Corticotropin-releasing hormone as the homeostatic rheostat of feto-maternal symbiosis and developmental programming In utero and neonatal life

A balanced interaction between the homeostatic mechanisms of mother and the devel- oping organism during pregnancy and in early neonatal life is essential in order to ensure optimal fetal development, ability to respond to various external and internal challenges, protection from adverse programming, and safeguard maternal care availability after parturition. In the majority of pregnancies, this relationship is highly effective resulting in successful outcomes. However, in a number of pathological settings, perturbations of the maternal homeostasis disrupt this symbiosis and initiate adaptive responses with unpre- dictable outcomes for the fetus or even the neonate. This may lead to development of pathological phenotypes arising from developmental reprogramming involving interaction of genetic, epigenetic, and environmental-driven pathways, sometimes with acute conse- quences (e.g., growth impairment) and sometimes delayed (e.g., enhanced susceptibility to disease) that last well into adulthood. Most of these adaptive mechanisms are activated and controlled by hormones of the hypothalamo-pituitary adrenal axis under the influ- ence of placental steroid and peptide hormones. In particular, the hypothalamic peptide corticotropin-releasing hormone (CRH) plays a key role in feto-maternal communication by orchestrating and integrating a series of neuroendocrine, immune, metabolic, and behavioral responses. CRH also regulates neural networks involved in maternal behavior and this determines efficiency of maternal care and neonate interactions. This review will summarize our current understanding of CRH actions during the perinatal period, focusing on the physiological roles for both mother and offspring and also how external challenges can alter CRH actions and potentially impact on fetus/neonate health

A multidimensional analysis of maternal separation impact: corticosteroids and oxytocin linkage

Dissertação de Mestrado em Psicologia ClínicaExposure to early life stress and emotional trauma appear to be critical for neurodevelopment, stress responsiveness, lifetime health, and behavioral programming. Importantly, the severity of these effects seems to be mediated by the glucocorticoid levels exposure and the specific development stage at which it occurs. Indeed, in the last decades elegant longitudinal research with humans informed about the impact of early life experiences on the adult general adaptation. However, the mechanisms underlying the stress programming are still unclear. Animal models have been developed to experimentally investigate the neural substracts of early chronic stress exposure. In the rat, maternal separation (MS) in early ages have been linked to endocrinal, neurochemical and behavioral disruptions in the rat. The present thesis aimed to investigate the long-term imprinting effects of early stress exposure into two developmental time windows (MS2-15, MS7-20), in terms of behavioral outcomes: spatial memory performance, anxiety behaviors, learn helplessness behavior and social behavior. Moreover, in order to clarify the cross-talk between corsticosteroid and oxytocinergic systems as possible mechanism underlying the proposed behavioral outcomes, we separately evaluated the long-term consequences of early life maternal separation in corticosteroid and oxytocinergic pathways. Independently of the temporal windows in which the stressor occurred, MS rats showed increased adrenal glands and body’s weight, which may reflect a disruption of the HPA axis, as corroborated by the higher levels of corticosteroids plasma found in the same animals. Behaviorally, MS2-15 rats presented depressive-like behaviors and, indepently of the brain maturity, both MS groups showed hyperanxious behavior in the elevated plus maze test. Finally, early adverse experiences showed to influence the mRNA OT-r expression in specific brain areas linked to HPA axis regulation and to several cognitive- and social-emotional processes. These findings could reflect the time-dependent imprinting effect of adverse experiences in childhood, since the impact of corticosteroids in the maturation of specific neuronal substract of behavior and neuroendocrine phenotypes were demonstrated.A exposição precoce a stress e a experiências traumáticas têm sido apontadas como críticas para o desenvolvimento neurocognitivo, da respostas ao stress, da saúde e da programação comportamental. Mais importante ainda, a severidade destes efeitos parece ser mediada pelos níveis de glucocorticóides e pelo período desenvolvimental em que as experiências ocorrem. De facto, nas últimas décadas estudos longitudinais realizados com humanos têm demonstrado o impacto das experiências precoces na adaptação global em idade adulta. No entanto, os mecanismos subjacentes à programação do stress ainda não estão totalmente clarificados. Neste sentido, têm-se desenvolvido modelos animais para identificar, experimentalmente, quais os substratos neurais subjacentes aos efeitos da exposição crónica ao stress. No rato, a separação materna (MS) em idades precoces tem sido associada a perturbações neurobioquímicas, neuroendócrinas e as perturbações de comportamento. A presente tese teve como objectivo avaliar, a nível comportamental, e em dois períodos sensitivos do desenvolvimento (MS2-15, MS7-20) os efeitos da programação a longo-prazo da exposição precoce a stress, nomeadamente: o desempenho da memória espacial, o comportamento ansioso, o comportamento depressivo e o comportamento social. Adicionalmente, e a fim de promover a compreensão sobre a relação entre os sistemas oxitocinérico e HPA como possível mecanismo subjacente aos outcomes comportamentais identificados, foram avaliadas separadamente as consequências a longo-prazo da separação maternal nas vias oxitocinérgica e na produção de corticoesteróides. Independentemente dos períodos temporais em que ocorreu o stress, os ratos sujeitos à separação materna apresentaram um aumento ao nível do peso corporal e das das glândulas adrenais, o que pode reflectir uma ruptura do eixo HPA, como corroborado pelos maiores níveis plasmáticos de corticosteróides encontrados nos mesmos animais. Ao nível comportamental, os ratos MS2-15 apresentaram comportamentos depressivos e, independente do nível de maturação cerebral, ambos os grupos experimentais apresentaram comportamentos ansiosos quando testados no Elevated Plus Maze. Finalmente, a experiência de stress em momentos precoces do desenvolvimento demonstrou influenciar a expressão do mRNA dos receptors de oxitocina em áreas específicas do cérebro associadas à regulação do eixo HPA e a vários processos cognitivos e sócio-emocionais. Os presentes resultados permitem demonstrar que o impacto de experiências adversas na infância está dependente do período desenvolvimental em que estas ocorrem, tendo sido demonstrado o impacto dos corticosteroides na maturação de redes neuronais especificamente associadas a determinados fenótipos comportamentais e neuroendócrinos

