Corticotropin Releasing Factor Receptor 1-deficient Mice Display Decreased Anxiety, Impaired Stress Response, and Aberrant Neuroendocrine Development

Neuron. 1998 Jun;20(6):1093-102. doi: 10.1016/s0896-6273(00)80491-2.

Abstract

Corticotropin releasing factor (CRF) is a major integrator of adaptive responses to stress. Two biochemically and pharmacologically distinct CRF receptor subtypes (CRFR1 and CRFR2) have been described. We have generated mice null for the CRFR1 gene to elucidate the specific developmental and physiological roles of CRF receptor mediated pathways. Behavioral analyses revealed that mice lacking CRFR1 displayed markedly reduced anxiety. Mutant mice also failed to exhibit the characteristic hormonal response to stress due to a disruption of the hypothalamic-pituitary-adrenal (HPA) axis. Homozygous mutant mice derived from crossing heterozygotes displayed low plasma corticosterone concentrations resulting from a marked agenesis of the zona fasciculata region of the adrenal gland. The offspring from homozygote crosses died within 48 hr after birth due to a pronounced lung dysplasia. The adrenal agenesis in mutant animals was attributed to insufficient adrenocorticotropic hormone (ACTH) production during the neonatal period and was rescued by ACTH replacement. These results suggest that CRFR1 plays an important role both in the development of a functional HPA axis and in mediating behavioral changes associated with anxiety.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptation, Physiological / physiology
  • Adrenal Gland Diseases / drug therapy
  • Adrenal Gland Diseases / genetics
  • Adrenal Gland Diseases / mortality
  • Adrenal Glands / growth & development
  • Adrenal Glands / pathology
  • Adrenocorticotropic Hormone / metabolism
  • Animals
  • Anxiety / genetics*
  • Anxiety / metabolism
  • Behavior, Animal / physiology
  • Chimera
  • Corticosterone / pharmacology
  • Female
  • Gene Expression Regulation, Developmental / physiology*
  • Homozygote
  • Male
  • Maze Learning / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Neurologic Mutants
  • Mutation / physiology
  • Neurosecretory Systems / growth & development*
  • Neurosecretory Systems / pathology
  • Paraventricular Hypothalamic Nucleus / chemistry
  • Paraventricular Hypothalamic Nucleus / metabolism
  • Pituitary Gland / growth & development
  • Receptors, Corticotropin-Releasing Hormone / genetics*
  • Stress, Physiological / genetics*
  • Stress, Physiological / metabolism
  • Survival Analysis

Substances

  • Receptors, Corticotropin-Releasing Hormone
  • Adrenocorticotropic Hormone
  • Corticosterone