The use of ball pits and playpens in laboratory Lister Hooded male rats induces ultrasonic vocalisations indicating a more positive affective state and can reduce the welfare impacts of aversive procedures

The advancement and quality of science rely on research that is robust and unbiased in its experimental design, execution, analysis, and reproducibility. In preclinical research, a better understanding of animal emotions and refinement of their husbandry, housing, and handling are important goals in providing good animal welfare in a laboratory setting which underpins rigorous research quality. Induction of positive emotional state in animals is a key component of their well-being, and one approach is to increase their environmental complexity using, for example, ball pits or playpens in rats. In this study, we recorded 50 kHz ultrasonic vocalisations (USVs) during animals’ exposure to the ball pit and playpen. We have previously shown that 50 kHz USVs provide a graded and quantifiable measure of an animal’s emotional state, and here find that access to the ball pit and playpen increases 50 kHz USVs, indicative of a more positive affective state. Using our affective bias test (ABT) we next quantified the animals’ emotional response to an aversive intervention and whether this could be attenuated by access to a playpen. The playpen exposure completely mitigated the negative affective state induced by an anxiogenic drug when compared with animals who experienced the drug in the home cage. Together, these findings suggest ball pits and playpens provide a simple and effective method to improve the welfare of laboratory rats and reduce the cumulative suffering they experience from their housing conditions and minor, aversive procedures

Evidence for deficits in behavioural and physiological responses in aged mice relevant to the psychiatric symptom of apathy

Apathy is widely reported in patients with neurological disorders or post viral infection but is also seen in otherwise-healthy aged individuals. This study investigated whether aged male mice express behavioural and physiological changes relevant to an apathy phenotype. Using measures of motivation to work for reward, we found deficits in the progressive ratio task related to rate of responding. In an effort-related decision-making task, aged mice were less willing to exert effort for high value reward. Aged mice exhibited reduced reward sensitivity but also lower measures of anxiety in the novelty supressed feeding test and an attenuated response to restraint stress with lower corticosterone and reduced paraventricular nucleus c-fos activation. This profile of affective changes did not align with those observed in models of depression but suggested emotional blunting. In a test of cognition (novel object recognition), aged mice showed no impairments, but activity was lower in a measure of exploration in a novel environment. Together, these data suggest aged mice show changes across the domains of motivated behaviour, reward sensitivity and emotional reactivity and may be a suitable model for the pre-clinical study of the psychiatric symptom of apathy

The Transient Receptor Potential Melastatin 2 (TRPM2) Channel Contributes to beta-Amyloid Oligomer-Related Neurotoxicity and Memory Impairment

In Alzheimer\u27s disease, accumulation of soluble oligomers of beta-amyloid peptide is known to be highly toxic, causing disturbances in synaptic activity and neuronal death. Multiple studies relate these effects to increased oxidative stress and aberrant activity of calcium-permeable cation channels leading to calcium imbalance. The transient receptor potential melastatin 2 (TRPM2) channel, a Ca2+-permeable nonselective cation channel activated by oxidative stress, has been implicated in neurodegenerative diseases, and more recently in amyloid-induced toxicity. Here we show that the function of TRPM2 is augmented by treatment of cultured neurons with beta-amyloid oligomers. Aged APP/PS1 Alzheimer\u27s mouse model showed increased levels of endoplasmic reticulum stress markers, protein disulfide isomerase and phosphorylated eukaryotic initiation factor 2 alpha, as well as decreased levels of the presynaptic marker synaptophysin. Elimination of TRPM2 in APP/PS1 mice corrected these abnormal responses without affecting plaque burden. These effects of TRPM2 seem to be selective for beta-amyloid toxicity, as ER stress responses to thapsigargin or tunicamycin in TRPM2(-/-) neurons was identical to that of wild-type neurons. Moreover, reduced microglial activation was observed in TRPM2(-/-)/APP/PS1 hippocampus compared with APP/PS1 mice. In addition, age-dependent spatial memory deficits in APP/PS1 mice were reversed in TRPM2(-/-)/APP/PS1 mice. These results reveal the importance of TRPM2 for beta-amyloid neuronal toxicity, suggesting that TRPM2 activity could be potentially targeted to improve outcomes in Alzheimer\u27s disease

A Systematic Mapping Approach of 16q12.2/FTO and BMI in More Than 20,000 African Americans Narrows in on the Underlying Functional Variation: Results from the Population Architecture using Genomics and Epidemiology (PAGE) Study

Genetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3×10-6) had not been highlighted in previous studies. While rs56137030was correlated at r2>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

STAT3 gain-of-function mutations connect leukemia with autoimmune disease by pathological NKG2Dhi CD8+T cell dysregulation and accumulation

The association between cancer and autoimmune disease is unexplained, exemplified by T cell large granular lymphocytic leukemia (T-LGL) where gain-of-function (GOF) somatic STAT3 mutations correlate with co -exist-ing autoimmunity. To investigate whether these mutations are the cause or consequence of CD8+ T cell clonal expansions and autoimmunity, we analyzed patients and mice with germline STAT3 GOF mutations. STAT3 GOF mutations drove the accumulation of effector CD8+ T cell clones highly expressing NKG2D, the receptor for stress-induced MHC-class-I-related molecules. This subset also expressed genes for granzymes, perforin, interferon-y, and Ccl5/Rantes and required NKG2D and the IL-15/IL-2 receptor IL2RB for maximal accumula-tion. Leukocyte-restricted STAT3 GOF was sufficient and CD8+ T cells were essential for lethal pathology in mice. These results demonstrate that STAT3 GOF mutations cause effector CD8+ T cell oligoclonal accumu-lation and that these rogue cells contribute to autoimmune pathology, supporting the hypothesis that somatic mutations in leukemia/lymphoma driver genes contribute to autoimmune disease.Peer reviewe

Transcriptional and genomic parallels between the monoxenous parasite Herpetomonas muscarum and Leishmania

Trypanosomatid parasites are causative agents of important human and animal diseases such as sleeping sickness and leishmaniasis. Most trypanosomatids are transmitted to their mammalian hosts by insects, often belonging to Diptera (or true flies). These are called dixenous trypanosomatids since they infect two different hosts, in contrast to those that infect just insects (monoxenous). However, it is still unclear whether dixenous and monoxenous trypanosomatids interact similarly with their insect host, as fly-monoxenous trypanosomatid interaction systems are rarely reported and under-studied–despite being common in nature. Here we present the genome of monoxenous trypanosomatid Herpetomonas muscarum and discuss its transcriptome during in vitro culture and during infection of its natural insect host Drosophila melanogaster. The H. muscarum genome is broadly syntenic with that of human parasite Leishmania major. We also found strong similarities between the H. muscarum transcriptome during fruit fly infection, and those of Leishmania during sand fly infections. Overall this suggests Drosophila-Herpetomonas is a suitable model for less accessible insect-trypanosomatid host-parasite systems such as sand fly-Leishmania