The topological framework of circuit topology has recently been introduced to complement knot theory and to help in understanding the physics of molecular folding. Naturally evolved linear... Show moreThe topological framework of circuit topology has recently been introduced to complement knot theory and to help in understanding the physics of molecular folding. Naturally evolved linear molecular chains, such as proteins and nucleic acids, often fold into 3D conformations with critical chain entanglements and local or global structural symmetries stabilised by formation contacts between different parts of the chain. Circuit topology captures the arrangements of intra-chain contacts within a given folded linear chain and allows for the classification and comparison of chains. Contacts keep chain segments in physical proximity and can be either mechanically hard attachments or soft entanglements that constrain a physical chain. Contrary to knot theory, which offers many established knot invariants, circuit invariants are just being developed. Here, we present polynomial invariants that are both efficient and sufficiently powerful to deal with any combination of soft and hard contacts. A computer implementation and table of chains with up to three contacts is also provided. Show less
Knop, J.; IJzendoorn, M.H. van; Bakermans-Kranenburg, M.J.; Joëls, M.; Veen, R. van der 2019
Sexual and social development is affected by a complex interplay between genetic makeup and the early-life rearing environment. While many rodent studies focused primarily on the detrimental... Show moreSexual and social development is affected by a complex interplay between genetic makeup and the early-life rearing environment. While many rodent studies focused primarily on the detrimental effects of early-life stress, human literature suggests that genetic susceptibility may not be restricted to negative environments; it may also enhance the beneficial effects of positive rearing conditions. To examine this interaction in a controlled setting, heterozygous mineralocorticoid receptor knockout (MR+/−) mice and control litter mates were exposed to a limited nesting/bedding (LN, impoverished), standard nesting (SN, control) or communal nesting (CN, enriched) paradigm from postnatal day 2–9 (P2-P9). Offspring was monitored for puberty onset between P24-P36 and, in females, maternal care-giving (i.e. as F1) during adulthood, after which basal corticosterone was measured. Different home-cage environments resulted in profound differences in received maternal care and offspring body weight. In male offspring, LN resulted in delayed puberty onset that was mediated by body weight and unpredictability of maternal care received during early development. In female offspring, rearing condition did not significantly alter sexual maturation and had little effect on their own maternal care-giving behavior. Genotype did affect maternal care: female MR+/− offspring exhibited a less active nursing style and upregulated fragmentation during adulthood, irrespective of early life conditions. Basal corticosterone levels were highest in MR+/− mice with a background of LN. Overall, we found a gene-by-environment interaction with respect to basal corticosterone levels, but not for sexual maturation or maternal behavior. Show less
Kentrop, J.; Smid, C.R.; Achterberg, E.J.M.; IJzendoorn, M.H. van; Bakermans-Kranenburg, M.J.; Joëls, M.; Veen, R. van der 2018
Early life context and stressful experiences are known to increase the risk of developing psychiatric disorders later in life, including disorders with deficits in the social domain. Our study... Show moreEarly life context and stressful experiences are known to increase the risk of developing psychiatric disorders later in life, including disorders with deficits in the social domain. Our study aimed to investigate the influence of early life environment on social behavior in a well-controlled animal model. To this end we tested the effects of maternal deprivation (MD) on rat social play behavior in adolescence and social interaction in adulthood. Additionally, we provided a stimulating environment during adolescence (complex housing) as a potential intervention to diminish the effects of early life stress. Male and female Wistar rats were deprived from their mother for 24 h on postnatal day 3 (PND 3) or were left undisturbed. Complex housing started 5 days after weaning and consisted of housing 10 same-sex conspecifics in large, two-floor MarlauTM cages until the end of the study. Social play behavior in adolescence was tested under different conditions (3 h vs. 24 h social isolation prior to testing). Maternally deprived males – but not females – showed a longer latency to play and a decreased total amount of social play behavior, after a 24 h isolation period. In adulthood, social discrimination was impaired in deprived male and female rats in the three-chamber social approach task. Complex housing did not moderate the effects of MD, but in itself induced a strong behavioral phenotype. Both complex housed males and females hardly displayed any play behavior after a 3 h isolation period. However, after 24 h of isolation, these animals showed shorter latencies to engage in social play behavior. Only complex housed males truly showed more social play behavior here, while showing less social interest in adulthood. We conclude that MD has mild negative effects on social behavior in adolescence and adulthood, which are not counteracted by complex housing. Complex housing induces a specific phenotype associated with rapid habituation; a lack of social play after short isolation periods, while increasing play behavior after a prolonged period of isolation in adolescence, and less social interest, paired with intact social discrimination in adulthood. In both early life settings, males seem to be more influenced by the early life environment compared to females. Show less
