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PURPOSE OF REVIEW: Perinatal mental health research provides an important perspective on neurobehavioral development. Here, we aim to review the association of maternal perinatal health with offspring neurodevelopment, providing an update on (self-)regulation problems, hypothesized mechanistic pathways, progress and challenges, and implications for mental health. RECENT FINDINGS: (1) Meta-analyses confirm that maternal perinatal mental distress is associated with (self-)regulation problems which constitute cognitive, behavioral, and affective social-emotional problems, while exposure to positive parental mental health has a positive impact. However, effect sizes are small. (2) Hypothesized mechanistic pathways underlying this association are complex. Interactive and compensatory mechanisms across developmental time are neglected topics. (3) Progress has been made in multiexposure studies. However, challenges remain and these are shared by clinical, translational and public health sciences. (4) From a mental healthcare perspective, a multidisciplinary and system level approach employing developmentally-sensitive measures and timely treatment of (self-)regulation and coregulation problems in a dyadic caregiver-child and family level approach seems needed. The existing evidence-base is sparse. SUMMARY: During the perinatal period, addressing vulnerable contexts and building resilient systems may promote neurobehavioral development. A pluralistic approach to research, taking a multidisciplinary approach to theoretical models and empirical investigation needs to be fostered.
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Trastornos Mentales , Autocontrol , Embarazo , Femenino , Humanos , Salud Mental , Trastornos Mentales/etiología , Emociones , Atención a la SaludRESUMEN
Fetal neuroinflammation and prenatal stress (PS) may contribute to lifelong neurological disabilities. Astrocytes and microglia, among the brain's non-neuronal "glia" cell populations, play a pivotal role in neurodevelopment and predisposition to and initiation of disease throughout lifespan. One of the most common neurodevelopmental disorders manifesting between 1-4 years of age is the autism spectrum disorder (ASD). A pathological glial-neuronal interplay is thought to increase the risk for clinical manifestation of ASD in at-risk children, but the mechanisms remain poorly understood, and integrative, multi-scale models are needed. We propose a model that integrates the data across the scales of physiological organization, from genome to phenotype, and provides a foundation to explain the disparate findings on the genomic level. We hypothesize that via gene-environment interactions, fetal neuroinflammation and PS may reprogram glial immunometabolic phenotypes that impact neurodevelopment and neurobehavior. Drawing on genomic data from the recently published series of ovine and rodent glial transcriptome analyses with fetuses exposed to neuroinflammation or PS, we conducted an analysis on the Simons Foundation Autism Research Initiative (SFARI) Gene database. We confirmed 21 gene hits. Using unsupervised statistical network analysis, we then identified six clusters of probable protein-protein interactions mapping onto the immunometabolic and stress response networks and epigenetic memory. These findings support our hypothesis. We discuss the implications for ASD etiology, early detection, and novel therapeutic approaches. We conclude with delineation of the next steps to verify our model on the individual gene level in an assumption-free manner. The proposed model is of interest for the multidisciplinary community of stakeholders engaged in ASD research, the development of novel pharmacological and non-pharmacological treatments, early prevention, and detection as well as for policy makers.
