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Development neurobiology of the stress response: multilevel regulation of corticotropin-releasing hormone function
T Z Baram1, S Yi, S Avishai-Eliner
1Department of Anatomy & Neurobiology, University of California, Irvine 92697-4475, USA.
Insights
Neonatal rats show an immature stress response, with corticotropin-releasing hormone (CRH) playing a key role. Glucocorticoid feedback and CRH receptor development are crucial for regulating this early-life stress adaptation.
Area of Science:
- Neuroscience
- Endocrinology
- Developmental Biology
Background:
- Neonatal and infant rats exhibit an immature capacity to respond to environmental stressors.
- The hormonal stress response involves hypothalamic corticotropin-releasing hormone (CRH) and vasopressin, but their roles in early development are debated.
- Understanding these mechanisms is crucial for comprehending early-life stress adaptation.
Purpose of the Study:
- To investigate the roles of CRH and its receptors in the developing stress-response system of neonatal and infant rats.
- To examine the developmental regulation of CRH synthesis and glucocorticoid feedback.
- To characterize the expression patterns of CRH receptors in key brain regions during early postnatal development.
Main Methods:
- CRH-mRNA levels in the hypothalamic paraventricular nucleus (PVN) were measured following cold stress.
- In vivo and in vitro experiments assessed glucocorticoid feedback on CRH synthesis.
- CRF1-mRNA expression was analyzed in the hippocampus, amygdala, and cortex at different postnatal ages.
Main Results:
- CRH synthesis up-regulation was observed by postnatal day 9 but not in the first week.
- Glucocorticoid feedback on CRH synthesis was immature during the first postnatal week.
- CRF1-mRNA showed distinct spatial and temporal expression patterns, with peaks in the hippocampus and amygdala at specific early ages.
Conclusions:
- The early postnatal stress response is regulated by multiple, developmentally controlled factors.
- CRH synthesis, glucocorticoid sensitivity, and CRH receptor distribution are key regulatory points.
- These mechanisms enable effective endocrine, autonomic, and behavioral adaptations to stress in early life.
Abstract:
The ability to respond to adverse environmental cues is present in the neonatal and infant rat, although in an immature form: A number of laboratories have demonstrated stress-induced elevations of plasma glucocorticoids during the first two postnatal weeks. The limbic and hypothalamic mechanisms controlling the hormonal stress-response during this period are not fully understood and are, therefore, the focus of this report. Both hypothalamic corticotropin-releasing hormone (CRH) and vasopressin contribute to the release of ACTH from the pituitary in the adult. The relative roles of these two peptides during the neonatal (first week) and infant (second week) developmental period, are controversial. Evidence is presented that argues strongly for a major role for CRH. Up-regulation of hypothalamic CRH synthesis is a major component in the mature stress response. CRH-mRNA levels in the hypothalamic PVN are increased with cold stress by ninth postnatal day, but not during the first postnatal week. Further, down-regulation of CRH gene expression by glucocorticoids (GC) constitutes a critical "shut-down" mechanism for the hormonal stress response. In vivo and in vitro experiments supporting the "immaturity" of GC feedback on CRH synthesis during the first postnatal week are described. CRH-mediated neurotransmission, in both the endocrine and neuronal effector arms of the response to stress may be modulated via alteration of receptor number. The first member of the CRH receptor family, CRF1, probably mediates the neuroendocrine effects of CRH. The developmental profile of CRF1-mRNA reveals several distinctive spatial and temporal patterns. In the hippocampal CA1, CA2, and CA3a peak (300-600% adult values) CRF1-mRNA is found on postnatal day 6. In the amygdala, CRH receptor mRNA levels are maximal on the ninth postnatal day (at 180% of adult values). In cortex, a steady decline from high postnatal day 2 levels results in adult levels by 12. These findings demonstrate distinct, regional, age-specific control of the synthesis of CRF1. Receptor expression profile may provide important information regarding modulation of the age-specific roles of CRH in different regions. For example, a high ratio of hippocampus/amygdala receptors may preferentially activate negative hippocampal input to the hypothalamus during the neonatal period. Additionally, increased CRH receptor mRNA in the infant compared with the adult provides a mechanism for enhanced excitatory effect of the peptide at this age. In conclusion, increasing evidence exists for multiple control points of the early postnatal response and adaptation to stress. CRH synthesis in hypothalamus and amygdala, its sensitivity to GC feedback, and the abundance and distribution of at least two distinct CRH receptors in the limbic central nervous system and the pituitary are developmentally regulated. All serve as control points permitting an effective endocrine, autonomic, and behavioral response to stressful environmental cues.