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

Pawedness trait test (PaTRaT) : a new paradigm to evaluate paw preference and dexterity in rats

Pawedness Trait Test (PaTRaT)-A New Paradigm to Evaluate Paw Preference and Dexterity in RatsIn rodents, dexterity is commonly analyzed in preference paradigms in which animals are given the chance to use either the left or the right front paws to manipulate food. However, paw preference and dexterity at population and individual levels are controversial as results are incongruent across paradigms. We have therefore developed a semi-quantitative method-the pawdeness trait test (PaTRaT)-to evaluate paw preference degree in rats. The PaTRaT consists in a classification system, ranging from +4 to 4 where increasingly positive and negative values reflect the bias for left or right paw use, respectively. Sprague-Dawley male rats were confined into a metal rectangular mesh cylinder, from which they can see, smell and reach sugared rewards with their paws. Due to its size, the reward could only cross the mesh if aligned with its diagonal, imposing additional coordination. Animals were allowed to retrieve 10 rewards per session in a total of four sessions while their behavior was recorded. PaTRaT was repeated 4 and 8 weeks after the first evaluation. To exclude potential bias, rats were also tested for paw fine movement and general locomotion in other behavioral paradigms as well as impulsivity (variable delay-to-signal, VDS), memory and cognitive flexibility (water maze). At the population level 54% of the animals presented a rightward bias. Individually, all animals presented marked side-preferences, >2 and <-2 for left-and right-sided bias, respectively, and this preference was stable across the three evaluations. Inter-rater consistency was very high between two experienced raters and substantial when two additional inexperienced raters were included. Left-and right-biased animals presented no differences in the ability to perform fine movements with any of the forelimbs (staircase) and general locomotor performance. Additionally, these groups performed similarly in executive function and memory tasks. In conclusion, PaTRaT is able to reliably classify rats' pawedness direction and degree.This work has been funded by the European Regional Development Fund (FEDER), through the Competitiveness Factors Operational Programme (COMPETE) and the Northern Portugal Regional Operational Programme (NORTE 2020) under the Portugal 2020 Partnership Agreement (project NORTE-01-0145-FEDER-000023). It was also funded by National funds, through the Foundation for Science and Technology (Fundacao para a Ciencia e a Tecnologia, FCT), under the scope of the projects POCI-01-0145-FEDER-007038 and PTDC/NEU-SCC/5301/2014. Researchers were supported by FCT grant numbers SFRH/BD/109111/2015 (AMC), SFRH/BD/52291/2013 (ME via Inter-University Doctoral Programme in Ageing and Chronic Disease, PhDOC), PD/BD/114120/2015 (SPN via PhDOC), SFRH/BD/89936/2012 (SB), PD/BD/114117/2015 (MRG via PhDOC) and SFRH/BPD/80118/2011 (HL-A).info:eu-repo/semantics/publishedVersio

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

Essential Role for a Link between the Tricarboxylic Acid (TCA) Cycle and Polyamine Metabolism in Malignant Cell Transformation

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Genetics, 2014.Malignant transformation requires reprogramming of the molecular network that underlies cell metabolism in order to convert available nutrients to biomass and energy to respond to biological demands of proliferation and tumor microenvironment. In this context two apparently distinct metabolic pathways, glutamine-dependent anaplerosis and polyamine metabolism are commonly found up-regulated in cancer cells. Here we show that, increased glutamine-dependent anaplerosis in cancer cells is partly driven by increased polyamine metabolism. Dependency of anaplerosis on polyamine metabolism is observed when glutamine carbon is selected over arginine carbon to synthesize the polyamine precursor, ornithine. This unexpected relationship between polyamine and glutamine metabolism is shared by multiple cancer types and controlled by an ornithine aminotransferase (Oat)-driven transamination reaction. Oat uses L-glutamate-semialdehyde, a glutamate derived intermediate, as an amine group acceptor and glutamate as an amine group donor, producing ornithine and α-ketoglutarate (α-KG), with the latter fueling the TCA cycle. Genetic suppression of this metabolic link by targeting Oat leads to inhibition of tumor formation, down-regulation of glutamine-dependent anaplerosis and disruption of cellular redox homeostasis. Furthermore, down-regulation of polyamine metabolism by suppressing expression of spermine synthase (Sms), a polyamine biosynthetic enzyme that we find to be commonly up-regulated in multiple cancers compared to normal samples, also inhibits tumor growth. Metabolic analysis of cancer cells with Sms depletion shows that synthesis of ornithine and α-KG from glutamine is also decreased showing that increased polyamine metabolism is critical for glutamine-dependent anaplerosis of the TCA cycle in cancer cells. Overall, our findings demonstrate a direct link between polyamine metabolism and glutamine-dependent anaplerosis that is essential for the cancer phenotype. As this pathway is non-essential to normal cells, its aberrant up-regulation in cancer cells may provide novel opportunities for therapeutic intervention in cancer