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BACKGROUND: Maternal stress before, during and after pregnancy has profound effects on the development and lifelong function of the infant's neurocognitive development. We hypothesized that the programming of the central nervous system (CNS), hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) induced by prenatal stress (PS) is reflected in electrophysiological and epigenetic biomarkers. In this study, we aimed to find noninvasive epigenetic biomarkers of PS in the newborn salivary DNA. RESULTS: A total of 728 pregnant women were screened for stress exposure using Cohen Perceived Stress Scale (PSS), 164 women were enrolled, and 114 dyads were analyzed. Prenatal Distress Questionnaire (PDQ) was also administered to assess specific pregnancy worries. Transabdominal fetal electrocardiograms (taECG) were recorded to derive coupling between maternal and fetal heart rates resulting in a 'Fetal Stress Index' (FSI). Upon delivery, we collected maternal hair strands for cortisol measurements and newborn's saliva for epigenetic analyses. DNA was extracted from saliva samples, and DNA methylation was measured using EPIC BeadChip array (850 k CpG sites). Linear regression was used to identify associations between PSS/PDQ/FSI/Cortisol and DNA methylation. We found epigenome-wide significant associations for 5 CpG with PDQ and cortisol at FDR < 5%. Three CpGs were annotated to genes (Illumina Gene annotation file): YAP1, TOMM20 and CSMD1, and two CpGs were located approximately lay at 50 kb from SSBP4 and SCAMP1. In addition, two differentiated methylation regions (DMR) related to maternal stress measures PDQ and cortisol were found: DAXX and ARL4D. CONCLUSIONS: Genes annotated to these CpGs were found to be involved in secretion and transportation, nuclear signaling, Hippo signaling pathways, apoptosis, intracellular trafficking and neuronal signaling. Moreover, some CpGs are annotated to genes related to autism, post-traumatic stress disorder (PTSD) and schizophrenia. However, our results should be viewed as hypothesis generating until replicated in a larger sample. Early assessment of such noninvasive PS biomarkers will allow timelier detection of babies at risk and a more effective allocation of resources for early intervention programs to improve child development. A biomarker-guided early intervention strategy is the first step in the prevention of future health problems, reducing their personal and societal impact.
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Enfermedades Fetales , Efectos Tardíos de la Exposición Prenatal , Biomarcadores , Niño , Metilación de ADN , Epigenoma , Femenino , Enfermedades Fetales/genética , Humanos , Hidrocortisona/análisis , Lactante , Recién Nacido , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética , Saliva/química , Proteínas de Transporte Vesicular/genéticaRESUMEN
The adverse effects of maternal prenatal stress (PS) on child's neurodevelopment warrant the establishment of biomarkers that enable early interventional therapeutic strategies. We performed a prospective matched double cohort study screening 2000 pregnant women in third trimester with Cohen Perceived Stress Scale-10 (PSS-10) questionnaire; 164 participants were recruited and classified as stressed and control group (SG, CG). Fetal cord blood iron parameters of 107 patients were measured at birth. Transabdominal electrocardiograms-based Fetal Stress Index (FSI) was derived. We investigated sex contribution to group differences and conducted causal inference analyses to assess the total effect of PS exposure on iron homeostasis using a directed acyclic graph (DAG) approach. Differences are reported for p < 0.05 unless noted otherwise. Transferrin saturation was lower in male stressed neonates. The minimum adjustment set of the DAG to estimate the total effect of PS exposure on fetal ferritin iron biomarkers consisted of maternal age and socioeconomic status: SG revealed a 15% decrease in fetal ferritin compared with CG. Mean FSI was higher among SG than among CG. FSI-based timely detection of fetuses affected by PS can support early individualized iron supplementation and neurodevelopmental follow-up to prevent long-term sequelae due to PS-exacerbated impairment of the iron homeostasis.
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Ferritinas , Feto , Biomarcadores , Estudios de Cohortes , Femenino , Sangre Fetal/metabolismo , Feto/metabolismo , Homeostasis , Humanos , Recién Nacido , Hierro/metabolismo , Masculino , Embarazo , Estudios ProspectivosRESUMEN
Functional development of affective and reward circuits, cognition and response inhibition later in life exhibits vulnerability periods during gestation and early childhood. Extensive evidence supports the model that exposure to stressors in the gestational period and early postnatal life increases an individual's susceptibility to future impairments of functional development. Recent versions of this model integrate epigenetic mechanisms of the developmental response. Their understanding will guide the future treatment of the associated neuropsychiatric disorders. A combination of non-invasively obtainable physiological signals and epigenetic biomarkers related to the principal systems of the stress response, the Hypothalamic-Pituitary axis (HPA) and the Autonomic Nervous System (ANS), are emerging as the key predictors of neurodevelopmental outcomes. Such electrophysiological and epigenetic biomarkers can prove to timely identify children benefiting most from early intervention programs. Such programs should ameliorate future disorders in otherwise healthy children. The recently developed Early Family-Centered Intervention Programs aim to influence the care and stimuli provided daily by the family and improving parent/child attachment, a key element for healthy socio-emotional adult life. Although frequently underestimated, such biomarker-guided early intervention strategy represents a crucial first step in the prevention of future neuropsychiatric problems and in reducing their personal and societal impact.
