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Policymakers aim to move toward animal-free alternatives for scientific research and have introduced very strict regulations for animal research. We argue that, for neuroscience research, until viable and translational alternatives become available and the value of these alternatives has been proven, the use of animals should not be compromised., We would like to thank Loren Frank, UCSF, USA; Sheena Josselyn, Hospital for Sick Children, University of Toronto, Canada; Shantanu Jadhav, Brandeis University, USA; the European Animal Research Association (EARA); the Federation of European Neuroscience Societies Committee on Animals in Research (CARE); the Swiss Society for Neuroscience; the Society for Neuroscience Committee on Animals in Research (CAR); and Stichting Informatie Dierproeven (the Dutch foundation for public information on animal testing: SID) for input on and support for this article.

The differential susceptibility hypothesis proposes that individuals who are more susceptible to the negative effects of adverse rearing conditions may also benefit more from enriched environments. Evidence derived from human experiments suggests the lower efficacy dopamine receptor D4 (DRD4) 7‐repeat as a main factor in exhibiting these for better and for worse characteristics. However, human studies lack the genetic and environmental control offered by animal experiments, complicating assessment of causal relations. To study differential susceptibility in an animal model, we exposed Drd4 +/− mice and control litter mates to a limited nesting/bedding (LN), standard nesting (SN) or communal nesting (CN) rearing environment from postnatal day (P) 2‐14. Puberty onset was examined from P24 to P36 and adult females were assessed on maternal care towards their own offspring. In both males and females, LN reared mice showed a delay in puberty onset that was partly mediated by a reduction in body weight at weaning, irrespective of Drd4 genotype. During adulthood, LN reared females exhibited characteristics of poor maternal care, whereas dams reared in CN environments showed lower rates of unpredictability towards their own offspring. Differential susceptibility was observed only for licking/grooming levels of female offspring towards their litter; LN reared Drd4 +/− mice exhibited the lowest and CN reared Drd4 +/− mice the highest levels of licking/grooming. These results indicate that both genetic and early‐environmental factors play an important role in shaping maternal care of the offspring for better and for worse., Heterozygous dopamine receptor D4 knock‐out mice (Drd4/−) reared in different environments exhibited alterations in licking/grooming behavior towards their own offspring in line with the differential susceptibility theory.

Early life environment influences the development of various aspects of social behavior, particularly during sensitive developmental periods. We studied how challenges in the early postnatal period or (early) adolescence affect pro-social behavior. To this end, we designed a lever-operated liberation task, to be able to measure motivation to liberate a trapped conspecific (by progressively increasing required lever pressing for door-opening). Liberation of the trapped rat resulted either in social contact or in liberation into a separate compartment. Additionally, a condition was tested in which both rats could freely move in two separate compartments and lever pressing resulted in social contact. When partners were not trapped, rats were more motivated to press the lever for opening the door than in either of the trapped configurations. Contrary to our expectations, the trapped configuration resulted in a reduced motivation to act. Early postnatal stress (24 h maternal deprivation on postnatal day 3) did not affect behavior in the liberation task. However, rearing rats from early adolescence onwards in complex housing conditions (Marlau cages) reduced the motivation to door opening, both in the trapped and freely moving conditions, while the motivation for a sucrose reward was not affected.

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 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.

Early life environment influences the development of various aspects of social behavior, particularly during sensitive developmental periods. Here, we aimed to study how challenges in the early postnatal period or (early) adolescence affect pro-social behavior. To this end, we adapted an existing paw operated liberation task to an automated operant task, to measure motivation (by progressively increasing required lever pressing) to liberate a trapped conspecific. Liberation of the trapped rat resulted either in social contact, or in liberation into a separate compartment. Additionally, a condition was tested in which both rats could freely move in two separate compartments and lever pressing resulted in social contact. When partners were not trapped, rats were more motivated to press the lever for opening the door than in either of the trapped configurations. Contrary to our expectation, the trapped configuration resulted in a reduced motivation to act. Early postnatal stress (24h maternal deprivation on postnatal day 3) did not affect behavior in the liberation task. However, rearing rats from early adolescence onwards in complex housing conditions (Marlau cages) reduced the motivation to door opening, both in the trapped and freely moving conditions, while motivation for a sucrose reward was not affected.

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 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.

Early life adversity has a profound impact on brain development and later life health. Animal models have provided insight how early life stress programs stress responsiveness and might contribute to the development of psychiatric disorders. In the present study, the long-term effects of maternal deprivation (MD) on behavioral inhibition and attention were examined in adult male Wistar rats. To this end animals were tested in the 5-choice serial reaction time task (5-choice SRTT). We also explored the potential of a 3-day treatment with the glucocorticoid receptor (GR) antagonist mifepristone during early adolescence to normalize putative behavioral effects of early life stress. Deprivation of the mother for 24 h on postnatal day (PND) 3 led to a modest but significant increase in premature responses in the 5-choice SRTT, but did not affect measures of attention. Body weight was lower in deprived animals from weaning until the start of testing. Early adolescent mifepristone treatment (PND 26–28) did not influence performance on the 5-choice SRTT and did not mitigate the deprivation-related impairment in behavioral inhibition. Our results indicate that MD leads to impaired behavioral inhibition, and that mifepristone treatment during early adolescence does not normalize the behavioral changes caused by early life stress.