Prenatal Cocaine Disrupts Serotonin Signaling-Dependent Behaviors: Implications for Sex Differences, Early Stress and Prenatal SSRI Exposure

Prenatal cocaine (PC) exposure negatively impacts the developing nervous system, including numerous changes in serotonergic signaling. Cocaine, a competitive antagonist of the serotonin transporter, similar to selective serotonin reuptake inhibitors (SSRIs), also blocks dopamine and norepinephrine transporters, leaving the direct mechanism through which cocaine disrupts the developing serotonin system unclear. In order to understand the role of the serotonin transporter in cocaine’s effect on the serotonergic system, we compare reports concerning PC and prenatal antidepressant exposure and conclude that PC exposure affects many facets of serotonergic signaling (serotonin levels, receptors, transporters) and that these effects differ significantly from what is observed following prenatal SSRI exposure. Alterations in serotonergic signaling are dependent on timing of exposure, test regimens, and sex. Following PC exposure, behavioral disturbances are observed in attention, emotional behavior and stress response, aggression, social behavior, communication, and like changes in serotonergic signaling, these effects depend on sex, age and developmental exposure. Vulnerability to the effects of PC exposure can be mediated by several factors, including allelic variance in serotonergic signaling genes, being male (although fewer studies have investigated female offspring), and experiencing the adverse early environments that are commonly coincident with maternal drug use. Early environmental stress results in disruptions in serotonergic signaling analogous to those observed with PC exposure and these may interact to produce greater behavioral effects observed in children of drug-abusing mothers. We conclude that based on past evidence, future studies should put a greater emphasis on including females and monitoring environmental factors when studying the impact of PC exposure

Resilience priming: translational models for understanding resiliency and adaptation to early life adversity

Despite the increasing attention to early life adversity and its long-term consequences on health, behavior, and the etiology of neurodevelopmental disorders, our understanding of the adaptations and interventions that promote resiliency and rescue against such insults are underexplored. Specifically, investigations of the perinatal period often focus on negative events/outcomes. In contrast, positive experiences (i.e. enrichment/parental care//healthy nutrition) favorably influence development of the nervous and endocrine systems. Moreover, some stressors result in adaptations and demonstrations of later-life resiliency. This review explores the underlying mechanisms of neuroplasticity that follow some of these early life experiences and translates them into ideas for interventions in pediatric settings. The emerging role of the gut microbiome in mediating stress susceptibility is also discussed. Since many negative outcomes of early experiences are known, it is time to identify mechanisms and mediators that promote resiliency against them. These range from enrichment, quality parental care, dietary interventions and those that target the gut microbiota

Early-life adversity and neurological disease: age-old questions and novel answers.