Over the past decades, the influence of parental care on offspring development has been a topic of extensive research in both human and animal models. Rodent models offer several unique advantages... Show moreOver the past decades, the influence of parental care on offspring development has been a topic of extensive research in both human and animal models. Rodent models offer several unique advantages over human studies, allowing for higher levels of environmental control, exploration of interventions, genetic control and examination of underlying neurobiological mechanisms in greater spatiotemporal detail. Although exploitation of these opportunities has led to increased understanding of the neurobiological mechanisms underlying susceptibility to the early-life environment, translation of results to human parenting and child development appears to be challenging. Attuning animal models to the human situation and application of novel structural and functional techniques is therefore of crucial importance to reduce the gap between rodent and human research. Show less
Kentrop, J.; Van der Tas, L.; Loi, M.; IJzendoorn, M.H. van; Bakermans, M.J.; Joels, M.; Veen, R. van der 2016
Rationale Glucocorticoid hormones facilitate sensitization to repeated administration of psychostimulants, an effect that is mediated by glucocorticoid receptors (GRs). It is still unclear, however... Show moreRationale Glucocorticoid hormones facilitate sensitization to repeated administration of psychostimulants, an effect that is mediated by glucocorticoid receptors (GRs). It is still unclear, however, at which stage of psychomotor sensitization are stress and GR-mediated effects involved.Objectives In the present study, we have tested the hypothesis that GR-mediated effects during the phase of repeated amphetamine injections play a crucial role in the long-term expression of sensitization. For this purpose, we used DBA/2 mice, an inbred strain commonly used for the study of stress effects on psychostimulant sensitization.Methods Animals were treated with the GR antagonist mifepristone (200 mg/kg) at 2.5 h before each daily injection of amphetamine (2.5 mg/kg) or saline in a 5-day protocol. The amphetamine or saline injections were given in the home or a novel context. This was followed by a 2.5-week withdrawal period, without any drug delivery. Following the withdrawal period, two low-dose amphetamine challenges (1.25 mg/kg) were given subsequently, without additional mifepristone.Results The animals receiving amphetamine in the novel context showed a higher expression of sensitization at challenge as compared to those in the home condition. Mifepristone treatment influenced locomotor response to repeated amphetamine injections, but this effect during the initial phase did not affect the expression of sensitization after a withdrawal period.Conclusion Our results indicate that GR-related processes during the initial phase of sensitization are involved in, but not crucial for, the development of long-term sensitization. Show less
Berendsen, B.; Dietz, A.J.; Schulte Nordholt, H.; Veen, R. van der 2013
Asian Tigers, African Lions is an anthology of contributions by scholars and (former) diplomats related to the 'Tracking Development' research project, funded by the Netherlands Ministry of... Show moreAsian Tigers, African Lions is an anthology of contributions by scholars and (former) diplomats related to the 'Tracking Development' research project, funded by the Netherlands Ministry of Foreign Affairs, and coordinated by the African Studies Centre and KITLV, both in Leiden, in collaboration with scholars based in Africa and Asia. The project compared the performance of growth and development of four pairs of countries in Southeast Asia and Sub-Sahara Africa during the last sixty years. It tried to answer the question how two regions with comparable levels of income per capita in the 1950s could diverge so rapidly. Why are there so many Asian tigers and not yet so many African lions? What could Africa learn from Southeast Asian development trajectories? Show less
Claessens, S.E.F.; Daskalakis, N.P.; Veen, R. van der; Oitzl, M.S.; Kloet, E.R. de; Champagne, D.L. 2011
