The main focus of the research that makes up this thesis was to translate rodent behavioural assays to larval zebrafish for better time and resource management in biomedical research,... Show moreThe main focus of the research that makes up this thesis was to translate rodent behavioural assays to larval zebrafish for better time and resource management in biomedical research, pharmaceutical research and development. __The larval zebrafish is a useful model in toxicology and drug discovery. However, its predictivity is restricted by compound class. __Light-dark cycle plays an important role in the normal development of the zebrafish embryo, and abnormal lighting regimes during rearing can result in malformations. __The hyperactivity displayed by zebrafish larvae following the onset of sudden darkness is an intrinsic characteristic. Zebrafish larvae quickly habituate with repeated stimuli of onset of darkness with short interstimulus interval. __Zebrafish larvae are able to discriminate colours, and they show a preference for orange and green, but aversion towards red, yellow, blue and black. The larvae also show freezing behaviour in the complex environment which is attenuated with diazepam.. __Zebrafish larvae raised in an abnormal lighting regime changed some aspects of their colour preference, although orange and red remained as preferred and avoided colours respectively. __In short, the zebrafish larvae is a useful complementary animal model in behavioural research amenable to high-throughput screening of compounds and drug discovery Show less
Through evolution the social amoebas have developed mechanisms to adapt to environmental changes and ensure survival. This thesis explores the evolutionary origins of cAMP signalling and regulation... Show moreThrough evolution the social amoebas have developed mechanisms to adapt to environmental changes and ensure survival. This thesis explores the evolutionary origins of cAMP signalling and regulation of developmental decisions in the model organism Dictyostelium discoideum. It also shows the first molecular-based phylogeny of the Dictyostelids. Development in Dictyostelium is characterized by the formation of a multicellular structure, the fruiting body, with a well-defined temporal and spatial pattern. cAMP, normally used as intracellular second messenger, in Dictyostelium is used also as an extracellular signal (chemoattractant) to mediate cell movement and cell differentiation. The study of the different components that control the formation of a multicellular fruiting body at a molecular level and from an evolutionary perspective shows that extracellular cAMP signalling was originally developed to control fruiting body morphogenesis. Furthermore it reinforces the idea that Dictyostelium is a simple but yet robust model to study the origins of multicellularity. Do to cAMP being so prevalent in Dictyostelium development I have studied the regulation of cAMP production during particular developmental stages showing in this thesis novel roles for the adenylyl cyclases that produce cAMP and their specific patters of expression during development. A thorough pharmacological analysis of these enzymes is also present in this work. Show less
Core deficits in people with autisme spectrum disorders (ASD) are difficulties in adapting their behaviour to the social environment which hampers the possibilities to communicate adequately and to... Show moreCore deficits in people with autisme spectrum disorders (ASD) are difficulties in adapting their behaviour to the social environment which hampers the possibilities to communicate adequately and to have reciprocal relationships. These problems have a serious impact on functioning in their daily life. Since ASD are severe and lifelong conditions, it is relevant to examine how children with ASD develop troughout their life and to investigate which factors constitute an unfavourable contribution to their development. This thesis reveals that children with ASD are at specific risk of poor quality of life in adulthood when compared to children with other psychiatric disorders. Secondly, the impact of ASD on specific domains of intellectual functioning is different at different ages, implicating that re-evaluation of cognitive function during development of children with ASD is recommended during their life. Thirdly, children with ASD who are at risk of schizophrenia spectrum pathology, may show negative schizotypal symptoms, but also disorganized and positive symptoms in addition to ASD symptomatology. These symptoms of schizotypy appear to be associated with inhibition problems. We should be aware of inhibition problems in children with ASD because they may be indicators of high risk to schizophrenia spectrum pathology later in life. Show less
