Down-regulation of hypothalamic corticotropin-releasing hormone messenger ribonucleic acid (mRNA) precedes early-life experience-induced changes in hippocampal glucocorticoid receptor mRNA

Early-life experiences, including maternal interaction, profoundly influenc e hormonal stress responses during adulthood. In rats, daily handling durin g a critical neonatal period leads to a significant and permanent modulatio n of key molecules that govern hormonal secretion in response to stress. Th us, hippocampal glucocorticoid receptor (GR) expression is increased, where as hypothalamic CRH-messenger RNA (mRNA) levels and stress-induced glucocor ticoid release are reduced in adult rats handled early in life. Recent stud ies have highlighted the role of augmented maternal sensory input to handle d rats as a key determinant of these changes. However, the molecular mechan isms, and particularly the critical, early events leading from enhanced sen sory experience to long-lasting modulation of GR and CRH gene expression, r emain largely unresolved. To elucidate the critical, primary genes governing this molecular cascade, we determined the sequence of changes in GR-mRNA levels and in hypothalamic and amygdala GRH-mRNA expression at three developmental ages, and the temp oral relationship between each of these changes and the emergence of reduce d hormonal stress-responses. Down-regulation of hypothalamic GRH-mRNA levels in daily-handled rats was e vident already by postnatal day 9, and was sustained through postnatal days 23 and 45, i.e. beyond puberty. In contrast, handling-related up-regulatio n of hippocampal GR-mRNA expression emerged subsequent to the 23rd postnata l day, i.e. much later than changes in hypothalamic CRH expression. The hor monal stress response of handled rats was reduced starting before postnatal day 23. These findings indicate that early, rapid, and persistent changes of hypothalamic CRH gene expression may play a critical role in the mechani sm(s) by which early-life experience influences the hormonal stress-respons e long-term.