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Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-Suprarrenal , Biomarcadores , Niño , Preescolar , Epigénesis Genética , Epigenómica , Femenino , Humanos , Lactante , EmbarazoRESUMEN
In the pregnant mother and her fetus, chronic prenatal stress results in entrainment of the fetal heartbeat by the maternal heartbeat, quantified by the fetal stress index (FSI). Deep learning (DL) is capable of pattern detection in complex medical data with high accuracy in noisy real-life environments, but little is known about DL's utility in non-invasive biometric monitoring during pregnancy. A recently established self-supervised learning (SSL) approach to DL provides emotional recognition from electrocardiogram (ECG). We hypothesized that SSL will identify chronically stressed mother-fetus dyads from the raw maternal abdominal electrocardiograms (aECG), containing fetal and maternal ECG. Chronically stressed mothers and controls matched at enrolment at 32 weeks of gestation were studied. We validated the chronic stress exposure by psychological inventory, maternal hair cortisol and FSI. We tested two variants of SSL architecture, one trained on the generic ECG features for emotional recognition obtained from public datasets and another transfer-learned on a subset of our data. Our DL models accurately detect the chronic stress exposure group (AUROC = 0.982 ± 0.002), the individual psychological stress score (R2 = 0.943 ± 0.009) and FSI at 34 weeks of gestation (R2 = 0.946 ± 0.013), as well as the maternal hair cortisol at birth reflecting chronic stress exposure (0.931 ± 0.006). The best performance was achieved with the DL model trained on the public dataset and using maternal ECG alone. The present DL approach provides a novel source of physiological insights into complex multi-modal relationships between different regulatory systems exposed to chronic stress. The final DL model can be deployed in low-cost regular ECG biosensors as a simple, ubiquitous early stress detection and monitoring tool during pregnancy. This discovery should enable early behavioral interventions.
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Bases de Datos Factuales , Aprendizaje Profundo , Electrocardiografía , Enfermedades Fetales/fisiopatología , Feto/fisiopatología , Complicaciones del Embarazo/fisiopatología , Procesamiento de Señales Asistido por Computador , Estrés Psicológico/fisiopatología , Adolescente , Adulto , Femenino , Humanos , Persona de Mediana Edad , EmbarazoRESUMEN
The autonomic nervous system (ANS) is one of the main biological systems that regulates the body's physiology. Autonomic nervous system regulatory capacity begins before birth as the sympathetic and parasympathetic activity contributes significantly to the fetus' development. In particular, several studies have shown how vagus nerve is involved in many vital processes during fetal, perinatal, and postnatal life: from the regulation of inflammation through the anti-inflammatory cholinergic pathway, which may affect the functioning of each organ, to the production of hormones involved in bioenergetic metabolism. In addition, the vagus nerve has been recognized as the primary afferent pathway capable of transmitting information to the brain from every organ of the body. Therefore, this hypothesis paper aims to review the development of ANS during fetal and perinatal life, focusing particularly on the vagus nerve, to identify possible "critical windows" that could impact its maturation. These "critical windows" could help clinicians know when to monitor fetuses to effectively assess the developmental status of both ANS and specifically the vagus nerve. In addition, this paper will focus on which factors-i.e., fetal characteristics and behaviors, maternal lifestyle and pathologies, placental health and dysfunction, labor, incubator conditions, and drug exposure-may have an impact on the development of the vagus during the above-mentioned "critical window" and how. This analysis could help clinicians and stakeholders define precise guidelines for improving the management of fetuses and newborns, particularly to reduce the potential adverse environmental impacts on ANS development that may lead to persistent long-term consequences. Since the development of ANS and the vagus influence have been shown to be reflected in cardiac variability, this paper will rely in particular on studies using fetal heart rate variability (fHRV) to monitor the continued growth and health of both animal and human fetuses. In fact, fHRV is a non-invasive marker whose changes have been associated with ANS development, vagal modulation, systemic and neurological inflammatory reactions, and even fetal distress during labor.
