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Persistent, but Paradoxical, Effects on HPA Regulation of Infants Maternally Deprived at Different Ages
van Oers HJ1, de Kloet ER, Levine
1Division of Medical Pharmacology, Leiden Amsterdam Center for Drug Research (LACDR), University of Leiden, 2300 RA Leiden, The Netherlands.
Insights
Neonatal maternal deprivation impacts the hypothalamic-pituitary-adrenal (HPA) axis, altering stress responses and glucocorticoid receptor (GR) gene expression. The effects depend on the age of deprivation, influencing ACTH reactivity and GR levels.
Area of Science:
- Neuroscience
- Endocrinology
- Developmental Psychology
Background:
- Maternal deprivation significantly affects the hypothalamic-pituitary-adrenal (HPA) axis.
- Early life stress can lead to long-term neuroendocrine alterations.
Purpose of the Study:
- To investigate the effects of maternal deprivation at different developmental stages on HPA axis responses.
- To examine the underlying changes in gene expression of mineralocorticoid (MR) and glucocorticoid receptors (GR) and corticotropin-releasing hormone (CRH).
Main Methods:
- Maternal deprivation was implemented at postnatal days 3-4, 7-8, and 11-12.
- ACTH and corticosterone (CORT) levels were measured following stress exposure.
- In situ hybridization was used to analyze MR, GR, and CRH mRNA expression in the hippocampus and paraventricular nucleus (PVN).
Main Results:
- Deprivation at postnatal days 3-4 led to a hyperreactive ACTH response, while later deprivation (7-8, 11-12) resulted in a hyporeactive ACTH response.
- GR mRNA was reduced in the PVN of all deprived pups.
- Permanent changes in hippocampal GR mRNA were observed only in pups deprived later in development.
Conclusions:
- Neonatal maternal deprivation alters ACTH stress responses and GR transcript levels.
- The age during which maternal deprivation occurs is critical in determining the direction and magnitude of these HPA axis alterations.
Abstract:
Twenty-four hours of maternal deprivation have been shown to have immediate and long-term effects on the hypothalamic-pituitary-adrenal (HPA) axis. In the first experiment the influence of such a maternal deprivation period (pnd 11-12) on basal and stress-induced ACTH and CORT levels 4 and 8 days following reunion was investigated. The results revealed a suppression of the ACTH response in the previously deprived animals which was not reflected in the CORT response. In the second experiment these persistent effects were studied in animals deprived during different stages of development. Deprivation early in development (pnd 3-4) produced an animal with a hyperreactive ACTH response whereas deprivation later (pnd 7-8, pnd 11-12) resulted in a hyporeactive ACTH response to stress at pnd 20. To study further the possible mechanisms leading to these different ACTH responses, we used in situ hybridization to investigate hippocampal mineralocorticoid (MR) and glucocorticoid receptor (GR) gene expression and corticotropin-releasing hormone (CRH) and GR mRNA levels in the paraventricular nucleus of the hypothalamus (PVN) of these 20-day old animals. Permanent changes in hippocampal GR mRNA were seen only in the later deprived pups, whereas GR mRNA was reduced in the PVN in all deprived pups. In conclusion, maternal deprivation during the neonatal period produces alterations in the ACTH response to a mild stress and sustained changes in GR transcript levels. The direction and magnitude of these effects are dependent upon the age at which maternal deprivation is experienced.