Nature Neuroscience6, 1100 - 1107 (2003)
Published online: 14 September 2003; | doi:10.1038/nn1123
Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress
Marianne B Müller1, 3, Stephan Zimmermann1, 3, Inge Sillaber1, Thomas P Hagemeyer1, Jan M Deussing1, Peter Timpl1, Michael S D Kormann1, Susanne K Droste1, Ralf Kühn2, Johannes M H M Reul1, Florian Holsboer1
& Wolfgang Wurst1, 2
1
Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, Munich 80804, Germany.
2
Institute of Developmental Genetics, GSF Forschungszentrum, Ingolstädter Landstr. 1, Neuherberg 85764, Germany.
3
These authors contributed equally to this work.
Correspondence should be addressed to Wolfgang Wurst wurst@gsf.de
Corticotropin-releasing hormone (CRH) is centrally involved in coordinating responses to a variety of stress-associated stimuli. Recent clinical data implicate CRH in the pathophysiology of human affective disorders. To differentiate the CNS pathways involving CRH and CRH receptor 1 (Crhr1) that modulate behavior from those that regulate neuroendocrine function, we generated a conditional knockout mouse line (Crhr1loxP/loxPCamk2a-cre) in which Crhr1 function is inactivated postnatally in anterior forebrain and limbic brain structures, but not in the pituitary. This leaves the hypothalamic-pituitary-adrenocortical (HPA) system intact. Crhr1loxP/loxPCamk2a-cre mutants showed reduced anxiety, and the basal activity of their HPA system was normal. In contrast to Crhr1 null mutants, conditional mutants were hypersensitive to stress corticotropin and corticosterone levels remained significantly elevated after stress. Our data clearly show that limbic Crhr1 modulates anxiety-related behavior and that this effect is independent of HPA system function. Furthermore, we provide evidence for a new role of limbic Crhr1 in neuroendocrine adaptation to stress.
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