The behavioral phenotype of early life adversity Bonapersona, V.; Kentrop, J.; Van Lissa, C. J.; van der Veen, R.; Joels, M.; Sarabdjitsingh, R. A. Citation for published version (APA): Bonapersona, V., Kentrop, J., Van Lissa, C. J., van der Veen, R., Joels, M., & Sarabdjitsingh, R. A. (2019). The behavioral phenotype of early life adversity: A 3-level meta-analysis of rodent studies. Neuroscience and Biobehavioral Reviews, 102, 299-307. https://doi.Altered cognitive performance is considered an intermediate phenotype mediating early life adversity (ELA) effects on later-life development of mental disorders, e.g. depression.Whereas most human studies are limited to correlational conclusions, rodent studies can prospectively investigate how ELA alters cognitive performance in several domains. Despite the volume of reports, there is no consensus on i) the behavioral domains being affected by ELA and ii) the extent of these effects. To test how ELA (here: aberrant maternal care) affects specific behavioral domains, we used a 3-level mixed-effect meta-analysis, and thoroughly explored heterogeneity with MetaForest, a novel machine-learning approach. Our results are based on > 400 independent experiments, involving ∼8600 animals. Especially in males, ELA promotes memory formation during stressful learning but impairs non-stressful learning. Furthermore, ELA increases anxiety-like and decreases social behavior. The ELA phenotype was strongest when i) combined with other negative experiences ("hits"); ii) in rats; iii) in ELA models of ∼10days duration. All data is easily accessible with MaBapp (https://osf.io/ra947/), allowing researchers to run tailor-made meta-analyses, thereby revealing the optimal choice of experimental protocols and study power.

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Adverse early life events are a well-established risk factor for the precipitation of behavioral disorders characterized by anomalies in the dopaminergic system, such as schizophrenia and addiction. The correlation between early life conditions and the dopaminergic system has been causally investigated in more than 90 rodent publications. Here, we tested the validity of the hypothesis that early life stress (ELS) alters dopamine signaling by performing an extensive 3-level mixed effect meta-analysis. We included several ELS models and biochemical indicators of the dopaminergic system in a variety of brain areas, for a total of 1009 comparisons. Contrary to our expectations, only a few comparisons displayed a significant effect. Specifically, the striatal area was the most vulnerable, displaying decreased dopamine precursor and increased metabolites after ELS. To make all data openly accessible, we created MaDEapp (https://osf.io/w25m4/), a tool to explore data of the meta-analysis with the intent to guide future (pre)clinical research and allow power calculations. All in all, ELS induces a few yet robust changes on biochemical indicators of the dopaminergic system.

Early life stress (ELS) is considered a major risk factor for developing psychopathology. Increasing evidence points towards sex-dependent dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis as a contributing mechanism. Additionally, clinical studies suggest that the mineralocorticoid receptor (MR) may further confer genetic vulnerability/resilience on a background of ELS. The link between ELS, sex and the HPA axis and how this interacts with MR genotype is understudied, yet important to understand vulnerability/resilience to stress. We used the early life-limited nesting and bedding model to test the effect of ELS on HPA properties in adult female and male mice carrying a forebrain-specific heterozygous knockout for MR. Basal HPA axis activity was measured by circadian peak and nadir corticosterone levels, in addition to body weight and weight of stress-sensitive tissues. HPA axis reactivity was assessed by mapping corticosterone levels after 10 min immobilization. Additionally, we measured the effects of ELS on steroid receptor [MR and glucocorticoid receptor (GR)] levels in the dorsal hippocampus and medial prefrontal cortex (mPFC) with western blot. Finally, behavioral reactivity towards a novel environment was measured as a proxy for anxiety-like behavior. Results show that HPA axis activity under rest conditions was not affected by ELS. HPA axis reactivity after immobilization was decreased by ELS in females and increased, at trend-level in males. This effect in females was further exacerbated by low expression of the MR. We also observed a sex*ELS interaction regarding MR and GR expression in the dorsal hippocampus, with a significant upregulation of MR in males only. The sex-dependent interaction with ELS was not reflected in the behavioral response to novel environment and time spent in a sheltered compartment. We did find increased locomotor activity in all groups after a history of ELS, which attenuated after 4 h in males but not females regardless of condition. Our findings support that ELS alters HPA axis functioning sex-dependently. Genetic predisposition to low MR function may render females more susceptible to the harmful effect of ELS whereas in males low MR function promotes resilience. We propose that this model may be a useful tool to investigate the underlying mechanisms of sex-dependent and genetic vulnerability/resilience to stress-related psychopathology.

