Diurnal regulation of hypothalamic CRH mRNA and anterior pituitary POMC expression.

Abstract

The hypothalamo-pituitary-adrenal axis is an important mediator of physiological responses to stress. The axis also exhibits a clear diurnal rhythm such that resting levels of adrenal corticosteroids and plasma ACTH levels increase periodically. These changes appear to be initiated by an intrinsic circadian mechanism in the brain which exerts its effect on the endocrine system by stimulating the ACTH secretagogue corticotropin-releasing hormone (CRH). In addition, the daily fluctuation of adrenal corticosteroids appears inhibit the diurnal secretion of ACTH and CRH in a feedback fashion. The effects of these two opposing influences on the daily expression of CRH mRNA in the hypothalamus are poorly characterized. Yet, since the mRNA status of this key neuroendocrine peptide has been shown to be crucial for setting the tone of the HPA response to stress, it is of foremost importance to determine how basal CRH mRNA levels oscillate during the circadian period. Experiments were conducted to characterize the diurnal pattern of CRH mRNA expression in the rat hypothalamus, and to determine the effects of endogenous corticosteroids on this rhythm. Results indicate that CRH mRNA levels oscillate rhythmically but in a pattern distinct from that of ACTH and corticosterone in plasma. Notable observations include the finding that CRH mRNA levels increase prior to the diurnal secretory event much in an anticipatory fashion. CRH mRNA levels decrease significantly as the glucocorticoid secretion reach the secretory peak but this decrease does not appear to result from rapid steroid inhibition. Instead, a central brain component appears to be responsible for both the anticipatory rise and the apparent inhibition. The effect of diurnal glucocorticoid oscillation on CRH mRNA expression is to maintain the overall level within a physiological norm without affecting the shape of the diurnal CRH mRNA rhythm. Finally, POMC gene expression parallels the circadian secretory rhythm, suggesting that the mechanism which affects CRH mRNA expression does not directly influence the POMC gene, but does so via CRH peptide secretion. Implications of the endogenous CRH mRNA rhythm are discussed.