Oxidation Based Mechanism for the Induction of Oligodendrocyte Precursor Differentiation

Thesis (Ph.D.)--University of Rochester. School of Medicine and Dentistry. Dept. of Biomedical Genetics, 2008.Thyroid hormone (TH) induces oligodendrocyte precursor cell (OPC) differentiation, in vitro and in vivo. While the effects of TH treatment on OPC gene expression are well established, differentiation initiation is not well understood. Previously, our lab showed that within 18 hours, TH treatment leads to a relative, whole-cell, OPC oxidation. The oxidation was required for the induction of differentiation and was completely blocked by co-treatment with an anti-oxidant N-acetyl-L-cysteine (NAC). In agreement, the intracellular redox state of freshly isolated precursors appeared to correlate with their responsiveness to TH, with the oxidized differentiating readily and reduced precursors continuing to self-renew extensively. The work presented herein describes the mechanism underlying the intracellular oxidation and initiation of precursor differentiation and provides an insight into the factors that establish the intracellular redox state and determine responsiveness to TH. We found that TH treatment appeared to stimulate the production of mitochondrial reactive oxygen species (ROS) and their release via the transiently opened mitochondrial permeability transition pore (MPTP). Once cytosolic, the ROS activated the c-Cbl ubiquitin ligase pathway and inhibited self-renewal. This process could be blocked by MPTP inhibitors, cyclosporin A (CysA) and Bcl-2, as well as the expression of ubiquitin ligase defective, dominant negative, c-Cbl or c-Cbl shRNA. Moreover, we discovered that freshly isolated oxidized and reduced precursors exhibited biochemical and physiological characteristics consistent with their redox state and responsiveness to TH

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

Stochastic modeling of oligodendrocyte generation in cell culture: model validation with time-lapse data

<p>Abstract</p> <p>Background</p> <p>The purpose of this paper is two-fold. The first objective is to validate the assumptions behind a stochastic model developed earlier by these authors to describe oligodendrocyte generation in cell culture. The second is to generate time-lapse data that may help biomathematicians to build stochastic models of cell proliferation and differentiation under other experimental scenarios.</p> <p>Results</p> <p>Using time-lapse video recording it is possible to follow the individual evolutions of different cells within each clone. This experimental technique is very laborious and cannot replace model-based quantitative inference from clonal data. However, it is unrivalled in validating the structure of a stochastic model intended to describe cell proliferation and differentiation at the clonal level. In this paper, such data are reported and analyzed for oligodendrocyte precursor cells cultured <it>in vitro</it>.</p> <p>Conclusion</p> <p>The results strongly support the validity of the most basic assumptions underpinning the previously proposed model of oligodendrocyte development in cell culture. However, there are some discrepancies; the most important is that the contribution of progenitor cell death to cell kinetics in this experimental system has been underestimated.</p

Hair trace elementary profiles in aging rodents and primates: links to altered cell homeodynamics and disease

Aging is associated with an increased incidence of pathological conditions such as neurodegeneration, cardiovascular and renal disease, and cancer. These conditions are believed to be linked to a disruption in cell homeodynamics, which is regulated by essential trace elements. In this study we used hair elementary analysis by inductively coupled plasma mass spectrometry (ICPMS) to examine age-related profiles of 47 elements in both rats and common marmoset monkeys. Hair was collected from young adult (6 months) and aged (18 months) Long-Evans male rats, and young adult (2 years), middle-aged (4 years) and aged (> 8 years) marmosets. The results revealed that aging reduces content levels of cobalt, potassium and selenium while content levels of aluminium, arsenic, boron, mercury, molybdenum, and titanium were elevated in aged rats. Similarly, aged marmosets showed reduced levels of cobalt and elevated levels of aluminium. Case studies in aged rats revealed that myocardial infarction was associated with elevated levels of sodium, potassium and cadmium and reduced zinc, while renal failure was linked to elevated content of potassium, chloride and boron and reduced contents of manganese. Carcinoma was linked to elevated arsenic and reduced selenium levels. These findings indicate that hair elementary profiles in healthy aging and age-related diseases reflect altered cell and organ metabolic functions. Cobalt and aluminium in particular may serve as biomarkers of aging in animal models. Thus, elementary deposition in hair may have predictive and diagnostic value in age-related pathological conditions, including cardiovascular and kidney disease and cancer