Intergenerational Mechanisms Of Paternal Stress Transmission

Evidence that the intergenerational transmission of parental experiences can influence offspring outcomes prompts new consideration for the molecular mechanisms underlying disease risk and resilience. The role of the paternal preconception environment has been of particular interest, stimulating characterization of germ cell epigenetic marks that can respond dynamically to environmental insults and transmit this information at fertilization. Given such exciting potential for sperm epigenetic marks, how these marks are changed by the environment and subsequently impact offspring development are key questions that require investigation. In this dissertation, we address these questions using our established mouse model of paternal stress, where specific sperm microRNA altered by paternal chronic stress exposure causally reprogram offspring hypothalamic-pituitary-adrenal (HPA) stress axis reactivity and the hypothalamic transcriptome. First, we examined the role of glucocorticoids, a major component of the HPA stress response, as a signal for sperm microRNA changes. To ensure similar levels of glucocorticoids are produced in response to stress and thus are available for paternal cellular signaling, we developed an approach to confirm the stress sensitivity and reactivity of experimental mice. We next demonstrated that glucocorticoids are involved in communicating stress to the caput epididymis, a somatic tissue that secretes extracellular vesicles (EVs) to deliver microRNA from epididymal epithelial cells to maturing sperm. Using an in vitro model where we administered glucocorticoids to caput epididymal epithelial cells, we showed altered EV microRNA content and within epithelial cells, changes to histone post-translational modifications and increased glucocorticoid receptor levels, mimicking aspects of our in vivo paternal stress model. Further, we demonstrated the crucial role of caput epididymal glucocorticoid receptors in paternal stress transmission by transgenic knockdown, preventing offspring HPA axis and hypothalamic programming. In our final study, we provided evidence for the specificity of paternal stress sperm microRNA effects on embryonic brain and placental transcriptomes, indicating a tightly regulated process by which sperm microRNA are coordinated and function to influence offspring development. Together, the research presented in this dissertation provides insight into the mechanisms contributing to paternal transmission and support the paternal preconception environment as an influential factor in offspring disease risk and resilience

The Epigenetic Effects of Preconception Paternal Alcohol Exposure on Adult Health and Disease

Alcohol is a notorious teratogen and a major driver of both mental and physical defects. Recently, alcohol has been discovered to exert intergenerational effects on offspring development. While maternal exposure to alcohol in-utero has been linked to the development of fetal alcohol spectrum disorders, paternal contributions to this disorder remain poorly understood. Emerging evidence suggest the association of paternal environmental exposures and long-term metabolic dysfunction1,2. Using a mouse model, our preliminary studies have identified an association between preconception paternal alcohol use and deficits in both the prenatal and postnatal growth of the offspring. These growth defects are accompanied by altered transcriptomic profiles in the fetal liver at gestation day (GD) 14.5, which persists into the adult stages. In this study, we will examine the mechanism by which paternal alcohol exposure drives the development of prenatal growth retardation and long-term postnatal growth restriction in the offspring, as well as the abnormal metabolic response of the offspring to dietary challenge

Developmental Lead and/or Prenatal Stress Exposures Followed by Different Types of Behavioral Experience Result in the Divergence of Brain Epigenetic Profiles in a Sex, Brain Region, and Time-Dependent Manner: Implications for Neurotoxicology.

Over a lifetime, early developmental exposures to neurocognitive risk factors, such as lead (Pb) exposures and prenatal stress (PS), will be followed by multiple varied behavioral experiences. Pb, PS and behavioral experience can each influence brain epigenetic profiles. Our recent studies show a greater level of complexity, however, as all three factors interact within each sex to generate differential adult variation in global post-translational histone modifications (PTHMs), which may result in fundamentally different consequences for life-long learning and behavioral function. We have reported that PTHM profiles differ by sex, brain region and time point of measurement following developmental exposures to Pb±PS, resulting in different profiles for each unique combination of these parameters. Imposing differing behavioral experience following developmental Pb±PS results in additional divergence of PTHM profiles, again in a sex, brain region and time-dependent manner, further increasing complexity. Such findings underscore the need to link highly localized and variable epigenetic changes along single genes to the highly-integrated brain functional connectome that is ultimately responsible for governing behavioral function. Here we advance the idea that increased understanding may be achieved through iterative reductionist and holistic approaches. Implications for experimental design of animal studies of developmental exposures to neurotoxicants include the necessity of a \u27no behavioral experience\u27 group, given that epigenetic changes in response to behavioral testing can confound effects of the neurotoxicant itself. They also suggest the potential utility of the inclusion of salient behavioral experiences as a potential effect modifier in epidemiological studies

