Gestational stress disrupts maternal behaviour through neuroendocrine, immune and oxidative dysregulation

Pregnancy and the postpartum period represent critical windows characterised by neuroendocrine and immune adaptations that support maternal behaviour while increasing vulnerability to stress. Gestational stress is a major risk factor for maternal psychopathology; however, its multi-systemic impact remains poorly defined. The aim of this study was to investigate the effects of gestational stress on maternal behaviour and to characterise the associated neuroendocrine, immune and oxidative alterations across pregnancy and the postpartum period, with a particular focus on identifying biological pathways potentially underlying stress-related maternal dysfunction.

Dams were exposed to restraint stress during the last week of gestation, and behavioural and molecular parameters were assessed during pregnancy and three weeks postpartum. Maternal behaviour was evaluated using standardised observational paradigms. Circulating hormones and inflammatory markers were quantified in plasma using a multiplex immunoassay (Bio-Plex Luminex), and hippocampal gene expression was analysed by quantitative real-time polymerase chain reaction (qRT-PCR). Statistical analyses were performed using unpaired Student’s t-tests for group comparisons and Pearson correlation analysis. All analyses were conducted using a two-tailed approach, with statistical significance set at p < 0.05.

Stress significantly impaired maternal care, as indicated by reduced licking behaviour (p = 0.039), increased time spent off-nest (p = 0.034), and a lower maternal index (p = 0.020), alongside increased self-directed behaviours (p = 0.017). These behavioural alterations were accompanied by dysregulation of the hypothalamic–pituitary–adrenal axis, including elevated corticosterone levels during pregnancy (p = 0.038) and postpartum (p = 0.008), as well as brain region-specific changes in the expression of stress-related genes, including NR3C1, CRHR1, and FKBP5. Corticosterone levels negatively correlated with maternal behaviour (r = −0.548, p = 0.028), linking endocrine dysregulation to caregiving deficits. In addition, stress reduced circulating oxytocin levels during pregnancy (p = 0.015) and altered the expression of oxytocin and vasopressin receptors in the hippocampus across both time points, indicating disrupted neuropeptidergic signalling and impaired regulation of maternal circuits. At the systemic level, stress induced a persistent pro-inflammatory profile, with increased tumour necrosis factor alpha (TNFα), interleukin-6 (IL-6), interleukin-2 (IL-2), and interferon gamma (IFNγ) during pregnancy and elevated TNFα, IL-2, interleukin-17 (IL-17), interleukin-1 alpha (IL1α), and granulocyte colony-stimulating factor (G-CSF) postpartum, alongside reduced interleukin-4 (IL-4) in both phases (all p < 0.05). This inflammatory state was accompanied by impaired redox regulation in the hippocampus, including downregulation of NFE2L2 and NQO1 and increased NOS2 expression postpartum, as well as altered circulating mitochondrial DNA (mtDNA) levels (increased during pregnancy and decreased postpartum), suggesting a disruption of mitochondrial homeostasis and oxidative balance.

In conclusion, gestational stress induces persistent multi-system alterations across endocrine, immune and oxidative pathways, associated with impaired maternal behaviour. These findings provide insight into converging biological mechanisms underlying stress-related maternal dysfunction and may contribute to the identification of early biomarkers and the development of targeted preventive strategies.

References

No references