Neurological illnesses, including cognitive impairment, memory decline and dementia, affect over 50 million people worldwide, imposing a substantial burden on individuals and society. These disorders arise from a combination of genetic, environmental and experiential factors, with the latter two factors having the greatest impact during sensitive periods in development. In this Review, we focus on the contribution of adverse early-life experiences to aberrant brain maturation, which might underlie vulnerability to cognitive brain disorders. Specifically, we draw on recent robust discoveries from diverse disciplines, encompassing human studies and experimental models. These discoveries suggest that early-life adversity, especially in the perinatal period, influences the maturation of brain circuits involved in cognition. Importantly, new findings suggest that fragmented and unpredictable environmental and parental signals comprise a novel potent type of adversity, which contributes to subsequent vulnerabilities to cognitive illnesses via mechanisms involving disordered maturation of brain 'wiring'

Mediation and Moderation of Intergenerational Epigenetic Effects of Trauma

Trauma and early-life stress have been linked to poor mental and physical health outcomes. In fact, research has identified trauma and stress can influence epigenetic marks on genes that can alter gene activity. It is suspected that epigenetically altered gene activity is involved in behavior and mental health. This may help explain why some individuals don’t experience great benefit from treatment for the effects of stress, and severe mental health symptoms can be chronic for decades or a lifetime. Moreover, some trauma-related mental health symptoms have shown generational patterns that appear linked to epigenetic marks. Therefore, this study sought to investigate the potential inter-generational influence of mother’s trauma history and mental health on her offspring’s DNA methylation and gene expression in umbilical cord blood. Standardized measures were used to assess mother’s trauma history and cumulative experienced fear (TLEQ), as well as mother’s mental health status during pregnancy (BSI). Genome-wide and candidate gene analyses were conducted after standard quality control data cleaning procedures. Batch and chip adjustments were made using the Combat package in R software, and the False Discovery Rate was employed to control for multiple comparisons. Results indicate mother’s exposure to trauma in childhood predicts DNA methylation and gene expression in offspring. Additionally, mother’s mental health status during pregnancy significantly predicts differential gene expression on 245 genes in males only. Finally, mother’s fear completely mediates the influence of trauma on her mental health functioning. In conclusion, a mother’s traumatic experience has potential to influence gene regulation in her offspring. Most importantly, mother’s mental health during pregnancy appears to exert a great influence on gene regulation in males compared to female offspring

Dev Psychobiol

Childhood poverty is associated with harsh parenting with a risk of transmission to the next generation. This prospective study examined the relations between childhood poverty and non-parent adults' neural responses to infant cry sounds. While no main effects of poverty were revealed in contrasts of infant cry versus acoustically matched white noise, a gender by childhood poverty interaction emerged. In females, childhood poverty was associated with increased neural activations in the posterior insula, striatum, calcarine sulcus, hippocampus, and fusiform gyrus, while, in males, childhood poverty was associated with reduced levels of neural responses to infant cry in the same regions. Irrespective of gender, neural activation in these regions was associated with higher levels of annoyance with the cry sound and reduced desire to approach the crying infant. The findings suggest gender differences in neural and emotional responses to infant cry sounds among young adults growing up in poverty.RC2 MD004767/MD/NIMHD NIH HHS/United StatesR49 CE002099/CE/NCIPC CDC HHS/United StatesRC2MD004767/MD/NIMHD NIH HHS/United States1R21HD078797-01A1/HD/NICHD NIH HHS/United StatesU49/CE002099/CE/NCIPC CDC HHS/United StatesR21 HD078797/HD/NICHD NIH HHS/United States2016-12-01T00:00:00Z25981334PMC482140

The epigenetic impacts of social stress: how does social adversity become biologically embedded?

Epigenetic mechanisms are implicated in the processes through which social stressors erode health in humans and other animals. Here I review progress in elucidating the biological pathways underlying the social gradient in health, with particular emphasis on how behavioral stresses influence epigenomic variation linked to health. The evidence that epigenetic changes are involved in embedding of social status-linked chronic stress is reviewed in the context of current knowledge about behavior within animal dominance hierarchies and the impacts of social position on behaviors that affect health. The roles of epigenetic mechanisms in responses to trauma and the evidence for their involvement in intergenerational transmission of the biological impacts of traumatic stress are also considered. Taken together, the emerging insights have important implications for development of strategies to improve societal health and well-being