This research describes the quest to create 'super-caffeines', substances that only produce the desired effects of caffeine, and unlike caffeine, substances that should only have to be taken in... Show moreThis research describes the quest to create 'super-caffeines', substances that only produce the desired effects of caffeine, and unlike caffeine, substances that should only have to be taken in measured, minute, controlled amounts to achieve these effects. Unless particular steps are taken to avoid it, caffeine is a very prevalent substance in our society, which almost all of us ingest in some manner on a daily basis. It is an integral part of coffee, tea and chocolate-based products, cola drinks and is even used as a supplement in painkillers. Most people recognise caffeine as a stimulant; however, have you ever wondered how and why we get not only the pick-me-up effect, but also less desirable ones, for example, the need to go to the toilet more often and the racing heart? Caffeine is an example of a ligand (a chemical compound) that acts via certain anchor points in the body, the adenosine receptors. These receptors are located throughout the body in a number of different tissues. There are four different categories of this receptor that respond specifically to a substance called adenosine, which is produced within the body when and where it is needed. Once a substance like caffeine enters the body the majority of its effects are as a result of blocking these receptors, thereby not allowing the body's own chemical compound, adenosine, to occupy the receptors. The often welcome stimulatory effects of caffeine have been found to be as a consequence of blocking a particular adenosine receptor, known as the adenosine A1 receptor. The unwelcome sideeffects mentioned earlier are often a result of caffeine's interaction with one or more of the other three adenosine receptors. The therapeutic potential for new __super-caffeines__ (so called adenosine A1 receptor antagonists) are great, for instance as cognition enhancers in the elderly. This thesis describes the design and development of several series of new compounds which help us to define, understand and further the research into adenosine receptor antagonists. The substances themselves are novel in chemical structure, have excellent affinity for the adenosine A1 receptor (very much better than that measured for caffeine) and are selective for this particular receptor above the rest of the adenosine receptor family. Show less
Synthetic glucocorticoids such as dexamethasone are frequently used to enhance pulmonary development in preterm ventilator-dependent infants. In contrast to the short-term benefit on survival and... Show moreSynthetic glucocorticoids such as dexamethasone are frequently used to enhance pulmonary development in preterm ventilator-dependent infants. In contrast to the short-term benefit on survival and lung maturation, early glucocorticoid exposure has been shown to adversely affect neurodevelopmental processes. Both human and animal studies have reported acute and long-lasting impairments, including shortening of the lifespan in rodents. Therefore, the objective of the studies described in this thesis was to investigate, using an animal model: 1) the short- and long-term consequences of neonatal dexamethasone treatment and 2) the possibility to prevent these effects using pharmacological and behavioural intervention strategies. We reported that systemic dexamethasone treatment acutely affects brain development by suppressing cell proliferation and glial activity. These acute effects on the brain can be partially prevented by central glucocorticoid receptor antagonist pre-treatment, which might serve as a protective strategy against the adverse effects of dexamethasone treatment on the developing brain. Although neonatal dexamethasone exposure clearly affects the developmental trajectory, we did not observe the frequently described detrimental long-lasting consequences of this treatment. We showed that daily handling of the neonate, which was an inevitable component of our experimental design and leads to enhanced levels of maternal care towards the offspring, may compensate for some of the adverse effects of dexamethasone treatment. We conclude that the impact of neonatal glucocorticoid exposure highly depends on interactions with other components of the early environment and is therefore susceptible to pharmacological and behavioural intervention strategies. Show less
Schizophrenia is a devastating mental disorder characterized by a hyperactive dopamine system and deregulated stress system. Human studies have suggested that the schizophrenia symptoms precipitate... Show moreSchizophrenia is a devastating mental disorder characterized by a hyperactive dopamine system and deregulated stress system. Human studies have suggested that the schizophrenia symptoms precipitate if a hyperactive dopaminergic genotype interacts with adverse life experiences that activate the stress system. To examine this gene-by-environment interaction, we exposed rats genetically-selected for enhanced apomorphine susceptibility to two stress-provoking life events, poor maternal care early-in-life, and isolation rearing later-in-life. This promoted the development of schizophrenia endophenotypes. Our experiments involved two complementary steps: First, we focused on the immediate endocrine adaptations to maternal separation in common rats. It is known that a single episode of prolonged maternal separation slowly increases corticosterone levels in the neonate rat. We discovered that if the pups had been previously exposed to maternal separation, this rise in corticosterone was abolished, suggesting that the pups