Cross-site reproducibility of social deficits in group-housed BTBR mice using automated longitudinal behavioural monitoring

Social withdrawal is associated with a variety of neuropsychiatric disorders, including neurodevelopmental disorders. Rodent studies provide the opportunity to study neurobiological mechanisms underlying social withdrawal, however, homologous paradigms to increase translatability of social behaviour between human and animal observation are needed. Standard behavioural rodent assays have limited ethological validity in terms of number of interaction partners, type of behaviour, duration of observation and environmental conditions. In addition, reproducibility of behavioural findings in rodents is further limited by manual and subjective behavioural scoring. Using a newly developed automated tracking tool for longitudinal monitoring of freely moving mice, we assessed social behaviours (approach, sniff, follow and leave) over seven consecutive days in colonies of BTBR and of C57BL/6J mice in two independent laboratories. Results from both laboratories confirmed previous findings of reduced social interaction in BTBR mice revealing a high level of reproducibility for this mouse phenotype using longitudinal colony assessments. In addition, we showed that detector settings contribute to laboratory specific findings as part of the behavioural data analysis procedure. Our cross-site study demonstrates reproducibility and robustness of reduced social interaction in BTBR mice using automated analysis in an ethologically relevant context

The reverse translation of a quantitative neuropsychiatric framework into preclinical studies:Focus on social interaction and behavior

Following the Research Domain Criteria (RDoC) concept, major brain circuits are conserved in evolution and malfunctioning of a brain circuit will lead to specific behavioral symptoms. Reverse translation of patient-based findings from Alzheimer’s disease (AD), schizophrenia (SZ) and major depression (MD) patients to preclinical models accordingly can be a starting point for developing a deeper understanding of the functional circuit biology and contribute to the validation of new hypotheses for therapeutic intervention in patients. In the context of the EU funded PRISM project, a preclinical test battery of tasks has been selected and aligned with the clinical test battery. It allows for assessment of social functioning, sensory processing, attention and working memory and is designed for validation of biological substrates from human molecular landscaping of social withdrawal. This review will broadly summarize the available literature on tasks for studying social behavior in rodents and outline the development of a preclinical test battery for the PRISM project by reverse translation

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Measuring social withdrawal: Using semi-natural social environments to identify translational measures in mice

Excessive social withdrawal is a symptom of multiple neuropsychiatric disorders, greatly impacting the quality of life. The heritability of neuropsychiatric disorders suggests that we can search for their cause in the genetics. Since humans and other animals show overlapping genes and social behavior, we can utilize model organisms to study the genetics behind social withdrawal. Conventional tests for social behavior, in which two interacting animals are observed in an artificial environment, have proven to be difficult to replicate and insufficient to develop a treatment for the patients. There is a need for a reliable and validated test for complex social behaviors. Thus, in this thesis we aim to develop a generalizable and ethologically valid method to reliably quantify social withdrawal in mice, laying a foundation for future translational research. Our methods focus on measuring social group-behavior in a semi-natural environment, in which the mice could interact freely, over a period of multiple days. We have shown that we can replicate findings from earlier research, which used conventional tests, in our semi-natural environments. Further, we were able to replicate the results from our own experiments in another laboratory, showing the robustness of our methods. We have demonstrated that our methods can be used to study human risk genes for excessive social withdrawal in genetic and pharmacological mouse models. This showed that a specific dopamine receptor impacts social behavior in different species. With this we provide a foundation for future translational research

Social withdrawal:An initially adaptive behavior that becomes maladaptive when expressed excessively

Social withdrawal is found across neuropsychiatric disorders and in numerous animal species under various conditions. It has substantial impact on the quality of life in patients suffering from neuropsychiatric disorders. Often it occurs prodromal to the disease, suggesting that it is either an early biomarker or central to its etiology. Healthy social functioning is supported by the social brain of which the building blocks go back millions of years, showing overlap between humans, rodents and insects. Thus, to elucidate social withdrawal, we have to approach its environmental triggers and its neural and molecular genetic determinants in an evolutionary context. Pathological social withdrawal may originate from a faulty regulation of specific neural circuits. As there is considerable heritability in social disorders, the genetic building blocks of the social decision making network might be our most relevant target to obtain an understanding of the transition of normal social interaction into social withdrawal