Acute stress leads to sequential activation of functional brain networks. A biologically relevant question is exactly which (single) cells belonging to brain networks are changed in activity over time after acute stress across the entire brain. We developed a preprocessing and analytical pipeline to chart whole-brain immediate early genes’ expression—as proxy for cellular activity—after a single stressful foot shock in four dimensions: that is, from functional networks up to three-dimensional (3D) single-cell resolution and over time. The pipeline is available as an R package. Most brain areas (96%) showed increased numbers of c-fos+ cells after foot shock, yet hypothalamic areas stood out as being most active and prompt in their activation, followed by amygdalar, prefrontal, hippocampal, and finally, thalamic areas. At the cellular level, c-fos+ density clearly shifted over time across subareas, as illustrated for the basolateral amygdala. Moreover, some brain areas showed increased numbers of c-fos+ cells, while others—like the dentate gyrus—dramatically increased c-fos intensity in just a subset of cells, reminiscent of engrams; importantly, this “strategy” changed after foot shock in half of the brain areas. One of the strengths of our approach is that single-cell data were simultaneously examined across all of the 90 brain areas and can be visualized in 3D in our interactive web portal.

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Low statistical power challenges the reliability of animal research; yet, increasing sample sizes to the required level raises important ethical and practical issues. We present an alternative solution, RePAIR, which capitalizes on the observation that control groups in general are 15 expected to be similar to each other. As shown in a simulation study, including information of previous control experiments in the statistical analysis using RePAIR reduced the required sample size by 49% or increased power up to 100%. We validated the potential of RePAIR in a unique dataset based on 7 independent experiments across the world, studying cognitive effects of early life adversity in mice. RePAIR comes with an open-source web-based tool and can be 20 widely used to largely improve quality of animal experimentation. One Sentence Summary:Prior studies' information can reduce use of animals or increase statistical power, improving animal research reliability 25

A challenge facing rigid polyurethane foam insulation today is the development of foam formulations and processing technologies that use blowing agents which are environmentally acceptable and produce foam having an excellent balance of properties. Rigid polyurethane foams are known for their outstanding combination of density, thermal resistivity, structural and fire performance, and cost-effectiveness. Such attributes are essential for, maintaining a competitive edge over alternate insulation materials. Currently, hydrocarbons and HFCs are the two leading classes of blowing agents under consideration to replace HCFCs. The benefits and challenges for each of the viable blowing agents are well known. This study focuses on hydrocarbon blown foam where the primary challenge is to meet the required regulatory firetests together with providing superior aged thermal resistance and structural performance at low densities. Learning from the ongoing commercial production with pentanes in Europe as well as from prior published works, this study systematically looks at the effects of selected polyurethane formulation and processing variables on the key polyurethane foam and laminate board performance characteristics. Formulation variables examined include pentane composition, index, and fire retardant. Processing variables examined include temperature, laydown, and the physical state of the blend. Physical properties of the laminate board and foam are discussed. ASTM E84 and Factory Mutual Calorimeter test results are presented. The results are analyzed keeping in perspective findings from years of experience with CFC-11 and HCFC-141b blown foam. Based on these evaluations, this paper outlines the key material and processing requirements for the successful use of hydrocarbon blowing agents in the North American boardstock industry.