Sex-Specific Effects of Ancestral Stress on Brain Health and Disease Across the Lifespan

Early life stress alters fetal brain development with lifetime consequences on individuals exposed and future generations. This thesis investigated the effects of ancestral stress on behaviour, brain aging, and disease incidence of the F1-F4 generation offspring. Two types of ancestral stress offspring were examined: transgenerational stress, where only great-great grandma was stressed and mutigenerational stress where four consecutive F0-F3 generations were stressed during pregnancy. Here were report three main findings: 1) ancestral stress induced sex-specific anxiety-like behaviour and brain plasticity through altered epigenetic regulation; 2) the effects of ancestral stress persisted across the lifespan, altered physical and mental health and increased risk of disease; and 3) social isolation stress altered stress and immune systems and contributed to sex-specific cognitive impairments. These findings contribute to the overall understanding of the perinatal origins of healthy brain aging and disease, and address the urgent need of recommendations to support healthy aging worldwide.Natural Sciences and Engineering Research Council (NSERC) PGS Canadian Institutes of Health Research (CIHR

Transgenerational programming of brain and behaviour by prenatal stress

xii, 105 leaves ; 29 cmExposure to adverse environmental factors such as prenatal stress (PS) can have longlasting effects on brain health and disease. Through direct and transgenerational genetic and epigenetic influences on healthy development and aging, PS may promote adaptive developmental plasticity, but at the same time also lead to increased health risks. Ultimately, the main goal of this research was to determine if PS-associated alterations of the fetal developmental programing can be transmitted across generations to affect brain development and behaviour, and ultimately increase the susceptibility to disease throughout lifespan. Work in Chapter 2 showed sexually dimorphic effects of multigenerational prenatal stress on behavioural traits, laterality and hemispheric dominance in male and female rats. In Chapter 3, hair elementary analysis was shown to be a sensitive, comprehensive and accurate screening tool of age-related metabolic and overall health status. Chapter 4 determined the manifestations of PS on behavioural and physiological outcomes in aging male rats after exposure to PS in one generation (F1-PS) vs. multiple generations (F4-PS). These results provide evidence that PSassociated alterations of the fetal developmental programming may be transmitted across regenerations altering brain development and inducing behavioural disturbances throughout lifespan

Transgenerational Effects of Early Environmental Insults on Aging and Disease Incidence

Adverse early life experiences are major influences on developmental trajectories with potentially life-long consequences. Prenatal or early postnatal exposure to stress, undernutrition or environmental toxicants may reprogram brain development and increase risk of behavioural and neurological disorders later in life. Not only experience within a single lifetime, but also ancestral experience affects health trajectories and chances of successful aging. The central mechanism in transgenerational programming of a disease may the formation of epigenetic memory. This review explores transgenerational effects of early adverse experience on health and disease incidence in older age. First, we address mechanisms of developmental and transgenerational programming of disease and inheritance. Second, we discuss experimental and clinical findings linking early environmental determinants to adverse aging trajectories in association with possible parental contributions and sex-specific effects. Third, we outline the main mechanisms of age-related functional decline and suggest potential interventions to reverse negative effects of transgenerational programming. Thus, strategies that support healthy development and successful aging should take into account the potential influences of transgenerational inheritanc

Synergistic Effects of Ancestral Stress and Aging on Anxiety-like Behaviours

Exposure to adverse environments such as prenatal stress early in life is associated with anxiety-like behaviours in adulthood, which is potentially further exacerbated by aging. Recent studies have indicated that ancestral prenatal stress can propagate across generations to alter emotional wellbeing of unexposed offspring. Here we investigated if exposure to prenatal stress in the great-grandmother (transgenerational stress), or exposure across four consecutive generations (multigenerational stress) can alter anxiety-like behaviours in male and female fourth (F4) generation offspring. Anxiety-like behaviours were evaluated by means of the elevated plus maze in both males and females across three different groups: transgenerational stress (SNNN), multigenerational stress (SSSS), and non-stressed controls (NNNN). Both sexes were evaluated at the age of 12 months (middle age) and 18 months (old age). Our results demonstrate that aging and ancestral stress synergistically heightened anxiety-like behaviour, especially in males. Interestingly, the highest levels of anxiety-like behaviours were observed in transgenerationally stressed offspring of both ages. Overall, these results indicate that males are more sensitive to ancestral stress and more likely to respond by developing anxiety-like behaviours. Thus, ancestral stress and aging may synergistically alter mental health outcomes particularly in males. *Indicates presente

Evidence for ancestral programming of resilience in a two-hit stress model

In a continuously stressful environment, the effects of recurrent prenatal stress (PS) may accumulate across generations and alter stress vulnerability and resilience. Here, we report in female rats that a family history of recurrent ancestral PS facilitates certain aspects of movement performance, and that these benefits are abolished by the experience of a second hit, induced by a silent ischemia during adulthood. Female F4-generation rats with and without a family history of cumulative multigenerational PS (MPS) were tested for skilled motor function before and after the induction of a minor ischemic insult by endothelin-1 infusion into the primary motor cortex. MPS resulted in improved skilled motor abilities and blunted hypothalamic-pituitary-adrenal (HPA) axis function compared to non-stressed rats. Deep sequencing revealed downregulation of miR-708 in MPS rats along with upregulation of its predicted target genes Mapk10 and Rasd2. Through miR-708 stress may regulate mitogen-activated protein kinase (MAPK) pathway activity. Hair trace elemental analysis revealed an increased Na/K ratio, which suggests a chronic shift in adrenal gland function. The ischemic lesion activated the HPA axis in MPS rats only; the lesion, however, abolished the advantage of MPS in skilled reaching. The findings indicate that MPS generates adaptive flexibility in movement, which is challenged by a second stressor, such as a neuropathological condition. Thus, a second “hit” by a stressor may limit behavioral flexibility and neural plasticity associated with ancestral stress. © 2017 Faraji, Soltanpour, Ambeskovic, Zucchi, Beaumier, Kovalchuk and Metz