Rapid Induction of Corticotropin-Releasing Hormone Gene Transcription in the Paraventricular Nucleus of the Developing Rat

Abstract

Neonates from postnatal days (pnd) 4 -14 display a minimal pituitary-adrenal response to mild stress, the so-called stress hyporesponsive period (SHRP). However, during the SHRP, maternal deprivation (deprived) alters the pituitary-adrenal system, enabling neonates to become endocrine responsive to specific stimuli. Although neonates do display stress-induced ACTH, there is limited evidence for enhanced CRH gene expression early in development. The present experiment examined whether a mild stimulus (isotonic saline injection) administered to deprived and nondeprived neonates would enhance CRH biosynthesis in the paraventricular nucleus. Using in situ hybridization we measured the time course of CRH heteronuclear RNA (hnRNA) and messenger RNA at 15, 30, and 240 min poststimulus. Pnd 6, 12, and 18 were included to examine the CRH gene response during and outside of the SHRP. Despite the minimal endocrine response of nondeprived pups during the SHRP, CRH hnRNA and messenger RNA were elevated at 15 min (all ages). Both transcripts were enhanced at 15-30 min in deprived (pnd 12 and 18) pups; however, the magnitude of the response was less than that in nondeprived pups. These data indicate that during ontogeny there is a rapid stimulus-induced CRH biosynthesis. Thus, during development, the central components of the hypothalamic-pituitary-adrenal axis may be stress hyperresponsive rather than hyporesponsive. (Endocrinology 141: [1593][1594][1595][1596][1597][1598] 2000) O NTOGENETIC STUDIES have described a period from postnatal days (pnd) 4 -14 during which neonates display a blunted adrenocortical stress response, the socalled stress-hyporesponsive period (SHRP) (1, 2). Although the adrenal is less responsive during this developmental period, the SHRP is not absolute. At the pituitary level, neonates show a robust ACTH response to excitatory amino acids (3), histamine, ether, cold (4), and interleukin-1 (5). Yet, the pituitary-adrenal system remains relatively unresponsive to mild perturbations such as novelty or a saline injection. Moreover, after 24 h of maternal deprivation, neonates show enhanced ACTH and corticosterone (CORT) in response to these mild stimuli (6, 7). Thus, the stress response during the SHRP is stimulus specific and is in part dependent upon which component of the hypothalamic-pituitaryadrenal (HPA) axis is evaluated and upon maternal factors.The central component of the HPA axis may be stress responsive during the SHRP; mild stimuli enhance c-fos and nerve growth factor I-B expression in the paraventricular nucleus (PVN) (8, 9). However, although stress seems to amplify neural activity in the neonatal PVN, stimulusinduced CRH gene expression has rarely been reported. During the first week of life, adrenalectomy (10), cold, (11), glucocorticoid receptor antagonism and surgical stress (12) reportedly did not increase CRH gene transcription. We recently reported that endotoxin treatment during the SHRP results in a hormonal response, without an increase in PVN-CRH messenger RNA (mRNA)...

Brain corticotropin-releasing hormone (CRH) circuits in the developing rat: Effect of maternal deprivation

“…Of interest is the fact that restraint, particularly in 12-and 18-day-old animals increased the septum, CRH, CRHbp and CRHr1 mRNA levels. This general pattern of upregulation is similar to what is observed in PVN in both adult and developing animals (Dent et al, 2000b;Makino et al, 1995). These findings provide evidence that there is sensitivity and specificity of the extra-hypothalamic CRH system to environmental manipulation during the neonatal period.…”

“…Surprisingly, although non-deprived animals have minimal adrenal response to this stressor, a rapid induction of CRH mRNA transcription was observed in the PVN. In addition, the small elevation in glucocorticoid level was capable of suppressing the early induction in all ages studied (Dent et al, 2000b). These data suggest that during ontogeny central brain elements are clearly responsive to environmental events even though adrenal responses may be limited and that small but significant elevations in glucocorticoids can elicit negative regulation of these responses.…”

Neuronal activity and stress differentially regulate hippocampal and hypothalamic corticotropin-releasing hormone expression in the immature rat

“…Using specific probes directed against heteronuclear (unedited) CRH RNA, our 6 and other 17 groups have shown a rapid activation of the CRH gene in the immature rat hypothalamus after appropriate challenges. The half-life of heteronuclear CRH RNA is short, permitting resolution of gene activation and inactivation in the range of minutes.…”

“…The half-life of heteronuclear CRH RNA is short, permitting resolution of gene activation and inactivation in the range of minutes. 6,17 However, steadystate CRH mRNA levels, with their slow turnover, may not fully reflect the kinetics of CRH gene activation in the immature rat.…”

Neurobiology of the stress response early in life: evolution of a concept and the role of corticotropin releasing hormone

“…[6][7][8][9][10] This stress hyporesponsiveness during development appears to be stressor-specific, since the hypothalamic pituitary adrenal (HPA) axis is fully capable of responding to stimuli that may be considered stressful to a neonatal rat (eg, cold or saline injection). 8,11,12 Although fully operational during development, the magnitude of the hormonal response to stress increases with developmental age. 11,13,14 This review focuses on studies highlighting the molecular chain of events triggered by stressful signals early in life, with an emphasis on the role of CRH, the key central nervous system transducer of stressful stimuli.…”