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Cocaine administration has been shown to induce plastic changes in the medial prefrontal cortex (mPFC), which could represent a mechanism by which cocaine facilitates the association between cocaine rewarding effects with contextual cues. Nicotinic acetylcholine receptors (nAChRs) in the mPFC have critical roles in cognitive function including attention and memory and are key players in plasticity processes. However, whether nAChRs in the mPFC are required for the acquisition and maintenance of cocaine-associated memories is still unknown. To assess this question, we used the conditioning place preference (CPP) model to study the effect of intra-mPFC infusion of methyllycaconitine, a selective antagonist of α7 nAChRs, on the acquisition, consolidation and expression of cocaine-associated memory in adult rats. Our findings reveal that mPFC α7 nAChRs activation is necessary for the acquisition and retrieval, but not consolidation, of cocaine induced CPP. Moreover, cocaine-induced sensitization during CPP conditioning sessions was abolished by methyllycaconitine infusion in the mPFC. Together, these results identify mPFC α7 nAChRs as critical players involved in both acquiring and retrieving cocaine-associated memories. Considering that drug seeking often depends on the association between drug-paired cues and the rewarding effects of the drug, α7 nAChRs in the mPFC could be considered as potential targets for the prevention or treatment of cocaine use disorder.
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Aconitina/análogos & derivados , Sensibilización del Sistema Nervioso Central/efectos de los fármacos , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Cocaína/farmacología , Condicionamiento Clásico/efectos de los fármacos , Inhibidores de Captación de Dopamina/farmacología , Consolidación de la Memoria/efectos de los fármacos , Recuerdo Mental/efectos de los fármacos , Antagonistas Nicotínicos/farmacología , Corteza Prefrontal/efectos de los fármacos , Receptor Nicotínico de Acetilcolina alfa 7/antagonistas & inhibidores , Aconitina/farmacología , Animales , Conducta Animal/efectos de los fármacos , Cocaína/administración & dosificación , Modelos Animales de Enfermedad , Inhibidores de Captación de Dopamina/administración & dosificación , Ratas , Ratas WistarRESUMEN
Prenatal stress (PS) impacts early postnatal behavioural and cognitive development. This process of 'fetal programming' is mediated by the effects of the prenatal experience on the developing hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS). We derive a multi-scale multi-species approach to devising preclinical and clinical studies to identify early non-invasively available pre- and postnatal biomarkers of PS. The multiple scales include brain epigenome, metabolome, microbiome and the ANS activity gauged via an array of advanced non-invasively obtainable properties of fetal heart rate fluctuations. The proposed framework has the potential to reveal mechanistic links between maternal stress during pregnancy and changes across these physiological scales. Such biomarkers may hence be useful as early and non-invasive predictors of neurodevelopmental trajectories influenced by the PS as well as follow-up indicators of success of therapeutic interventions to correct such altered neurodevelopmental trajectories. PS studies must be conducted on multiple scales derived from concerted observations in multiple animal models and human cohorts performed in an interactive and iterative manner and deploying machine learning for data synthesis, identification and validation of the best non-invasive detection and follow-up biomarkers, a prerequisite for designing effective therapeutic interventions.
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Efectos Tardíos de la Exposición Prenatal , Animales , Biomarcadores , Encéfalo , Recolección de Datos , Femenino , Desarrollo Fetal , Humanos , Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-Suprarrenal , EmbarazoRESUMEN
We review evidence supporting the role of early life programming in the susceptibility for adult neurodegenerative diseases while highlighting questions and proposing avenues for future research to advance our understanding of this fundamental process. The key elements of this phenomenon are chronic stress, neuroinflammation triggering microglial polarization, microglial memory and their connection to neurodegeneration. We review the mediating mechanisms which may function as early biomarkers of increased susceptibility for neurodegeneration. Can we devise novel early life modifying interventions to steer developmental trajectories to their optimum?