Background Adult hippocampal neurogenesis, which is involved in the physiopathology of hippocampal functions, is genetically determined and influenced by early life events. However, studies on the interaction of these determining forces are lacking. This prompted us to investigate whether adult hippocampal neurogenesis can be modulated by maternal care and whether this influence depends upon the genetic background of the individual. Methods We used a model of fostering that allows singling out the influence of the genetic make-up of the pups on the outcome of maternal behavior. Mice from two different inbred strains (C57BL/6J and DBA/2J) known to differ in their baseline neurogenesis as well as in their sensitivity to the influence of environmental experiences were raised by nonrelated mothers from the AKR/Ola (AKR) and C3H/He (C3H) strains exhibiting low- and high-pup-oriented behavior, respectively. Neurogenesis was then assessed in the dentate gyrus of the adult adopted C57BL/6J and DBA/2J mice. Results We show that both the number and the morphological features of newborn granule cells in the dentate gyrus are determined by the maternal environment to which mice were exposed as pups and that this sensitivity to maternal environment is observed only in genetically vulnerable subjects. Conclusions Altogether, our data indicate interplay between early environment and the genetic envelop of an individual in determining adult hippocampal neurogenesis. Our experimental approach could thus contribute to the identification of factors determining the neurogenic potential of the adult hippocampus.

Parenting has an impact on the offspring's social and behavioral outcomes. However, not all individuals are affected equally; according to the differential susceptibility hypothesis, temperamental traits may moderate the effects of early life experiences. We examined the association between young adults’ experiences of maternal love-withdrawal and their perception of infant crying, and the potentially moderating role of temperamental orienting sensitivity. In an ecologically valid but standardized setting, 132 female participants spent two consecutive evenings taking care of an infant simulator. Orienting sensitivity moderated the relation between experienced love-withdrawal and the perception of infant crying: Participants with high orienting sensitivity who experienced low levels of love-withdrawal perceived the crying bouts as less negative than others. We conclude that the long-term impact of early life experiences may be moderated by temperamental characteristics, with implications for individual dif...

Rapid adaptation to changes, while maintaining a certain level of behavioral inhibition is an important feature in every day functioning. How environmental context and challenges in life can impact on the development of this quality is still unknown. In the present study, we examined the effect of a complex rearing environment during adolescence on attention and behavioral inhibition in adult male rats. We also tested whether these effects were affected by an adverse early life challenge, maternal deprivation. We found that animals that were raised in large, two floor MarlauTM cages, together with 10 conspecifics, showed improved attention, but impaired behavioral inhibition in the 5-choice serial reaction time task. The early life challenge of 24h maternal deprivation on postnatal day 3 led to a decline in bodyweight during adolescence, but did not by itself influence responses in the 5-choice task in adulthood, nor did it moderate the effects of complex housing. Our data suggest that a complex rearing environment leads to a faster adaptation to changes in the environment, but at the cost of lower behavioral inhibition.

Oxytocin has been implicated in parent-infant attachment and social recognition. With respect to emotion recognition memory, both memory-enhancing and impairing effects have been observed, suggesting an influence of individual factors. We assessed the effects of oxytocin on memory for infant cues, and whether these effects are moderated by self-reported childhood emotional maltreatment. Nulliparous females (N = 102) participated in a randomized, double-blind, between-subjects study with intranasal oxytocin or placebo administration. Participants' memory was tested using the Baby Social Reward Task, where participants were asked to select the happier infant from a pair of two infants based on the information that they received about the infants' mood in the previous phase. Participants reporting more childhood emotional maltreatment were less accurate in this task after inhaling oxytocin. Our findings add to a growing body of literature showing that the effects of intranasal oxytocin on memory and social behavior are moderated by adverse early life experiences. © 2014 Taylor and Francis.

Children vary hugely in how demanding of their caregivers they are. This creates differences in demands on parents during observation, making the comparison of sensitivity between parents difficult. It would therefore be of interest to create standard situations in which all caregivers are faced with the same level of demand. This study developed an ecologically valid but standardized setting using an infant simulator with interactive features, the Leiden Infant Simulator Sensitivity Assessment (LISSA). The infant simulator resembles a real infant in appearance and it produces crying sounds that are life-like. The simulator begins with fussing and progresses to more intense crying in case of no care or inappropriate care. It responds by being calm again if appropriate care is given. One hundred and eighty-one female participants took care of the infant simulator for two evenings and in a 30 min lab session with increasing competing demands. Sensitive parenting behavior during the lab session was coded with the Ainsworth Sensitivity Scale. Sensitivity ratings covered the whole range of the scale (1-9), and were stable across settings (free play, competing demands). Sensitivity was related to an increase of positive affect during caretaking, and insensitivity was related to intended harsh caregiving response during a computerized cry paradigm. Sensitivity was unrelated to social desirability and self-reported quality of care given to the infant simulator. We discuss the potentials of the infant simulator for research on sensitive parenting, for preventive interventions, and for clinical practices.

