An interesting aspect of developmental programming is the existence of transgenerational effects that influence offspring characteristics and performance later in life. These transgenerational effects have been hypothesized to allow individuals to cope better with predictable environmental fluctuations and thus facilitate adaptation to changing environments. Here, we test for the first time how early-life stress drives developmental programming and transgenerational effects of maternal exposure to early-life stress on several phenotypic traits in their offspring in a functionally relevant context using a fully factorial design. We manipulated pre- and/or post-natal stress in both Japanese quail mothers and offspring and examined the consequences for several stress-related traits in the offspring generation. We show that pre-natal stress experienced by the mother did not simply affect offspring phenotype but resulted in the inheritance of the same stress-coping traits in the offspring across all phenotypic levels that we investigated, shaping neuroendocrine, physiological and behavioural traits. This may serve mothers to better prepare their offspring to cope with later environments where the same stressors are experienced.

The acute stress response functions to prioritize behavioural and physiological processes that maximize survival in the face of immediate threat. There is variation between individuals in the strength of the adult stress response that is of interest in both evolutionary biology and medicine. Age is an established source of this variation—stress responsiveness diminishes with increasing age in a range of species—but unexplained variation remains. Since individuals of the same chronological age may differ markedly in their pace of biological ageing, we asked whether biological age—measured here via erythrocyte telomere length—predicts variation in stress responsiveness in adult animals of the same chronological age. We studied two cohorts of European starlings in which we had previously manipulated the rate of biological ageing by experimentally altering the competition experienced by chicks in the fortnight following hatching. We predicted that individuals with greater developmental telomere attrition, and hence greater biological age, would show an attenuated corticosterone (CORT) response to an acute stressor when tested as adults. In both cohorts, we found that birds with greater developmental telomere attrition had lower peak CORT levels and a more negative change in CORT levels between 15 and 30 min following stress exposure. Our results, therefore, provide strong evidence that a measure of biological age explains individual variation in stress responsiveness: birds that were biologically older were less stress responsive. Our results provide a novel explanation for the phenomenon of developmental programming of the stress response: observed changes in stress physiology as a result of exposure to early-life adversity may reflect changes in ageing.

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The morphological changes that occur in the central nervous system of patients with severe acute intermittent porphyria (AIP) have not yet been clearly established. The aim of this work was to analyse brain involvement in patients with severe AIP without epileptic seizures or clinical posterior reversible encephalopathy syndrome, as well as in a mouse model receiving or not liver-directed gene therapy aimed at correcting the metabolic disorder. We conducted neuroradiologic studies in 8 severely affected patients (6 women) and 16 gender- and age-matched controls. Seven patients showed significant enlargement of the cerebral ventricles and decreased brain perfusion was observed during the acute attack in two patients in whom perfusion imaging data were acquired. AIP mice exhibited reduced cerebral blood flow and developed chronic dilatation of the cerebral ventricles even in the presence of slightly increased porphyrin precursors. While repeated phenobarbital-induced attacks exacerbated ventricular dilation in AIP mice, correction of the metabolic defect using liver-directed gene therapy restored brain perfusion and afforded protection against ventricular enlargement. Histological studies revealed no signs of neuronal loss but a denser neurofilament pattern in the periventricular areas, suggesting compression probably caused by imbalance in cerebrospinal fluid dynamics. In conclusion, severely affected AIP patients exhibit cerebral ventricular enlargement. Liver-directed gene therapy protected against the morphological consequences of the disease seen in the brain of AIP mice. The observational study was registered at Clinicaltrial.gov as NCT02076763.

Stress exposure during prenatal and postnatal development can have persistent and often dysfunctional effects on several physiological systems, including immune function, affecting the ability to combat infection. The neuroimmune response is inextricably linked to the action of the hypothalamic-pituitary-adrenal (HPA) axis. Cytokines released from neuroimmune cells, including microglia, activate the HPA axis, while glucocorticoids in turn regulate cytokine release from microglia. Because of the close links between these two physiological systems, coupled with potential for persistent changes to HPA axis activity following developmental stress, components of the neuroimmune system could be targets for developmental programming. However, little is known of any programming effects of developmental stress on neuroimmune function. We investigated whether developmental stress exposure via elevated prenatal corticosterone (CORT) or postnatal unpredictable food availability had long-term effects on pro-(IL-1β) and anti-inflammatory (IL-10) cytokine and microglia-dependent gene (CSF1R) expression within HPA axis tissues in a precocial bird, the Japanese quail (Coturnix japonica). Following postnatal stress, we observed increased IL-1β expression in the pituitary gland, reduced IL-10 expression in the amygdala and hypothalamus, and reduced CSF1R expression within the hypothalamus and pituitary gland. Postnatal stress disrupted the ratio of IL-1β:IL-10 expression within the hippocampus and hypothalamus. Prenatal stress only increased IL-1β expression in the pituitary gland. We found no evidence for interactive or cumulative effects across life stages on basal cytokine and glia expression in adulthood. We show that postnatal stress may have a larger impact than elevated prenatal CORT on basal immunity in HPA-axis-specific brain regions, with changes in cytokine homeostasis and microglia abundance. These results provide evidence for postnatal programming of a pro-inflammatory neuroimmune phenotype at the expense of reduced microglia, which could have implications for central nervous system health and subsequent neuroimmune responses.