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Experiencias Adversas de la Infancia , Microglía , Adulto , Biomarcadores , Humanos , InflamaciónRESUMEN
Neuroinflammation in utero may result in lifelong neurological disabilities. Astrocytes play a pivotal role in this process, but the mechanisms are poorly understood. No early postnatal treatment strategies exist to enhance neuroprotective potential of astrocytes. We hypothesized that agonism on α7 nicotinic acetylcholine receptor (α7nAChR) in fetal astrocytes will augment their neuroprotective transcriptome profile, while the inhibition of α7nAChR will achieve the opposite. Using an in vivo-in vitro model of developmental programming of neuroinflammation induced by lipopolysaccharide (LPS), we validated this hypothesis in primary fetal sheep astrocytes cultures re-exposed to LPS in the presence of a selective α7nAChR agonist or antagonist. Our RNAseq findings show that a pro-inflammatory astrocyte transcriptome phenotype acquired in vitro by LPS stimulation is reversed with α7nAChR agonistic stimulation. Conversely, α7nAChR inhibition potentiates the pro-inflammatory astrocytic transcriptome phenotype. Furthermore, we conducted a secondary transcriptome analysis against the identical α7nAChR experiments in fetal sheep primary microglia cultures. Similar to findings in fetal microglia, in fetal astrocytes we observed a memory effect of in vivo exposure to inflammation, expressed in a perturbation of the iron homeostasis signaling pathway (hemoxygenase 1, HMOX1), which persisted under pre-treatment with α7nAChR antagonist but was reversed with α7nAChR agonist. For both glia cell types, common pathways activated due to LPS included neuroinflammation signaling and NF-κB signaling in some, but not all comparisons. However, overall, the overlap on the level of signaling pathways was rather minimal. Astrocytes, not microglia-the primary immune cells of the brain, were characterized by unique inhibition patterns of STAT3 pathway due to agonistic stimulation of α7nAChR prior to LPS exposure. Lastly, we discuss the implications of our findings for fetal and postnatal brain development.
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Astrocitos/fisiología , Encéfalo/metabolismo , Microglía/fisiología , Inflamación Neurogénica/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Animales , Encéfalo/patología , Bovinos , Células Cultivadas , Feto , Perfilación de la Expresión Génica , Lipopolisacáridos/inmunología , Neuroprotección , Factor de Transcripción STAT3/metabolismo , Transducción de SeñalRESUMEN
Prenatal stress (PS) induces molecular changes that alter neural connectivity, increasing the risk for neuropsychiatric disorders. Here we analyzed -in the hippocampus of adult rats exposed to PS- the epigenetic signature mediating the PS-induced neuroplasticity changes. Furthermore, using cultured hippocampal neurons, we investigated the effects on neuroplasticity of an epigenetic modulator. PS induced significant modifications in the mRNA levels of stress-related transcription factor MEF2A, SUV39H1 histone methyltransferase, and TET1 hydroxylase, indicating that PS modifies gene expression through chromatin remodeling. In in vitro analysis, histone acetylation inhibition with apicidin increased filopodium density, suggesting that the external regulation of acetylation levels might modulate neuronal morphology. These results offer a way to enhance neural connectivity that could be considered to revert PS effects.
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Epigénesis Genética , Código de Histonas , Plasticidad Neuronal , Efectos Tardíos de la Exposición Prenatal/genética , Estrés Psicológico/genética , Animales , Células Cultivadas , Dioxigenasas/genética , Dioxigenasas/metabolismo , Femenino , Hipocampo/citología , Hipocampo/crecimiento & desarrollo , Hipocampo/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Factores de Transcripción MEF2/genética , Factores de Transcripción MEF2/metabolismo , Masculino , Metiltransferasas/genética , Metiltransferasas/metabolismo , Neurogénesis , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Péptidos Cíclicos/farmacología , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatologíaRESUMEN
Prenatal stress (PS) impacts early behavioral, neuroimmune, and cognitive development. Pregnant rat models have been very valuable in examining the mechanisms of such fetal programming. A newer pregnant sheep model of maternal stress offers the unique advantages of chronic in utero monitoring and manipulation. This chapter presents the techniques used to model single and multigenerational stress exposures and their pleiotropic effects on the offspring.