had learned to predict the return of the dam. While readily adapting to repeated maternal absence, the pups, surprisingly, stayed alert and displayed a rapid response to an acute stressor. We then investigated whether pup__s stress responsiveness was influenced by the context of maternal separation. It appeared that the experience of being kept in isolation in a novel environment during repeated maternal separation, rather than the maternal absence per se, caused priming of the amygdala fear pathway, with lasting consequences for the responsiveness of the neuroendocrine and behavioral stress system. These endocrine and behavioral alterations, caused by early-life stress experience, consisted of schizophrenia-like phenotypes. Second, we sought to investigate the interplay of such early-life stress experience with schizophrenia genetic predisposition and/or later-life social stress experience. Thus, we were able to test the three-hit (cumulative stress) and the developmental mismatch hypotheses. The former states that exposure to earlylife adversity and later-life psychosocial stressors, superimposed on genetic susceptibility, result in a severe schizophrenia-like phenotype. The latter proposes that experiences early-in-life program the developing brain in preparation for the future. In the case of genetically-predisposed apomorphine susceptible rats (schizophrenia-susceptible), we provide strong evidence for the three-hit hypothesis. In the case of the nongenetically selected Wistar rats, the mismatch hypothesis is supported since the outcome of early-life stress often negatively interacted with the pre-puberty social context. In agreement with the three-hit hypothesis of schizophrenia, we conclude from the current experiments that early-life stress experience in interaction with highly reactive dopaminergic alleles, leads to amygdala priming that, together with additional stressors, precipitate schizophrenia. Show less
Primordial germ cells (PGCs) are the progenitors of the gametes, responsible for transmitting genetic information from generation to generation. Although there is a long history of gamete biology... Show morePrimordial germ cells (PGCs) are the progenitors of the gametes, responsible for transmitting genetic information from generation to generation. Although there is a long history of gamete biology research, there is still a lot to be learned about many of the mechanisms underlying germ cell development. This dissertation describes and discusses the dynamics of PGCs in the chicken, with a focus on their migration to the gonads and meiosis that takes place when PGCs are already settled there. We also discussed the advantages of using the avian model in epithelial ovarian cancer research. Moreover, we revisited an often overlooked model for amniogenesis in which the proamnion plays a crucial role. Show less
Why do some children easily find their way in social situations and are satisfied with their social lives, while others experience more difficulties? One key component that may explain this is... Show moreWhy do some children easily find their way in social situations and are satisfied with their social lives, while others experience more difficulties? One key component that may explain this is social competence: the ability to fulfill both own and other’s social goals. This thesis focused on individual differences in social competence from childhood to adolescence by examining contextual, developmental and neurobiological influences on aggressive and prosocial responses to social evaluation. Findings showed robust neural processes related to social feedback and subsequent aggression already in middle childhood. Additionally, this thesis revealed that the period between childhood and adolescence is important for the behavioral and neural development of inhibition of aggression following negative, neutral and positive social feedback. Aggression following social feedback decreased towards adolescence, but aggression following positive feedback decreased earlier in childhood than following negative feedback. Moreover, the involvement of the dorsolateral prefrontal cortex, known for its role in executive functioning, decreased over time. Finally, results indicated that the co-occurrence of aggression following rejection and prosocial behavior following observed rejection may possibly protect against externalizing behaviors and promote wellbeing. This thesis highlights the importance of examining the interplay of developmental processes across social contexts to understand mental health outcomes. Show less
In this thesis we describe normal and abnormal pulmonary vein development in human and mouse hearts, and focus on the histo(patho)logy of the pulmonary venous and left atrial dorsal wall, in order... Show moreIn this thesis we describe normal and abnormal pulmonary vein development in human and mouse hearts, and focus on the histo(patho)logy of the pulmonary venous and left atrial dorsal wall, in order to elucidate the role of the posterior heart field in the formation and differentiation of the pulmonary venous vessel wall and its possible consequences for the onset of arrhythmias and susceptibility for pulmonary vein stenosis. Another aim of this thesis is that the understanding of normal pulmonary vein development will contribute to the understanding of the development of abnormal pulmonary venous connections and its clinical consequences. Show less
