Population neuroimaging:generation of a comprehensive data resource within the ALSPAC pregnancy and birth cohort

Neuroimaging offers a valuable insight into human brain development by allowing in vivo assessment of structure, connectivity and function. Multimodal neuroimaging data have been obtained as part of three sub-studies within the Avon Longitudinal Study of Parents and Children, a prospective multigenerational pregnancy and birth cohort based in the United Kingdom. Brain imaging data were acquired when offspring were between 18 and 24 years of age, and included acquisition of structural, functional and magnetization transfer magnetic resonance, diffusion tensor, and magnetoencephalography imaging. This resource provides a unique opportunity to combine neuroimaging data with extensive phenotypic and genotypic measures from participants, their mothers, and fathers

General psychopathology factor and unresolved-disorganized attachment uniquely correlated to white matter integrity using diffusion tensor imaging

Multivariate analysis of psychological dat

Becoming dad: Exploring the neurobiology of the transition into fatherhood

Item does not contain fulltextVrije Universiteit Amsterdam, 22 juni 2021Promotores : Bakermans-Kranenburg, M.J., Schuengel, C. Co-promotor : Riem, M.M.E.177 p

Associations between prenatal, childhood, and adolescent stress and variations in white-matter properties in young men

Objective Previous studies have shown that both pre- and post-natal adversities, the latter including exposures to stress during childhood and adolescence, explain variation in structural properties of white matter (WM) in the brain. While previous studies have examined effects of independent stress exposures within one developmental period, such as childhood, we examine effects of stress across development using data from a prospective longitudinal study. More specifically, we ask how stressful events during prenatal development, childhood, and adolescence relate to variation in WM properties in early adulthood in young men recruited from a birth cohort. Method Using data from 393 mother-son pairs from a community-based birth cohort from England (Avon Longitudinal Study of Parents and Children), we examined how stressful life events relate to variation in different structural properties of WM in the corpus callosum and across the whole brain in early adulthood in men aged 18–21 years. We distinguish between stress occurring during three developmental periods: a) prenatal maternal stress, b) postnatal stress within the first four years of life, c) stress during adolescence (age 12–16 years). To obtain a comprehensive quantification of variation in WM, we assess structural properties of WM using four different measures, namely fractional anisotropy (FA), mean diffusivity (MD), magnetization transfer ratio (MTR) and myelin water fraction (MWF). Results The developmental model shows that prenatal stress is associated with lower MTR and MWF in the genu and/or splenium of the corpus callosum, and with lower MTR in global (lobar) WM. Stress during early childhood is associated with higher MTR in the splenium, and stress during adolescence is associated with higher MTR in the genu and lower MD in the splenium. We see no associations between postnatal stress and variation in global (lobar) WM. Conclusions The current study found evidence for independent effects of stress on WM properties during distinct neurodevelopmental periods. We speculate that these independent effects are due to differences in the developmental processes unfolding at different developmental time points. We suggest that associations between prenatal stress and WM properties may relate to abnormalities in neurogenesis, affecting the number and density of axons, while postnatal stress may interfere with processes related to myelination or radial growth of axons. Potential consequences of prenatal glucocorticoid exposure should be considered in obstetric care

El papel de la actividad física, el sedentarismo y la condición física en la salud mental y la sustancia blanca en niños y adolescentes

Childhood and adolescence are periods of dynamic behavioral, cognitive and emotional development that can increase vulnerability to mental disorders. Obesity and related issues represent important public health concerns in terms of prevalence, incidence and economic burden. In addition, nearly 75% of young people have insufficient levels of physical activity in developed countries. In tandem with this fact, most of the young people are “digital natives”, which means that they have grown up surrounded by digital information and entertainment on screens. All these facts together prove that a major change in the lifestyle of young people is taking place in the last decades, which in turn might have an effect on their mental and brain health. In this context, white matter, which is important for efficient transmission of information between brain areas, has been considered one of the brain features susceptible of being modified by physical activity and other related factors (i.e., sedentary behavior and physical fitness) in young people, yet the body of evidence is still in its infancy, and further studies are needed to shed light on the many questions that remain unanswered. Therefore, the overall aim of the present International Doctoral Thesis is to study the role of physical activity, sedentary behavior and physical fitness in the mental health (part I), and white matter (part II) in young people.Tesis Univ. Granada

