Down-Regulation of Hypothalamic Corticotropin-Releasing Hormone Messenger Ribonucleic Acid (mRNA) Precedes Early-Life Experience-Induced Changes in Hippocampal Glucocorticoid Receptor mRNA**This work was supported by NIH Grants NS-28912 and NS-39307.

Abstract

Early-life experiences, including maternal interaction, profoundly influence hormonal stress responses during adulthood. In rats, daily handling during a critical neonatal period leads to a significant and permanent modulation of key molecules that govern hormonal secretion in response to stress. Thus, hippocampal glucocorticoid receptor (GR) expression is increased, whereas hypothalamic CRH-messenger RNA (mRNA) levels and stress-induced glucocorticoid release are reduced in adult rats handled early in life. Recent studies have highlighted the role of augmented maternal sensory input to handled rats as a key determinant of these changes. However, the molecular mechanisms, and particularly the critical, early events leading from enhanced sensory experience to long-lasting modulation of GR and CRH gene expression, remain 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 CRH-mRNA expression at three developmental ages, and the temporal relationship between each of these changes and the emergence of reduced hormonal stress-responses. Down-regulation of hypothalamic CRH-mRNA levels in daily-handled rats was evident already by postnatal day 9, and was sustained through postnatal days 23 and 45, i.e. beyond puberty. In contrast, handling-related up-regulation of hippocampal GR-mRNA expression emerged subsequent to the 23rd postnatal day, i.e. much later than changes in hypothalamic CRH expression. The hormonal 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 mechanism(s) by which early-life experience influences the hormonal stress-response long-term.EARLY-LIFE EXPERIENCE influences both hormonal and behavioral responses to stress throughout life (1-5). In the human, early-life experiences may modulate stress-responses and coping, with long-term implications for emotional health and cognitive function (5). In rats, daily handling during a critical neonatal period leads to a significantly reduced stress response (compared with animals raised without any disturbance) that persists throughout

Early Paternal Deprivation Alters Levels of Hippocampal Brain-Derived Neurotrophic Factor and Glucocorticoid Receptor and Serum Corticosterone and Adrenocorticotropin in a Sex-Specific Way in Socially Monogamous Mandarin Voles

“…However, in the DG the decrease in GR was only evident in father-deprived females, and not males. This result is in agreement with previous studies whereby maternal deprivation reduced GR in the hippocampus in mice (particularly males) [29,38], and high levels of LG induce increased GR mRNA expression in rats (again, particularly in males) [39,40,41], accompanied by an attenuated response to stress [26,42,43]. Because hippocampal GR exerts a negative feedback regulation on the stress response of the HPA axis [24], it is not surprising that a reduction in hippocampal GR led by PD is also accompanied by increased stress reactivity, as indicated by higher levels of CORT here and in other studies [26,27,28,38].…”

Neonatal repetitive pain in rats leads to impaired spatial learning and dysregulated hypothalamic-pituitary-adrenal axis function in later life

“…The tactile stimulation was applied gently to the mid-plantar area of the corresponding paw using a cotton-tipped swab, at same interval and same paw order as the Needle group. The separation time of the rat pups from their dams was no more than 5 minutes for either group to avoid the effects of maternal separation and neonatal handling6061. The neonatal stimulation for both groups lasted for 8 days, from day of birth (P0) to postnatal day 7 (P7).…”

Maternal hormonal milieu influence on fetal brain development

“…High concentrations of CRH are found in situations of maternal stress and growthretarded fetuses (Weinstock et al, 1992;Weinstock, 2005). Handling of neonatal rat pups reduced hypothalamic CRH expression and reduced stress-induced glucocorticoid release, enhancing hippocampal GR expression in adult animals, in a well-defined sequence (Avishai-Eliner et al, 2001).…”

“…Particularly, repeated betamethasone administration to pregnant baboons resulted in impaired learning and attention disorders in 3-year-old female offspring(Rodriguez et al, 2011).The molecular mechanisms underlying the resetting of HPA axis, after endogenous or synthetic prenatal glucocorticoid exposure, have also been extensively studied. Clear key roles of epigenetic changes in CRH, intracellular GR and MR, 11β-HSD1, and 11β-HSD2 have been established(Avishai-Eliner, Eghbal-Ahmadi, Tabachnik, Brunson, & Baram, 2001;Diaz et al, 1998;Waffarn & Davis, 2012). Some of the epigenetic alterations were also found to occur in primordial germ cell formation, which can persist through fertilization and development of the subsequent generation(Cottrell & Seckl, 2009;Moisiadis & Matthews, 2014a, 2014b.…”