Critical biological systems linking early-life stress to later-life outcomes: A systematic review of animal models.

Jorgensen CC, Thöne-Reineke C, Moscovice LR, Gimsa U

Neuroscience and biobehavioral reviews15 Oct 2025Cited by 1 (Europe PMC)

PMID41106648DOI10.1016/j.neubiorev.2025.106425PepBankPUB-41106648

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Summary

Adverse and stressful early life events can impact on later-life cognitive, physiological and neurological outcomes, but direct mechanisms through which these so-called "programming effects" occur are still under investigation. In this review, we systematically examine early-life stress (ELS) paradigms in non-human animals, focusing on three key biological systems: the hypothalamic-pituitary-adrenal (HPA) axis, immune system and oxytocinergic system. We developed a ranking system to assess and compare stress severity across different ELS paradigms. We also consider how different theoretical frameworks influence the interpretation of ELS outcomes, from primarily adaptive to pathological. Effects of chronic ELS on peripheral measures of HPA- and oxytocinergic system function were variable, but centrally, ELS more consistently triggered region-specific alterations in mRNA expression, including increased hypothalamic corticotropin-releasing hormone (CRH) mRNA and decreased oxytocin (OXT) mRNA in the amygdala. Altered gene expression in amygdala was linked to later-life behavioral alterations. Central markers of immune function were consistently altered following ELS, including higher microglia or astrocyte densities or ameboid microglial morphology. These changes are likely mechanisms linking ELS to cognitive deficits and depressive symptoms, which were consistently found across studies assessing behavior. Other behaviors, including anxiety and risk-taking, were less consistently altered by ELS. Increasing stress severity scores of ELS paradigms predicted the likelihood of long-term alterations in key biological systems, emphasizing the importance of greater standardization of ELS paradigms to increase comparability across studies. Interventions that provided social support during ELS, or increased post-ELS maternal care showed promise for promoting resilience, and deserve more attention in future studies.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study2

No result from this study comes from a test of the peptide.

Natural levels measured2

These results measure the body's own peptide. Nobody was given the peptide. They are not evidence about taking it. They are left out of key results, evidence counts and charts.

01AnimalEndogenous levelAnimal study (in vivo)Mechanism
In non-human animal models of early-life stress, oxytocin (OXT) mRNA expression in the amygdala was decreased.
In plain wordsIn animals exposed to early-life stress, the body's own oxytocin gene activity was lower in the amygdala.
Peptide
Oxytocin
Outcome
DecreaseAmygdala oxytocin mRNA after early-life stress
Study
non-human animalsn: not reported in source
early-life stress paradigms
Outcome group
Receptor activity and mechanism · Nervous system and cognition
Source sentences
Summary
decreased oxytocin (OXT) mRNA in the amygdala.
1 context sentence(design, population, supporting numbers)
Summary · context
In this review, we systematically examine early-life stress (ELS) paradigms in non-human animals, focusing on three key biological systems: the hypothalamic-pituitary-adrenal (HPA) axis, immune system and oxytocinergic system.
This result measures the body's own Oxytocin. Nobody was given the peptide. It is not evidence about taking it.
Show in the study text Report a problemFND-4110664801
02AnimalEndogenous levelAnimal study (in vivo)Mechanism
In non-human animal models, chronic early-life stress had variable effects on peripheral measures of oxytocinergic system function.
In plain wordsIn animals, early-life stress changed the body's own oxytocin system in the blood and body in varied ways.
Peptide
Oxytocin
Outcome
MixedPeripheral oxytocinergic function after chronic early-life stress
Study
non-human animalsn: not reported in source
early-life stress paradigms
Outcome group
Receptor activity and mechanism · Nervous system and cognition
Source sentences
Summary
Effects of chronic ELS on peripheral measures of HPA- and oxytocinergic system function were variable
1 context sentence(design, population, supporting numbers)
Summary · context
In this review, we systematically examine early-life stress (ELS) paradigms in non-human animals, focusing on three key biological systems: the hypothalamic-pituitary-adrenal (HPA) axis, immune system and oxytocinergic system.
This result measures the body's own Oxytocin. Nobody was given the peptide. It is not evidence about taking it.
Show in the study text Report a problemFND-4110664802

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Version history

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Version 2Current
11 Oct 2026, 00:50 UTC
Study results updated
Version 1
9 Oct 2026, 02:48 UTC
First added · source update from Europe PMC

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