Early-Life Adversities and Neurocognitive Outcomes:An Epidemiological Study

This thesis is the compilation of studies that assessed stress and adversity using different approaches, and investigated the relation between adversities and early‑life stress with subsequent neurocognitive outcomes in the general population. This thesis also includes studies that addressed the role of protective factors, and the interplay between adversity and multiple protective factors in relation to brain morphology. Data from the population‑based Generation R Study, and the high‑risk Mannheim Study of Children at Risk were used in the studies presented here

Myelin plasticity in mouse resilience and susceptibility to psychosocial stress : implications for anxiety disorders

Psychiatric disorders are very common, with anxiety disorders being the most prevalent (16 % lifetime prevalence). While moderately heritable, their incidence is also strongly influenced by environmental risk factors, chiefly psychosocial stress. However, our knowledge of how, in neurobiological terms, these disorders arise is lacking, slowing down the development of efficient treatments. The aim of this thesis was firstly to identify which brain regions are recruited by chronic psychosocial stress, by using mice as model organisms. To model psychosocial stress we used chronic social defeat stress (CSDS), which involves short confrontations between intruder and resident-aggressor male mice, repeated daily for 10 consecutive days. A week after stress exposure C57BL/6NCrl (B6) mice had a higher number of cells expressing ΔFOSB, a marker of repeated neural activation, in several stress-related brain regions. These included the bed nucleus of the stria terminalis (BNST) and ventral hippocampus (vHPC). We also found significant correlations in the numbers of ΔFOSB+ cells between medial prefrontal cortex (mPFC) subregions (infralimbic and prelimbic cortices) and the vHPC of stress-exposed but not non-stressed control mice. Our second aim was to discover, by using unbiased RNA-sequencing (RNA-seq) of stress-related brain regions (the mPFC and vHPC), biological pathways perturbed by CSDS. Additionally, we used mice from two inbred strains, representing different levels of baseline anxiety-like behaviour: B6 (low-anxiety) and DBA/2NCrl (D2, high-anxiety). This enabled us to explore how genetic background modulates the response to stress. While some mice exposed to CSDS show social avoidance (called stress-susceptibility), others are behaviourally similar to non-stressed control mice. This phenomenon, known as resilience, is also observed in humans. We found that B6 and D2 mice showed vastly different behavioural responses to CSDS. B6 mice displayed a predominantly resilient phenotype (66.1 % of CSDS-exposed mice across several cohorts), while the majority (85.0 %) of D2 mice were susceptible. Pathway analysis of RNA-seq data suggested that differentially expressed genes (DEGs) were enriched in genes related to oligodendrocytes (OLGs), the myelin-producing cells of the CNS. For example, genes encoding myelin components were downregulated in the mPFC and vHPC of B6 susceptible mice compared to controls. Myelin is a lipid-rich ensheathment around axons, and it enables both fast nerve conduction and adjustment thereof via myelin plasticity. We followed up the gene expression findings with a structural analysis of myelinated axons using transmission electron microscopy (TEM). We found that in the vHPC, B6 susceptible mice had thinner myelin sheaths than controls. In the mPFC, B6 resilient mice had thicker myelin than controls, restricted to axons with small diameters. By contrast, D2 resilient mice had thinner myelin in this region than susceptible mice, indicating potential bidirectional dynamics of myelin plasticity in resilience. Lastly, we performed RNA-seq of enriched OLGs and myelin from the mPFC. The aim of this experiment was to identify pathways affected by CSDS specifically in these cells and in myelin. Additionally, we used this dataset to identify genes (24.8 % of all genes and 18.8 % of expressed micro-RNAs [miRNAs]) which were enriched in the myelin fraction compared to OLGs in nonstressed control mice. This suggests selective transport of certain mRNAs and microRNAs into the myelin sheath, potentially for local regulation. When comparing