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Encéfalo/patología , Desarrollo Fetal/fisiología , Enfermedades Fetales/patología , Exposición Materna , Efectos Tardíos de la Exposición Prenatal , Psiconeuroinmunología/métodos , Estrés Fisiológico , Animales , Animales Recién Nacidos , Femenino , Masculino , Embarazo , Complicaciones del Embarazo , Ratas , Ratas Wistar , OvinosRESUMEN
Prenatal stress (PS) induces long-lasting molecular alterations in brain circuits of the offspring and increases the propensity to develop neuropsychiatric diseases during adulthood, including mood disorders and drug addiction. A major goal of this study was to assess the impact of PS on pubertal behaviour and adult vulnerability to cocaine-induced conditioning place preference (CPP). We therefore evaluated pubertal novelty response and anxiety-like behaviour in control (C) and PS rats, and then, we examined cocaine-induced CPP in those animals during adulthood. We found no differences between C and PS groups on pubertal behaviour, however, only PS rats showed a significant cocaine-induced CPP. To further analyze our results, we classified cocaine-treated rats regarding their CPP score in Low CPP or High CPP and we then analysed their pubertal behaviour. We found different relations of anxiety-like behaviour to cocaine reward as a function of PS exposure: for C group, High CPP and Low CPP had shown similar levels of anxiety-like behaviour at puberty; on the contrary, for PS group, High CPP had shown lower anxiety-like behaviour than Low CPP rats. This study underscores the importance of considering prenatal exposure to stress when analysing the relationship between anxiety and cocaine vulnerability. Moreover, the evaluation of behavioural traits at puberty opens the possibility of early intervention and will allow the development of specific prevention strategies to avoid the devastating consequences of drug addiction later in life.
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Ansiedad/tratamiento farmacológico , Cocaína/farmacología , Condicionamiento Psicológico/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Animales , Ansiedad/fisiopatología , Trastornos de Ansiedad/tratamiento farmacológico , Trastornos de Ansiedad/fisiopatología , Condicionamiento Psicológico/fisiología , Conducta Exploratoria/fisiología , Femenino , Masculino , Actividad Motora/efectos de los fármacos , Ratas Wistar , RecompensaRESUMEN
Prenatal development constitutes a critical time for shaping adult behaviour and may set the stage for vulnerability to disease later in life. A wealth of information from humans as well as from animal research has revealed that exposure to hostile conditions during gestation may result in a series of coordinated biological responses aimed at enhancing the probability of survival, but could also increase the susceptibility to mental illness. Prenatal stress has been linked to abnormal cognitive, behavioural and psychosocial outcomes both in animals and in humans, but the underlying molecular and physiological mechanisms remain largely unknown. In this chapter, we shall review experimental data from studies reported for rats, since more information is available for them than for other species. The major focus of the present chapter is to update and discuss data on behavioural, functional and morphological effects of prenatal stress in rats that may have counterparts in prospective and/or retrospective studies of gestational stress in humans. This work contributes to understanding the role of neuronal plasticity in the long-term effects of developmental adversity on brain function and its implications for vulnerability to disease.
