our data show that targeted interference specifically with hypothalamic Crh expression results in anxiolysis. Our data identify neurons that express both Sim1 and Crh as a cellular entry point into the study of CRH-mediated, anxiety-like behaviors and their therapeutic attenuation.
Subject(s)
Anxiety/metabolism , Corticotropin-Releasing Hormone/deficiency , Hypothalamus/metabolism , Adrenocorticotropic Hormone/metabolism , Amygdala/metabolism , Animals , Corticosterone/blood , Corticotropin-Releasing Hormone/isolation & purification , Corticotropin-Releasing Hormone/metabolism , Female , Glucocorticoids/metabolism , Hypothalamo-Hypophyseal System/metabolism , Mice , Mice, Inbred ICR , Mice, Mutant Strains , Neurons/metabolism , Pituitary Hormone-Releasing Hormones/metabolism , Pituitary-Adrenal System/metabolism , RNA, Messenger/metabolism , Receptors, Corticotropin-Releasing Hormone/genetics , Receptors, Corticotropin-Releasing Hormone/metabolism , Receptors, Glucocorticoid/metabolismABSTRACT
Using a rat creatine kinase (brain form) cDNA clone for in situ hybridization, we have localized the gene in both the human and the rabbit complement. An analysis of the data shows that the locus in the human is at 14q32, confirming previous assignments based on somatic hybridization studies and Southern blot analysis. In the rabbit, significant accumulation on 20q13----qter with the predominant labeling at the end of the chromosome provides evidence for the localization of the gene at this site. The heterologous hybridizations of a rat probe to both human and rabbit metaphases underscore the highly conserved nature of the sequences for this enzyme.