Human epidemiology and animal studies have convincingly shown the long-lasting impact of early life experiences on the development of individual differences in stress responsiveness in later life.... Show moreHuman epidemiology and animal studies have convincingly shown the long-lasting impact of early life experiences on the development of individual differences in stress responsiveness in later life. The interplay between genes and environment underlies this phenomenon.We provide an overview of studies investigating the impact of early life experiences on the development of individual differences in neuroendocrine stress responsiveness in adulthood and address (1) impact of environment on later stress phenotypes, (2) role of genetic factors in modulating the outcome of environment, and (3) role of nonshared environmental experience in the outcome of gene x environment interplays. We present original findings where we investigated the influence of nonshared experiences in terms of individual differences in maternal care received, on the development of stress phenotype in later life in rats.Environmental influences in early life exert powerful effects on later stress phenotypes, but they do not always lead to expression of diseases. Heterogeneity in response is explained by the role of particular genetic factors in modulating the influence of environment. Nonshared experiences are important in the outcome of gene x environment interplays in humans. We show that nonshared experiences acquired through within-litter variation in maternal care in rats predict the stress phenotype of the offspring.The outcome of early experience is not deterministic and depends on several environmental and genetic factors interacting in an intricate manner to support stress adaptation. The degree of "match" and "mismatch" between early and later life environments predicts resilience and vulnerability to stress-related diseases, respectively. Show less
Oitzl, M.S.; Champagne, D.L.; Veen, R. van der; Kloet, E.R. de 2010
One of the conundrums in today's stress research is why some individuals flourish and others perish under similar stressful conditions. It is recognized that this individual variability in... Show moreOne of the conundrums in today's stress research is why some individuals flourish and others perish under similar stressful conditions. It is recognized that this individual variability in adaptation to stress depends on the outcome of the interaction of genetic and cognitive/emotional inputs in which glucocorticoid hormones and receptors play a crucial role. Hence one approach towards understanding individual variation in stress coping is how glucocorticoid actions can change from protective to harmful. To address this question we focus on four hypotheses that are connected and not mutual exclusive. First, the classical Glucocorticoid Cascade Hypothesis, in which the inability to cope with chronic stress causes a vicious cycle of excess glucocorticoid and downregulation of glucocorticoid receptors (GR) in the hippocampus triggering a feed-forward cascade of degeneration and disease. Second, the Balance Hypothesis, which takes also the limbic mineralocorticoid receptors (MR) into account and proposes that an integral limbic MR:GR imbalance is causal to altered processing of information in circuits underlying fear, reward, social behaviour and resilience, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and impairment of behavioural adaptation. The MR:GR balance is altered by gene variants of these receptor complexes and experience-related factors, which can induce lasting epigenetic changes in the expression of these receptors. A particular potent epigenetic stimulus is the maternal environment which is fundamental for the Maternal Mediation Hypothesis. The outcome of perinatal gene x environ-environment interaction, and thus of MR:GR-mediated functions depends however, on the degree of 'matching' with environmental demands in later life. The Predictive Adaptation Hypothesis therefore presents a conceptual framework to examine the role of glucocorticoids in understanding individual phenotypic differences in stress-related behaviours over the lifespan. (C) 2009 Elsevier Ltd. All rights reserved. Show less
The objective of the research described in this thesis was to demonstrate the role of gene-environment interactions in the emergence of individual differences in cocaine use. For this purpose we... Show moreThe objective of the research described in this thesis was to demonstrate the role of gene-environment interactions in the emergence of individual differences in cocaine use. For this purpose we used two inbred mouse strains, the C57Bl/6 (C57) and DBA/2 (DBA), which are known to differ in drug-intake and to be differentially sensitive to several stressors. We studied the impact of early life experiences (long-term influence) as well as a later life psychosocial stressor (short-term influence) on adult drug intake behavior in these two mouse strains. To study the impact of the early life environment, we manipulated the maternal environment of the mice by fostering them with non-related mother strains showing either high or low pup-oriented behaviour. The late life experience consisted of a short-lasting period of group housing in adulthood. Cocaine self-administration in mice with a C57 background was not affected by either changes in postnatal maternal environment or a short group housing experience in adulthood, while these same experiences did affect mice with a DBA background. As a first step towards the biological mechanisms underlying this gene-environment interaction we found that vasopressin was differentially regulated in the extended amygdala of the DBA mice. Show less
