Neonatal endotoxin exposure alters the development of the hypothalamic-pituitary-adrenal axis: early illness and later responsivity to stress
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The long-term consequences of neonatal endotoxin exposure on hypothalamic-pituitary-adrenal axis (HPA) function were assessed in adult female and male Long-Evans rats. At 3 and 5 d of age, pups were administered endotoxin (Salmonella enteritidis, 0.05 mg/kg, i.p.) at a dose that provokes a rapid and sustained physiological response, but with no mortality. As adults, neonatally endotoxin-treated animals exhibited significantly greater adrenocorticotrophic hormone (ACTH) and corticosterone responses to restraint stress than controls. In addition, dexamethasone pretreatment was less effective in suppressing ACTH responses to restraint stress in endotoxin-treated animals than in controls, suggesting decreased negative-feedback sensitivity to glucocorticoids. Neonatal endotoxin treatment elevated resting-state median eminence levels of corticotropin-releasing hormone (CRH) and arginine vasopressin in adult male animals, and arginine vasopressin in both adult males and females. Neonatal exposure to endotoxin also increased CRH mRNA expression in the paraventricular nucleus of the hypothalamus of adult males, with no difference in females. Finally, glucocorticoid receptor density was reduced across a wide range of brain regions in the neonatal endotoxin-treated, adult animals. These data illustrate the interactive nature of immune and endocrine systems during development. It appears that endotoxin exposure during critical stages of development decreases glucocorticoid negative-feedback inhibition of ACTH secretagogue synthesis, thus increasing HPA responsiveness to stress. The implication of these findings is that exposure to gram-negative LPS in early life can alter the development of neural systems which govern endocrine responses to stress and may thereby predispose individuals to stress-related pathology.
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Exposure of neonatal animals to low-dose endotoxins resulted in activation of Toll-like receptors.
“Exposure of neonatal animals to low-dose endotoxins resulted in the activation of TLRs (364, 365).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [364]
Neonatal animals exposed to low-dose endotoxins showed long-term HPA axis alterations, with increased mean glucocorticoid concentrations resulting from an increase in glucocorticoid pulse frequency and amplitude.
“In addition, they showed long-term HPA axis alterations in activity, as evidenced by increased mean glucocorticoid concentrations resulting from an increase in glucocorticoid pulse frequency and amplitude.”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [364]
Colonization by microbiota regulates expression of critical HPA axis genes in hippocampus and modulates hippocampal serotonin concentration, which affects HPA activation.
“Colonization by microbiota has been shown to regulate the expression of critical HPA axis genes in hippocampus and modulate hippocampal serotonin concentration, which also affects HPA activation (Luo et al., 2018; Farzi et al., 2015; Shanks et al., 1995; Clarke et al., 2013).”
From Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells (2021) · cites this paper as Shanks et al., 1995
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- Authors
- Shanks, N., Larocque, S., & Meaney, M.
- Affiliations
- Douglas Mental Health University Institute (CA)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 1995-01-01
- Volume
- 15
- Issue
- 1
- Pages
- 376-384
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6578303
- OpenAlex
- W2097726093
- Cited by
- 278
- References
- 66
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 11 · 2020: 9 · 2019: 5 · 2018: 7 · 2017: 16 · 2016: 12 · 2015: 9 · 2014: 10 · 2013: 10 · 2012: 18
- FWCI
- 3.56
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Pittsburgh
- Medical Research Council Canada
- Medical Center, University of Pittsburgh
- Natural Sciences and Engineering Research Council of Canada
- Medical Research Council
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- lipopolysaccharide, hypothalamic-pituitary-adrenal axis, stress responsivity, glucocorticoid negative feedback, ACTH, corticosterone, restraint stress, corticotropin-releasing factor, vasopressin, paraventricular nucleus, endocrine-immune interaction, developmental programming, sex differences, Long-Evans rats
- MeSH terms
- Adrenocorticotropic Hormone, Animals, Animals, Newborn, Arginine Vasopressin, Corticotropin-Releasing Hormone, Dexamethasone, Endotoxins, Female, Hypothalamo-Hypophyseal System, Male, Median Eminence, Paraventricular Hypothalamic Nucleus, Pituitary-Adrenal System, Rats, Inbred Strains, Receptors, Glucocorticoid, Restraint, Physical, RNA, Messenger, Stress, Physiological, Transcortin, Rats
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