CSDS-exposed mice and controls, we found lower expression of myelin-related genes in B6 susceptible, D2 susceptible and D2 resilient mice compared to same-strain controls. In the B6 strain this was found in the myelin fraction, while in the D2 strain these genes were differentially expressed only in OLGs. Ingenuity Pathway Analysis (IPA) predicted TCF7L2, a transcription factor, to be an upstream regulator of these DEGs. In summary, we showed involvement of a broad but selective network of brain regions in CSDS. Genetic background had a large influence on the response to stress, highlighting a source of individual variation with implications for understanding human stress-resilience and -susceptibility. This moderation by genetic background was also seen at the level of gene expression in the brain. Finally, our findings suggest that myelin plasticity is an important part of the chronic response to stress. Future work will identify by which mechanisms stress influences myelin, and how this could be best harnessed for improving therapeutic strategies.Ahdistuneisuushäiriöt ovat yleisiä ja kohtalaisen periytyviä sairauksia, mutta myös ympäristötekijät, kuten psykososiaalinen stressi, vaikuttavat niiden puhkeamiseen. Tämän väitöskirjan ensimmäinen tavoite oli tunnistaa mitkä aivoalueet krooninen psykososiaalinen stressi aktivoi, käyttäen hiirtä malliorganismina. Stressatuilla hiirillä ventraalinen aivoturso (eng. ventral hippocampus, vHPC) aktivoitui voimakkaammin kuin stressille altistamattomilla verrokkihiirillä. Lisäksi aktivoituneiden hermosolujen määrät korreloivat useiden aivoalueiden, kuten etuaivokuoren (eng. medial prefrontal cortex, mPFC) ja vHPC:n välillä, stressatuilla muttei verrokkihiirillä. Toinen tavoitteemme oli selvittää, mihin toimintoihin stressi näillä aivoalueilla vaikuttaa. Käytimme tähän tarkoitukseen RNA-sekvensointia, jolla tutkitaan, mitä geenejä kudoksessa ilmentyy tietyllä hetkellä. Tämän lisäksi selvitimme, miten perinnölliset tekijät muokkaavat näitä vaikutuksia käyttämällä hiiriä kahdesta eri kannasta. Stressin jälkeen osa hiiristä oli stressialttiita, mikä tarkoittaa niiden välttäneen sosiaalista kanssakäymistä. Osa stressille altistetuista hiiristä puolestaan oli resilienttejä, eli ne käyttäytyivät sosiaalisessa tilanteessa samoin kuin verrokkihiiret. Osoitimme, että B6-kannan hiiret olivat pääasiassa resilienttejä, kun taas suurin osa D2-kannan hiiristä oli stressialttiita. Lisäksi huomasimme, että oligodendrosyyttien toimintaan liittyvät geenit ilmentyivät eri tasoilla resilienttien, stressialttiiden ja verrokkihiirten välisissä vertailuissa. Oligodendrosyytit tuottavat myeliiniä hermosyiden eristeeksi, mikä nopeuttaa hermosolujen välistä viestintää. Pienetkin muutokset myeliinissä vaikuttavat hermosolujen johtonopeuteen. Transmissioelektronimikroskopialla selvitimme esimerkiksi, että B6 stressialttiilla hiirillä oli vHPC:ssä ohuemmat myeliinitupet kuin verrokeilla, ja resilienteillä hiirillä puolestaan oli paksummat myeliinitupet mPFC:n ohuissa hermosyissä. Viimeisessä osatyössä eristimme stressattujen hiirten mPFC:stä oligodendrosyytit ja myeliinin tavoitteenamme selvittää, mitkä geenit erityisesti oligodendrosyyteissä reagoivat stressiin. Verratessamme stressin kokeneita ja verrokkihiiriä totesimme myeliiniin liittyvien geenien ilmentyvän alemmalla tasolla B6 stressialttiissa, D2 stressialttiissa sekä D2 resilienteissä hiirissä verrokkeihin nähden. Bioinformatiivisella analyysillä selvitimme, että näiden geenien mahdollinen säätelijä on TCF7L2-säätelyproteiini. Vaikuttamalla tämän säätelytekijän toimintaan stressi voisi vaikuttaa myeliinigeenien ilmentymiseen, ja sitä kautta myeliinin määrään ja hermosolujen viestintään, mutta lisätutkimuksia tarvitaan näiden yhteyksien selvittämiseksi. Yhteenvetona, osoitimme laajan aivoalueiden verkoston aktivoituvan stressialtistuksessa. Hiirten geneettinen tausta vaikutti merkitsevästi stressinjälkeiseen käyttäytymiseen, mikä viittaa siihen, että geneettisellä tautalla on merkitystä myös ihmisyksilöiden välisissä eroissa resilienssissä ja stressialttiudessa. Löydöksemme viittaavat myeliiniplastisuuteen tärkeänä kroonisen stressin seurauksena. Jatkotutkimuksia tarvitaan tunnistamaan, minkä mekanismien kautta stressi vaikuttaa myeliiniin, ja miten tätä tietoa voisi hyödyntää ahdistuneisuushäiriöiden hoidon kehityksessä