An adverse early life event is considered a risk factor for stress-related psychiatric disorders in genetically predisposed individuals, probably because of its lasting effect on susceptibility to... Show moreAn adverse early life event is considered a risk factor for stress-related psychiatric disorders in genetically predisposed individuals, probably because of its lasting effect on susceptibility to stress. The objective of this thesis research was to examine in the mouse CD1 strain the immediate and permanent effects of an adverse early experience on the neuroendocrine stress system. For this purpose the hypothalamic-pituitary-adrenal (HPA) axis was examined of mouse pups that were refrained from maternal care, a laboratory model for neglect mimicking aspects of abuse. The data show that the infants__ stress response system readily adapts to daily repeated 8 hours of maternal separation, but that it continues to respond to a novelty stressor. The rapid adaptation to repeated maternal absence seems rather due to the ability to predict return of the mother than to adjust metabolism to episodic food deprivation. If maternal separation was extended to a single episode of 24 hours the immediate outcome was more profound but transient, although subtle effects on stress reactions and cognitive performance did persist. The findings demonstrate the amazing plasticity of the newborn brain and provide a basis to study the mechanistic underpinning of vulnerability or resilience to psychopathology. Show less
In this thesis, four studies on children and adolescents with Down syndrome are described. The first study showed that the number of live births of children with Down syndrome in the Netherlands... Show moreIn this thesis, four studies on children and adolescents with Down syndrome are described. The first study showed that the number of live births of children with Down syndrome in the Netherlands remained stable over the period 1997-2007 on 14.6 per 10,000 births. Of these, 85% were live born. In the second study is observed that growth retardation in children with Down syndrome meanly occurs in three critical periods of growth, resulting in shorter final stature and smaller head circumference than the general Dutch population shows. Furthermore, Dutch children with Down syndrome have alarmingly high prevalence rates of overweight and obesity during childhood and adolescence. The third study showed that eight-year-old children with Down syndrome have an average developmental delay of four years, more often have emotional and behavioral problems, and have a less favorable health-related quality of life (HRQoL) compared with children from the general population. Children with Down syndrome and recurrent respiratory tract infections showed relatively more delayed development. In the fourth study, results showed that adolescents with Down syndrome remain dependent to a large degree and have serious difficulties in functioning socially. Additionally, results showed that serious problem behavior is highly prevalent in adolescents with Down syndrome. Show less
In the Netherlands, information provision about fertility preservation (FP) for young women with breast cancer is not sufficient. Since an increasing number of Dutch breast cancer patients will... Show moreIn the Netherlands, information provision about fertility preservation (FP) for young women with breast cancer is not sufficient. Since an increasing number of Dutch breast cancer patients will face this preference-sensitive decision each year, there is a clear need for improvement of information provision about FP. The overall aim of this thesis was therefore to (a) develop and (b) evaluate a Decision Aid (DA) about FP that is targeted to improve information provision and decision making about FP for young women with breast cancer. This thesis describes consecutively the development and evaluation of such a DA with values clarification exercise (VCE) Show less
This thesis provides a comparison of mostly perceptual development during vocal learning in songbirds (zebra finches) and human infants. The aim is to disentangle experience dependent and... Show moreThis thesis provides a comparison of mostly perceptual development during vocal learning in songbirds (zebra finches) and human infants. The aim is to disentangle experience dependent and independent processes during vocal learning. In both human infants and juvenile songbirds, a perceptual preference for __universal__ sounds was found, independent of adult auditory input. Later in development, both infants and juvenile songbirds show a change is preference. The juvenile songbirds clearly change their preference towards sounds they have been auditorily exposed to (chapter 3). In human infants in the influence of experience is less clear in this thesis. In combination with previous literature the most likely scenario is a combination of experience dependent and independent processes (chapter 2). To further compare human and birdsong phonology, a __typology__ of zebra finch song elements was performed (chapter 4). The results of this study indicate commonality as well as variation between populations in terms of phonology. In the order of elements within a sequence however, there is little evidence for common patterns across populations and there is variation within and between populations. In summary, this thesis shows similarities in developmental mechanisms in two vocally learning species. There might be a link between development and typology. Show less
