Conditional CRF receptor 1 knockout mice show altered neuronal activation pattern to mild anxiogenic challenge.
BACKGROUND
Regional-specific corticotropin-releasing factor receptor 1 (CRF-R1) knockout mice have been generated recently as a tool to dissociate CNS functions modulated by this receptor. In these mice, CRF-R1 function is postnatally inactivated in the anterior forebrain including limbic brain structures but not in the pituitary leading to normal activity of the hypothalamic-pituitary-adrenocortical (HPA) axis under basal conditions and reduced anxiety-related behavior in the light-dark box and the elevated plus maze (EPM) as compared to wild-type (WT) mice (Müller et al., Nat Neurosci 6:1100-1107, 2003).


OBJECTIVE
To identify neurobiological correlates underlying this reduced anxiety-like behavior, the expression of c-Fos, an established marker for neuronal activation, which was examined in response to a mild anxiogenic challenge.


METHODS
Mice were placed for 10 min on the open arm (OA) of the EPM, and regional c-Fos expression was investigated by immunohistochemistry.


RESULTS
OA exposure enhanced c-Fos expression in both conditional CRF-R1 knockout and WT mice in a number of brain areas (39 of 55 quantified), including cortical, limbic, thalamic, hypothalamic, and hindbrain regions. The c-Fos response in conditional CRF-R1 knockout animals was reduced in a restricted subset of activated neurons (4 out of 39 regions) located in the medial amygdala, ventral lateral septum, prelimbic cortex, and dorsomedial hypothalamus.


CONCLUSIONS
These results underline the importance of limbic CRF-R1 in modulating anxiety-related behavior and suggest that reduced neuronal activation in the identified limbic and hypothalamic key structures of the anxiety circuitry may mediate or contribute to the anxiolytic-like phenotype observed in mice with region-specific deletion of forebrain CRF-R1.
Nguyen
Ngoc Khoi
NK
Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Peter-Mayrstr. 1, 6020, Innsbruck, Austria.
Keck
Martin E
ME
Hetzenauer
Alfred
A
Thoeringer
Christoph K
CK
Wurst
Wolfgang
W
Deussing
Jan M
JM
Holsboer
Florian
F
Müller
Marianne B
MB
Singewald
Nicolas
N
D000679:Amygdala / Q000033:anatomy & histology / Q000378:metabolism; D000818:Animals; D001008:Anxiety Disorders / Q000235:genetics / Q000503:physiopathology*; D001522:Behavior, Animal / Q000502:physiology; D007034:Hypothalamus, Posterior / Q000033:anatomy & histology / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008953:Models, Anatomic; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D017397:Prefrontal Cortex / Q000033:anatomy & histology / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D018019:Receptors, Corticotropin-Releasing Hormone / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D012686:Septal Nuclei / Q000033:anatomy & histology / Q000378:metabolism; D013997:Time Factors; D000099052:CRF Receptor, Type 1
D016760:Proto-Oncogene Proteins c-fos; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1