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Encéfalo/fisiopatología , Plasticidad Neuronal/fisiología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Estrés Fisiológico/fisiología , Estrés Psicológico/fisiopatología , Animales , Femenino , Sistema Hipotálamo-Hipofisario/fisiopatología , Sistema Hipófiso-Suprarrenal/fisiopatología , Embarazo , RatasRESUMEN
There is a large consensus that the prenatal environment determines the susceptibility to pathological conditions later in life. The hypothesis most widely accepted is that exposure to insults inducing adverse conditions in-utero may have negative effects on the development of target organs, disrupting homeostasis and increasing the risk of diseases at adulthood. Several models have been proposed to investigate the fetal origins of adult diseases, but although these approaches hold true for almost all diseases, particular attention has been focused on disorders related to the central nervous system, since the brain is particularly sensitive to alterations of the microenvironment during early development. Neurobiological disorders can be broadly divided into developmental, neurodegenerative and neuropsychiatric disorders. Even though most of these diseases share genetic risk factors, the onset of the disorders cannot be explained solely by inheritance. Therefore, current understanding presumes that the interactions of environmental input, may lead to different disorders. Among the insults that can play a direct or indirect role in the development of neurobiological disorders are stress, infections, drug abuse, and environmental contaminants. Our laboratories have been involved in the study of the neurobiological impact of gestational stress on the offspring (Dr. Antonelli's lab) and on the effect of gestational exposure to toxicants, mainly methyl mercury (MeHg) and perfluorinated compounds (PFCs) (Dr. Ceccatelli's lab). In this focused review, we will review the specialized literature but we will concentrate mostly on our own work on the long term neurodevelopmental consequences of gestational exposure to stress and neurotoxicants.
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Neurotoxinas/efectos adversos , Efectos Tardíos de la Exposición Prenatal , Estrés Psicológico/complicaciones , Animales , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/embriología , Femenino , Humanos , EmbarazoRESUMEN
The aim of the present article is to review experimental evidence which suggest joint involvement of both the dopaminergic and neurotensinergic systems in stress conditions. At present, the concept of stress refers to an environmental demand exceeding the normal regulatory ability of an organism, particularly during unpredictable and uncontrollable situations. Chronic stress yields devastating effects including cognitive and working memory dysfunctions, for which neurotransmission mediated by the catecholamines dopamine and noradrenaline is crucial. Catecholamine synthesis depends on the rate-limiting enzyme, tyrosine hydroxylase, whose expression is associated with working memory and the response to chronic stress. Neurotensin is a tridecapeptide widely distributed in the nervous system, at both central and peripheral levels, which behaves as a neurotransmitter or neuromodulator. It mediates diverse biological actions including reward, locomotion, pain modulation and stress. Neurotensin and its high affinity NTS1 receptor are densely localized in areas that process emotion (amygdala nucleus), cognition (such as hippocampal nuclei and cortical areas) and the response to stress (hypothalamic nucleus). Experimental evidence indicates a crosstalk between the dopaminergic and the neurotensinergic systems either from an anatomical or a biochemical point of view. It is suggested that a concomitant alteration of dopaminergic and neurotensinergic systems takes place in diverse stress conditions.
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Dopamina/metabolismo , Neurotensina/metabolismo , Estrés Fisiológico , Animales , HumanosRESUMEN
The impact of sub-lethal doses of herbicides on human health and the environment is a matter of controversy. Due to the fact that evidence particularly of the effects of glyphosate on the central nervous system of rat offspring by in utero exposure is scarce, the purpose of the present study was to assess the neurobehavioral effects of chronic exposure to a glyphosate-containing herbicide during pregnancy and lactation. To this end, pregnant Wistar rats were exposed through drinking water to 0.2% or 0.4% of a commercial formulation of glyphosate (corresponding to a concentration of 0.65 or 1.30g/L of glyphosate, respectively) during pregnancy and lactation and neurobehavioral alterations in offspring were analyzed. The postnatal day on which each pup acquired neonatal reflexes (righting, cliff aversion and negative geotaxis) and that on which eyes and auditory canals were fully opened were recorded for the assessment of sensorimotor development. Locomotor activity and anxiety levels were monitored via open field test and plus maze test, respectively, in 45- and 90-day-old offspring. Pups exposed to a glyphosate-based herbicide showed early onset of cliff aversion reflex and early auditory canal opening. A decrease in locomotor activity and in anxiety levels was also observed in the groups exposed to a glyphosate-containing herbicide. Findings from the present study reveal that early exposure to a glyphosate-based herbicide affects the central nervous system in rat offspring probably by altering mechanisms or neurotransmitter systems that regulate locomotor activity and anxiety.
