Behavioral responses to stress are intact in CRF-deficient mice

doi:10.1016/S0006-8993(99)01912-5

Brain Research

Volume 845, Issue 1, 16 October 1999, Pages 14-20

https://doi.org/10.1016/S0006-8993(99)01912-5 Get rights and content

Abstract

Corticotropin-releasing factor (CRF) has been implicated in endocrine and behavioral responses associated with stress. We have now studied the behavior of mice lacking the CRF gene (CRFko), comparing them to wild-type (WT) mice. Behaviors were observed in untreated mice, as well as following restraint or intraperitoneal administration of mouse interleukin-1β (mIL-1β). In the multicompartment chamber (MCC), the behaviors of CRFko and WT mice were very similar, and prior restraint and IL-1β induced similar decreases in stimulus-contact times in both genotypes. In the elevated plus maze (EPM), restraint decreased the number of open arm entries but the behavior of both genotypes was very similar. In the open field (OF), the changes in locomotor activity in response to restraint were similar in both genotypes, although CRFko mice displayed slightly increased locomotor activity compared to WT mice. In both the MCC and the EPM, grooming behavior was increased by restraint, and was higher in the CRFko than in the WT mice. Compared to WT mice, CRFko mice had lower basal plasma concentrations of corticosterone which did not increase significantly following footshock. Thus, CRFko mice showed a clear dichotomy; the stress-related activation of the hypothalamo-pituitary-adrenal (HPA) axis was absent, whereas the stress-related behavioral responses thought to be mediated by brain CRF were unaffected. These results suggest that when mice develop in the absence of CRF, another factor (or factors) assumes the behavioral functions normally ascribed to brain CRF, but not activation of the HPA axis. Alternatively, the natural modulator of behavior may not be CRF, but some other molecule that can act on receptors sensitive to CRF. Thus, redundant CNS mechanisms appear to be involved in stress-related behaviors.

Introduction

Corticotropin-releasing factor (CRF) was originally identified as a critical hypophysiotropic factor that could mediate the activation of the hypothalamo-pituitary-adrenocortical (HPA) axis in response to environmental stimuli [29]. CRF-containing cell bodies in the hypothalamic paraventricular nucleus project to the median eminence region of the hypothalamus where it is released and transported to the anterior pituitary from which it elicits secretion of ACTH. However, neurons containing CRF, mRNA for CRF, and various subtypes of CRF receptors have been identified outside the hypothalamus throughout much of the brain 6, 21, 22. Stressful stimuli have been shown to increase the apparent release of CRF in the central amygdaloid nucleus as determined by in vivo microdialysis [17].

Intracerebroventricular (i.c.v.) administration of CRF induces a variety of behavioral patterns that resemble those observed during stress 10, 15, 20. I.c.v. CRF administration also induces other physiological indices of stress, such as endocrine responses, changes in sympathetic and adrenomedullary activity, and activation of cerebral noradrenergic and dopaminergic but not serotonergic systems (for reviews, see Refs. 10, 20). The concept that brain CRF or its receptors may mediate some of these responses has been bolstered by the repeated observation that administration of CRF receptor antagonists can attenuate or reverse many of the behavioral and endocrine responses observed during stress, but not the neurochemical ones 10, 20. Also, transgenic mice with hypersecretion of CRF display behavior suggestive of increased anxiety 14, 26.

It was of interest to observe the behavioral and endocrine responses to restraint of mice lacking the ability to synthesize CRF to test the hypothesis that CRF is an essential mediator of physiological responses in stress. We also tested the responses to peripheral administration of interleukin-1β (IL-1β) which has been shown to mimic behavioral responses commonly observed during stress 9, 25.

Section snippets

Animals and materials

Adult male mice were provided by Drs. Joseph A. Majzoub and Louis Muglia of the Children's Hospital in Boston, MA. Wild type controls (WT) were homozygotes (Crf^+/+) and the CRF knockout mice (CRFko) were transgenic homozygotes (crf^−/−) inserted with an inactivated CRF gene produced as described previously [19]. Two separate batches of mice of each genotype were shipped to Shreveport. The mice were separated by genotype, but the identity of the genotype was not known by the experimenters until

Behavioral observations in the MCC

Mice were first tested in the MCC with or without prior restraint. Consistent with our earlier studies [3], restraint induced a statistically significant (F_1,30=72, p<0.0001) reduction in the mean time per contact (Fig. 1). There were no significant differences between WT and CRFko mice (F_1,30=1.37), but there was a significant restraint×genotype interaction (F_1,30=6.0, p<0.05). A significant interaction was not observed in an earlier experiment, and the effect in this experiment probably

Discussion

Behavior in the MCC has been shown to be reliably affected by a variety of stressors, such that the stimulus-contact time is reduced without consistent changes in locomotor activity in rats [1]and mice 3, 5. These responses were closely mimicked by i.c.v. administration of low doses of CRF in mice 3, 5and rats [24]. I.c.v. pretreatment with the CRF-receptor antagonist, α-helical CRF_9–41, prevented the restraint-induced changes in behavior [4], suggesting that brain CRF plays an important role

Acknowledgements

This research was supported by grants from the US National Institute of Mental Health (MH46261) and the US National Institute of Neurological Diseases and Stroke (NS25370). We thank Dr. Joseph A. Majzoub and Dr. Louis Muglia (Children's Hospital, Boston, MA) for providing the homozygous CRF knockout mice (crf^−/−) and the wild type (crf^+/+) mice. The technical assistance of Michael Adamkiewicz and Galina Mikhaylova is greatly appreciated.

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Research reportBehavioral responses to stress are intact in CRF-deficient mice

Abstract

Introduction

Section snippets

Animals and materials

Behavioral observations in the MCC

Discussion

Acknowledgements

Pharmacol. Biochem. Behav.

Life Sci.

Regul. Pept.

Horm. Behav.

Eur. J. Pharmacol.

Brain Res. Bull.

Brain Res. Rev.

Peptides

Neurosci.

Neuron

Pharmacol. Biochem. Behav.

Brain Behav. Immunol.

Pharmacol. Biochem. Behav.

Restraint-stress-induced changes in exploratory behavior appear to be mediated by norepinephrine-stimulated release of CRF

J. Neurosci.

Corticotropin-releasing factor receptors are widely distributed within the rat central nervous system: an autoradiographic study

J. Neurosci.

Research report
Behavioral responses to stress are intact in CRF-deficient mice