DIURNAL CRH MESSENGER-RNA RHYTHM IN THE HYPOTHALAMUS - DECREASED EXPRESSION IN THE EVENING IS NOT DEPENDENT ON ENDOGENOUS GLUCOCORTICOIDS

被引:60
作者
KWAK, SP
MORANO, MI
YOUNG, EA
WATSON, SJ
AKIL, H
机构
[1] Mental Health Research Institute, University of Michigan, Ann Arbor, MI
关键词
ADRENALECTOMY; HPA AXIS; TRANSCRIPTION; ACTH; FEEDBACK INHIBITION; CORTICOSTERONE; TYPE-I CORTICOSTEROID RECEPTOR; MINERALOCORTICOID RECEPTOR;
D O I
10.1159/000126347
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Levels of hypothalamic corticotropin-releasing hormone (CRH) mRNA and plasma glucocorticoids vary diurnally as a result of circadian influences on the hypothalamopituitary-adrenal axis. CRH mRNA expression increases from morning to aftemoon in rats but decreases rapidly near the onset of dark as glucocorticoids reach peak concentrations in plasma. Since glucocorticoids are normally inhibitory on hypothalamic CRN mRNA expression, we determined whether the glucocorticoid secretion at the diurnal peak reduced CRH mRNA concentration in the evening. We found that adrenalectomy did not prevent the decrease in CRH mRNA levels near the onset of dark. It appears that the drop in CRH mRNA expression occurs via a steroid-independent mechanism. While the mean CRH mRNA level increased after adrenalectomy, the shape of the CRH mRNA rhythm remained unchanged except in the moming. Interestingly, adrenalectomy increased CRH mRNA levels disproportionately in the moming, producing a sharp rise followed by a plateau during the light phase instead of the gradual rise observed in intact animals. We subsequently treated adrenalectomized animals with corticosterone pellets to determine whether a constant steroid signal was sufficient in restoring the normal shape of the mRNA rhythm during the light phase. Results indicate that the endogenous steroid rhythm is not necessary for generating the normal CRH mRNA rhythm during the light phase. Instead, a constant exposure to corticosterone at approximately 50% of the daily mean (2.4-3 mug/dl) appears to be sufficient for regulation of the mRNA rhythm. Additionally, corticosterone replacement achieving a lower concentration of 1.5 mug/dl seems effective in regulating basal ACTH secretion in the moming despite being insufficient for regulating CRH or POMC mRNA levels at this time. We conclude that the shape of the diurnal CRH mRNA rhythm in the hypothalamus is largely independent of steroid regulation, although a steroid-dependent component appears to exist during the circadian nadir. A constant steroid level in the range primarily for type I corticosteroid receptor binding can reinstate CRH mRNA variation which occurs during the light phase, indicating that corticosterone oscillation is not necessary for diurnal CRH mRNA regulation. Finally, corticosterone may regulate basal ACTH secretion more effectively than CRH mRNA expression at the diurnal nadir.
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页码:96 / 105
页数:10
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