The research described in this thesis mainly focussed on making and refining a model that describes axial patterning during gastrulation in the frog Xenopus laevis. Chapter 2 and 3 describe that... Show moreThe research described in this thesis mainly focussed on making and refining a model that describes axial patterning during gastrulation in the frog Xenopus laevis. Chapter 2 and 3 describe that axial information arises in the mesoderm and subsequently in the neurectoderm. Also is shown that this information, under influence of the Spemann organiser and cellular movements, is translated from a time sequence into a space sequence. The function of the Spemann organiser, important for AP patterning is neural induction. In chapter 4 is described that retinoids, important for axial patterning and formed in the mesoderm, have a patterning effect on neurectoderm. An important conclusion in this chapter is that retinoids are candidates for transfer of axial information from mesoderm to neurectoderm and can, in this way, coordinate the expression of axial information between mesoderm and neurectoderm. In chapter 5 a study is described where the transcriptional targets of Hoxc6 or Antennapedia in the frog Xenopus laevis and the fruitfly Drosophila melanogaster are compared. From this comparison conclusions can be drawn about the processes that are important for the function of Hoxc6/Antp. From this study could be concluded that celldivision, cellmigration, and suppresion of head formation are processes that are important for the function of Hoxc6/Antp. Show less
It is well known that complex mental abilities develop at least until late adolescence. Yet, there are also skills that children master perfectly, sometimes even better than adults. The goal of... Show moreIt is well known that complex mental abilities develop at least until late adolescence. Yet, there are also skills that children master perfectly, sometimes even better than adults. The goal of this thesis was to learn more about the possibilities of cognitive functioning in children and young adults, and the constraints set by the developing brain. An fMRI training approach was used to examine age- and experience-related effects in the development of working memory and resting-state functional connectivity. More specifically, we studied age differences on task performance and brain activation during a working memory task with various demands and difficulty levels, both before and after 6 weeks of practice with the task. In addition, to learn more about the interaction between different brain regions, we also examined age differences and practice effects on functional connectivity during resting-state. Show less
Simultaneous with the improved survival of very preterm and low birth weight infants, the awareness increased that not all survive without sequelae. Mild developmental disturbances that interfere... Show moreSimultaneous with the improved survival of very preterm and low birth weight infants, the awareness increased that not all survive without sequelae. Mild developmental disturbances that interfere with the acquisition of everyday skills and normal learning appeared to be very frequent and were not detected until at school age. The expectation was that such developmental disabilities were temporary side effects and would diminish with increasing perinatal knowledge and experience. The data in this thesis show that impairments, disabilities and handicaps remain invariably high, with the exception of the decreased incidence of visual problems. The increased incidence of cerebral palsy of children born in 1993, compared to 1983, is worrisome. Factors that are responsible for a decreased mortality such as antenatal steroids, artificial ventilation and surfactant, do not decrease these developmental problems in the surviving children. The use of dexamethasone in the neonatal period is a serious extra risk factor for developmental problems. Severe developmental problems are mostly diagnosed at the age oaf two years. Diagnosis of mild motor problems, learning disabilities and problem behaviour however, is mostly delayed until school age. When with advancing age the demands imposed by society increase, the problem rate increases even further. Singularly, these deficits may be subtle, but combined, without compensation in other domains, they may pose a lifelong burden. Therefore, long term longitudinal follow up of these children is necessary. Paediatricians who assess very preterm and low birth weight infants with assessments that include structured elements from the Touwen examination, Denver Development Screening Test, Dutch Language Screening Test and a shortlist from the Child behaviour Checklist overlook developmental motor coordination disorders and learning and behavioural problems. As the