IMPAIRED DIURNAL ADRENAL RHYTHMICITY RESTORED BY CONSTANT INFUSION OFCORTICOTROPIN-RELEASING HORMONE IN CORTICOTROPIN-RELEASING HORMONE-DEFICIENT MICE

The normal pattern of daily glucocorticoid production in mammals requi res circadian modulation of hypothalamic-pituitary-adrenal axis activi ty. To assess both the factors responsible for imparting this diurnal profile and its physiologic importance, we have exploited corticotropi n-releasing hormone (CRH)-deficient mice generated by homologous recom bination in embryonic stem cells. CRH-deficient mice have lost normal circadian variations in plasma ACTH and glucocorticoid while maintaini ng normal circadian locomotor activity. Constant peripheral infusion o f CRH produced marked diurnal excursions of plasma glucocorticoid, ind icating that CRH acts in part as a permissive factor for other circadi an modulators of adrenocortical activity. The presence of atrophic adr enals in CRH-deficient mice without an overt deficit in basal plasma A CTH concentration suggests that the diurnal increase in ACTH is essent ial to maintain normal adrenal function.