Rationale 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.

We addressed the question how long salivary oxytocin levels remain elevated after intranasal administration, and whether it makes a difference when 16 or 24 IU of oxytocin administration is used. Oxytocin levels were measured in saliva samples collected from 46 female participants right before intranasal administration (at 9:30 a.m.) of 16 IU (n = 18) or 24 IU (n = 10) of oxytocin, or a placebo (n = 18), and each hour after administration, for 7 h in total. Oxytocin levels did not differ among conditions before use of the nasal spray. Salivary oxytocin levels in the placebo group showed high stability across the day. After oxytocin administration oxytocin levels markedly increased, they peaked around 1 h after administration, and were still significantly elevated 7 h after administration. The amount of oxytocin (16 or 24 IU) did not make a difference for oxytocin levels. The increase of oxytocin levels for at least 7 h shows how effective intranasal administration of oxytocin is. Our findings may raise ethical questions about potentially persisting behavioral effects after participants have left the lab setting. More research into the long-term neurological and behavioral effects of sniffs of oxytocin is urgently needed.

The glucocorticoid receptor is a ubiquitous transcription factor mediating adaptation to environmental challenges and stress. Selective Nr3c1 (the glucocorticoid receptor gene) ablation in mouse dopaminoceptive neurons expressing dopamine receptor 1a, but not in dopamine-releasing neurons, markedly decreased the motivation of mice to self-administer cocaine, dopamine cell firing and the control exerted by dopaminoceptive neurons on dopamine cell firing activity. In contrast, anxiety was unaffected, indicating that glucocorticoid receptors modify a number of behavioral disorders through different neuronal populations.

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 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.

Background Accumulating epidemiological evidence points to the role of genetic background as a modulator of the capacity of adverse early experiences to give rise to mental illness. However, direct evidence of such gene-environment interaction in the context of substance abuse is scarce. In the present study we investigated whether the impact of early life experiences on cocaine intake in adulthood depends on genetic background. In addition, we studied other behavioral dimensions associated with drug abuse, i.e. anxiety- and depression-related behaviors. Methodology/Principal Findings For this purpose, we manipulated the maternal environment of two inbred mouse strains, the C57BL/6J and DBA/2J by fostering them with non-related mothers, i.e. the C3H/HeN and AKR strains. These mother strains show respectively high and low pup-oriented behavior. As adults, C57BL/6J and DBA/2J were tested either for cocaine intravenous self-administration or in the elevated plus-maze and forced swim test (FST). We found that the impact of maternal environment on cocaine use and a depression-related behavior depends upon genotype, as cocaine self-administration and behavior in the FST were influenced by maternal environment in DBA/2J, but not in C57BL/6J mice. Anxiety was not influenced by maternal environment in either strain. Conclusions/Significance Our experimental approach could contribute to the identification of the psychobiological factors determining the susceptibility or the resilience of certain individuals to develop psychopathologies.

Individual differences in cocaine-taking behavior and liability to develop abuse are clearly observed, but underlying mechanisms are still poorly understood. A role for gene-environment interactions has been proposed but remains hypothetical.We investigated whether gene-environment interactions influence intravenous cocaine self-administration (SA) in mice. We tested the effect of a past short group housing experience on cocaine SA in two inbred strains of mice, the C57BL/6J (C57) and DBA/2J (DBA).Adult C57 and DBA mice were individually housed upon arrival in the laboratory. After 3 weeks, half of the animals of each strain were group housed for 19 days. One week after the end of group housing, cocaine SA or measurement of brain cocaine levels took place.Individually and ex-group-housed C57 mice did not differ for cocaine SA. On the contrary, the ex-group-housed DBA mice showed an upward shift in the dose-response curve as compared to individually housed DBA. Differences in brain cocaine levels could not account for the observed behavioral differences.These results demonstrate that vulnerability to cocaine reinforcing effects can be affected by gene-environment interactions. We propose a mouse model for the characterization of gene-environment interactions in the vulnerability to cocaine-taking behavior.

Rationale 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. The interplay between genes and environment underlies this phenomenon. Objectives 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 × 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. Results 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 × 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. Conclusion 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. Electronic supplementary material The online version of this article (doi:10.1007/s00213-010-2118-y) contains supplementary material, which is available to authorized users.

Childhood emotional maltreatment has been associated with a higher risk for maltreating one's own offspring. In the current study, we explored a possible role of oxytocin in mediating the association between childhood emotional maltreatment and participants' interpretation of infant facial expressions. Oxytocin levels were measured in 102 female participants using saliva samples. They rated the mood of thirteen infants with happy, sad and neutral facial expressions. Emotional maltreatment indirectly influenced responses to happy infant faces by modulating oxytocin levels: higher self-reported emotional maltreatment was related to higher levels of salivary oxytocin which were in turn related to a more positive evaluation of happy infant expressions, but not to the evaluation of sad infant expressions. Oxytocin receptor polymorphism rs53576 did not moderate the relation between maltreatment experiences and salivary oxytocin levels. Early emotional maltreatment might indirectly affect emotional information processing by altering the oxytonergic system.