movement ABC is an accurate and widely used instrument to detect these motor coordination disorders, the movement ABC should be included in the follow up of very preterm and low birth weight infants at the age of five. To detect all neurological problems a neurological assessment is also necessary. Cognitive problems are indicated by the appearance of learning difficulties at school. As the presence of learning difficulties in very preterm and low birth weight infants is an alarm-signal for cognitive delay, referral and formal cognitive assessment by a child psychologist is indicated. Repeating the school year may not be a good solution. To identify cognitive delays that may interfere with learning before school age, formal cognitive assessment before six years of age should be incorporated in a systematic follow up program. As over one half of all very preterm and low birth weight infants show these developmental problems, routine assessment of all very preterm and low birth weight infants before school age is necessary. Standardised and normalised test instruments that cover all developmental domains must have a rigid structure for managing the test process and calculating the results General judgement by paediatricians in a routine outpatient clinic, even when these paediatricians are well trained, is insufficient. Follow up studies that do not include detailed standardised tests for several domains will underestimate developmental problems in survivors of neonatal intensive care. There is no simple way to identify children in need of extra help or to enable a true evaluation of neonatal intensive care. This thesis deals with problems in very preterm and low birth weight infants. It also documented, however, that modern intensive care saves the lives of many children 'born to soon or born too small' 56 and that many of them grow up without any problem at all. Although modern neonatal intensive care will not restore complete integrity of all preterm born infants, it certainly is worthwhile. Show less
In this thesis the evolutionary background, function and localization of the domesticated transposase DAYSLEEPER are described. We found that DAYSLEEPER-like genes can be found in angiosperms, but... Show moreIn this thesis the evolutionary background, function and localization of the domesticated transposase DAYSLEEPER are described. We found that DAYSLEEPER-like genes can be found in angiosperms, but not in lower plants. We also found that DAYSLEEPER interacts with several proteins and is probably involved in regulating protein degradation through involvement in ubiquitin-mediated protein degradation. Show less
This is the first time developmental outcome following hearing screening in children with permanent childhood hearing impairment was studied in a unique, pseudo-randomized design. We found that... Show moreThis is the first time developmental outcome following hearing screening in children with permanent childhood hearing impairment was studied in a unique, pseudo-randomized design. We found that early detection of hearing loss by newborn hearing screening (and subsequent early intervention) is beneficial for the development of children with permanent childhood hearing impairment, although their development at 3-5 years is not yet comparable to that of children with normal hearing. We showed that the yield of the current hearing screening program is large, but that there is ample room for improvement in the timing following early detection of hearing loss. We would like to emphasize that the aetiology of permanent childhood hearing impairment should be investigated and the cause taken into account when evaluating the development of the child. Show less
Multiple processes are influenced by a protein family named the function of Mitogen Activated Protein Kinases (MAPK), where among tissue morphogenesis, cell-proliferation, cell-differentiation,... Show moreMultiple processes are influenced by a protein family named the function of Mitogen Activated Protein Kinases (MAPK), where among tissue morphogenesis, cell-proliferation, cell-differentiation, cell-survival and immune reactions. A consequence of this broad role of these proteins is that disturbed MAPK signaling possibly leads to severe affects, and could even lead to the development of a disease or disturb embryogenesis. The human genome encodes for 14 mapk genes. One of the best characterized MAPK signaling transductions pathways is the Extracellular signal Regulated Kinase 1 and 2 (ERK1/ERK2). The zebrafish is a relatively new, genetic accessible model organism, which is because of their transparency of the embryos, very suitable to study the role of the MAPKs in embryonic development. The study described in this thesis shows that the zebrafish genome encodes for the same mapk genes, which makes it possible to study the functions of these proteins, using the zebrafish. Further investigations to the roles of ERK1 and ERK2 during embryonic development led to the new insight that ERK1 and ERK2 have distinct roles during crucial developmental cell migration processes and the differentiation of tissues and cell types. In addition, it was found that ERK1 and ERK2 affect the expression of common as well as distinct target genes. Show less