Brain Function and Chromatin Plasticity

The characteristics of epigenetic control, including the potential for long-lasting, stable effects on gene expression that outlive an initial transient signal, could be of singular importance for post-mitotic neurons, which are subject to changes with short- to long-lasting influence on their activity and connectivity. Persistent changes in chromatin structure are thought to contribute to mechanisms of epigenetic inheritance. Recent advances in chromatin biology offer new avenues to investigate regulatory mechanisms underlying long-lasting changes in neurons, with direct implications for the study of brain function, behaviour and diseases.Molecular and Cellular Biolog

Biological evolution and human cognition are analogous information processing systems

The mechanisms that govern biological evolution and human cognition are analogous, as both follow the same principles of natural information processing systems. In this article, we describe the following five principles that provide an analogy between biological evolution and human cognition: (a) Randomness as Genesis Principle and (b) Borrowing and Reorganizing Principle, which indicate how natural information processing systems obtain information; (c) Narrow Limits of Change Principle and (d) Information Store Principle, which indicate how information is processed and stored; and (e) Environmental Organizing and Linking Principle, which indicate how stored information is used to generate actions appropriate to an environment. In human cognition, these analogs only apply to cognitive processes associated with biologically secondary knowledge, the knowledge typically taught in educational institutions. Based on these five principles, cognitive load theory researchers have provided diverse prescriptions to optimize instructional activities and materials. We conclude by discussing general instructional implications and future research directions based on this analogy

Investigating modularity and transparency within bioinspired connectionist architectures using genetic and epigenetic models

Machine learning algorithms allow computers to deal with incomplete data in tasks such as speech recognition and object detection. Some machine learning algorithms take inspiration from biological systems due to useful properties such as robustness, allowing algorithms to be flexible and domain agnostic. This comes at a cost, resulting in difficulty when one attempts to understand the reasoning behind decisions. This is problematic when such models are applied in realworld situations where accountability, legality, and maintenance are of concern. Artificial gene regulatory networks (AGRNs) are a type of connectionist architecture inspired by gene regulatory mechanisms. AGRNs are of interest within this thesis due to their ability to solve tasks in chaotic dynamical systems despite their relatively small size.The overarching aim of this work was to investigate the properties of connectionist architectures to improve the transparency of their execution. Initially, the evolutionary process and internal structure of AGRNs were investigated. Following this, the creation of an external control layer used to improve the transparency of execution of an external connectionist architecture was attempted.When investigating the evolutionary process of AGRNs, pathways were found that when followed, produced more performant networks in a shorter time frame. Evidence that AGRNs are capable of performing well despite internal interference was found when investigating their modularity, where it was also discovered that they do not develop strict modularity consistently. A control layer inspired by epigenetics that selectively deactivates nodes in trained artificial neural networks (ANNs) was developed; the analysis of its behaviour provided an insight into the internal workings of the ANN

Desenvolvimento Humano: Da Concepção à Maturidade

The main objective of this review was to describe and emphasize the care that a woman must have in the period prior to pregnancy, as well as throughout pregnancy and after the birth of the baby, cares and duties that should continue to be followed by mother and child throughout the first years of the child’s life. Such cares are of nutritional, behavioral and lifestyle natures, and also involve the father and the whole family. Human development, from conception to maturity, consists of a critical and important period due to the multitude of intrinsic genetic and environmental factors that influence, positively or negatively, the person's entire life. The human being, who originated and passed his/her first phase of development in the womb, receives influence from different factors: a) of parental origin (father and mother), including health and lifestyle of the father and mother, genetic inheritance, nutrition of the mother prior to and during pregnancy; b) events that affected the mother and hence the child under development in intrauterine life, at birth (delivery), during perinatal period, and throughout the early years of life. The fragility of development continues throughout the preschool, school and adolescent periods during which proper nutrition with a balanced lifestyle is essential and depends on guidance from the parents, caregivers and teachers.2

Epigenetic regulation of gene expression in physiological and pathological brain processes

Over the past decade, it has become increasingly obvious that epigenetic mechanisms are an integral part of a multitude of brain functions that range from the development of the nervous system over basic neuronal functions to higher order cognitive processes. At the same time, a substantial body of evidence has surfaced indicating that several neurodevelopmental, neurodegenerative, and neuropsychiatric disorders are in part caused by aberrant epigenetic modifications. Because of their inherent plasticity, such pathological epigenetic modifications are readily amenable to pharmacological interventions and have thus raised justified hopes that the epigenetic machinery provides a powerful new platform for therapeutic approaches against these diseases. In this review, we give a detailed overview of the implication of epigenetic mechanisms in both physiological and pathological brain processes and summarize the state-of-the-art of "epigenetic medicine" where applicable. Despite, or because of, these new and exciting findings, it is becoming apparent that the epigenetic machinery in the brain is highly complex and intertwined, which underscores the need for more refined studies to disentangle brain-region and cell-type specific epigenetic codes in a given environmental condition. Clearly, the brain contains an epigenetic "hotspot" with a unique potential to not only better understand its most complex functions, but also to treat its most vicious diseases