Cited by 368Stress Responses and CortisolAdrenal Hormones and DisordersNeuroendocrine regulation and behavior

Long-term adaptations in glucocorticoid receptor and mineralocorticoid receptor mrna and negative feedback on the hypothalamo-pituitary-adrenal axis following neonatal maternal separation

Ladd, Charlotte O, Huot, Rebecca L, Thrivikraman, K.V, Nemeroff, Charles B, Plotsky, Paul M·2004·Biological Psychiatry

Abstract

Background Maternally separated rats exhibit exaggerated hypothalamic-pituitary-adrenal responses to an acute stressor but normal diurnal trough functioning. We hypothesized that maternally separated rats experience adequate proactive glucocorticoid negative feedback but deficient "reactive" negative feedback, contributing to prolonged hypothalamic-pituitary-adrenal stress responses.Methods We measured plasma adrenocorticotropic hormone and corticosterone concentrations following an acute stressor or 6 to 8 hours after dexamethasone administration in adult rats previously exposed to daily handling-maternal separation for 15 minutes (HMS15) or 180 minutes (HMS180) during postnatal days 2 to 14. We also examined regional mineralocorticoid receptor and glucocorticoid receptor messenger RNA density in these two groups.Results HMS180 rats appeared to escape dexamethasone suppression of plasma adrenocorticotropic hormone and corticosterone faster than their HMS15 counterparts (p <.01). In situ hybridization analysis revealed increased hippocampal mineralocorticoid receptor messenger RNA density (p <.05) with decreased cortical (p <.05) and hippocampal (p <.05) glucocorticoid receptor messenger RNA density in HMS180 versus HMS15 animals.Conclusions These results are consistent with the hypothesis that in rats exposed to moderate neonatal handling-maternal separation, enhanced proactive feedback maintains the hypothalamic-pituitary-adrenal axis during the diurnal trough, while decreased reactive feedback contributes to prolonged responsiveness of the hypothalamic-pituitary-adrenal axis following an acute stressor.

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Crossref · 10.1016/j.biopsych.2003.10.007

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  • Childhood adversity may both up-regulate HPA stress responses and reduce serotonin neuron firing in parallel; the former amplifies neuroinflammation and the latter dampens neurotrophic factors.

    “Childhood adversity may both up-regulate HPA stress responses (122) and reduce serotonin neuron firing (108) in parallel (123), the former amplifying neuroinflammation (124) and the latter dampening neurotrophic factors (125).”

    From A brain-centric model of suicidal behavior (2020) · cites this paper as [122]

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Authors
Ladd, C. O., Huot, R. L., Thrivikraman, K. V., Nemeroff, C. B., & Plotsky, P. M.
Affiliations
Emory University (US)
Corresponding author
Plotsky, Paul M
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2004-02
Volume
55
Issue
4
Pages
367-375
ISSN
0006-3223 (ISSN-L)
OpenAlex
W2140973156
Cited by
368
References
94
Citations by year
2026: 3 · 2025: 6 · 2024: 6 · 2023: 7 · 2022: 6 · 2021: 7 · 2020: 22 · 2019: 12 · 2018: 22 · 2017: 18 · 2016: 17 · 2015: 25 · 2014: 21 · 2013: 18 · 2012: 20
FWCI
8.21
Type
journal article
Language
en
Open access
closed
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5f30mh012163-02)
  • National Institute of Mental Health (P50MH058922, MH58922, MH12163, MH-50113, R01MH050113)
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
Keywords
neonatal maternal separation, hypothalamic-pituitary-adrenal axis, glucocorticoid receptor, mineralocorticoid receptor, negative feedback, ACTH, corticosterone, dexamethasone suppression, acute stress response, hippocampus, cortex, diurnal cycle
MeSH terms
Adaptation, Physiological, Adrenocorticotropic Hormone, Animals, Animals, Newborn, Corticosterone, Densitometry, Dexamethasone, Female, Glucocorticoids, Hippocampus, Hypothalamo-Hypophyseal System, Male, Maternal Deprivation, Pituitary-Adrenal System, Pregnancy, Radioimmunoassay, Receptors, Glucocorticoid, RNA, Messenger, Time Factors, In Situ Hybridization, Receptors, Mineralocorticoid, Rats, Long-Evans, Feedback, Physiological, Rats

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