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Conducta Animal/efectos de los fármacos , Glicina/análogos & derivados , Herbicidas/toxicidad , Sistema Nervioso/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Factores de Edad , Animales , Animales Recién Nacidos , Ingestión de Alimentos/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Femenino , Edad Gestacional , Glicina/toxicidad , Lactancia , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Destreza Motora/efectos de los fármacos , Fuerza Muscular/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Ratas , Ratas Wistar , Reflejo/efectos de los fármacos , GlifosatoRESUMEN
Previous studies from our laboratory have shown that male adult offspring of stressed mothers exhibited higher levels of ionotropic and metabotropic glutamate receptors than control rats. These offspring also showed long-lasting astroglial hypertrophy and a reduced dendritic arborization with synaptic loss. Since metabolism of glutamate is dependent on interactions between neurons and surrounding astroglia, our results suggest that glutamate neurotransmitter pathways might be impaired in the brain of prenatally stressed rats. To study the effect of prenatal stress on the metabolism and neurotransmitter function of glutamate, pregnant rats were subjected to restrain stress during the last week of gestation. Brains of the adult offspring were used to assess glutamate metabolism, uptake and release as well as expression of glutamate receptors and transporters. While glutamate metabolism was not affected it was found that prenatal stress (PS) changed the expression of the transporters, thus, producing a higher level of vesicular vGluT-1 in the frontal cortex (FCx) and elevated levels of GLT1 protein and messenger RNA in the hippocampus (HPC) of adult male PS offspring. We also observed increased uptake capacity for glutamate in the FCx of PS male offspring while no such changes were observed in the HPC. The results show that changes mediated by PS on the adult glutamatergic system are brain region specific. Overall, PS produces long-term changes in the glutamatergic system modulating the expression of glutamate transporters and altering synaptic transmission of the adult brain.
Asunto(s)
Ácido Glutámico/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Estrés Psicológico/metabolismo , Transmisión Sináptica/fisiología , Animales , Femenino , Hipocampo/metabolismo , Masculino , Técnicas de Cultivo de Órganos , Embarazo , Efectos Tardíos de la Exposición Prenatal/etiología , Ratas , Ratas Wistar , Estrés Psicológico/complicacionesRESUMEN
Prenatal stress (PS) strongly impacts fetal brain development and function in adulthood. In normal aging and Alzheimer's disease, there is hypothalamic-pituitary-adrenal axis dysfunction and loss of cholinergic neurons and neuronal nicotinic acetylcholine receptors (nAChRs). This study investigated whether prenatal restraint stress affects nAChR expression in the brain of adult offspring. For PS, pregnant dams were placed in a plastic restrainer for 45 min, three times daily during the last week of pregnancy; controls were undisturbed. Male offspring were analyzed at postnatal day (PND) 60 (n = 4 rats per group). Western blot (WB) and fluorescence microscopy showed that PS decreased α7-AChR subunit expression (â¼50%) in the frontal cortex in the adult offspring. PS decreased significantly the number of α7-AChR-expressing cells in the medial prefrontal cortex (by â¼25%) and in the sensory-motor cortex (by â¼20%) without affecting the total cell number in those areas. No alterations were found in the hippocampus by quantitative polymerase chain reaction (qPCR), or WB analysis, but a detailed fluorescence microscopy analysis showed that PS affected α7-AChR mainly in the CA3 and dentate gyrus subfields: PS decreased α7-AChR subunit expression by â¼25 and â¼30%, respectively. Importantly, PS decreased the number of α7-AChR-expressing cells and the total cell number (by â¼15 and 20%, respectively) in the dentate gyrus. PS differently affected α4-AChR: PS impaired its mRNA expression in the frontal cortex (by â¼50%), without affecting protein levels. These results demonstrate that disturbances during gestation produce long-term alterations in the expression pattern of α7-AChR in rat brain.