Bale Tracy L, Picetti Roberto, Contarino Angelo, Koob George F, Vale Wylie W, Lee Kuo-Fen
Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California 92037, USA.
J Neurosci. 2002 Jan 1;22(1):193-9. doi: 10.1523/JNEUROSCI.22-01-00193.2002.
Corticotropin-releasing factor (CRF) and its family of peptides are critical coordinators of homeostasis whose actions are mediated through their receptors, CRF receptor 1 (CRFR1) and CRFR2, found throughout the CNS and periphery. The phenotypes of mice deficient in either CRFR1 or CRFR2 demonstrate the critical role these receptors play. CRFR1-mutant mice have an impaired stress response and display decreased anxiety-like behavior, whereas CRFR2-mutant mice are hypersensitive to stress and display increased anxiety-like behavior. To further elucidate the roles of both CRF receptors and determine their interaction in behaviors, we have generated mice deficient in both CRFR1 and CRFR2. The behavioral phenotype of these mice demonstrates a novel role of the mother's genotype on development of pup anxiety. We have found that although the female double-mutant mice display anxiolytic-like behavior, the male double-mutant mice show significantly more anxiety-like behavior compared with the females. We have also determined that the dam's CRFR2 genotype affects the anxiety-like behavior of the male mice, such that a pup born to a heterozygous or mutant dam displays significantly more anxiety-like behavior regardless of that pup's genotype. Double-mutant mice also display an even greater impairment of their hypothalamic-pituitary-adrenal axis response to stress than that of the CRFR1-mutant mice. CRF mRNA levels are elevated in CRFR1- and double-mutant mice, and urocortin III and vasopressin mRNA levels are increased in CRFR2- and double-mutant mice. These results indicate that both CRFR1 and CRFR2 have critical roles in gene regulation and the maintenance of homeostasis in response to stress.
促肾上腺皮质激素释放因子（CRF）及其肽家族是体内稳态的关键协调因子，其作用通过遍布中枢神经系统和外周的受体——CRF受体1（CRFR1）和CRFR2介导。缺乏CRFR1或CRFR2的小鼠的表型证明了这些受体所起的关键作用。CRFR1突变小鼠的应激反应受损，焦虑样行为减少，而CRFR2突变小鼠对应激高度敏感，焦虑样行为增加。为了进一步阐明两种CRF受体的作用并确定它们在行为中的相互作用，我们培育出了同时缺乏CRFR1和CRFR2的小鼠。这些小鼠的行为表型证明了母亲的基因型在幼崽焦虑发育中的新作用。我们发现，尽管雌性双突变小鼠表现出抗焦虑样行为，但雄性双突变小鼠与雌性相比表现出明显更多的焦虑样行为。我们还确定，母鼠的CRFR2基因型会影响雄性小鼠的焦虑样行为，因此，无论幼崽的基因型如何，由杂合或突变母鼠所生的幼崽都表现出明显更多的焦虑样行为。双突变小鼠对压力的下丘脑 - 垂体 - 肾上腺轴反应的损害也比CRFR1突变小鼠更大。CRFR1和双突变小鼠中CRF mRNA水平升高，CRFR2和双突变小鼠中促肾上腺皮质激素原III和加压素mRNA水平升高。这些结果表明，CRFR1和CRFR2在基因调控以及应激反应中体内稳态的维持方面都起着关键作用。
