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Biology subjects

Chase, R.

Publications and source records attributed to Chase, R..

7 recordsLinked to original sources

Sex differences in exploration-exploitation strategies during home-cage decision making

The exploration-exploitation trade-off refers to the conflict between using known strategies that reliably yield reward (exploitation) and sampling uncertain options that might yield better outcomes (exploration). Dysregulation of this balance is implicated in neuropsychiatric disease, and while sex differences in this balance have been described, the biological bases remain unclear. To quantify sex differences in this trade-off, we tested mice (n=74 male, 62 female) on four home-cage based foraging tasks with an operant pellet dispensing device, Feeding Experimentation Device 3 (FED3). Mice completed the tasks continuously over multiple days and the tasks were their only source of food. Across multiple tasks, males showed higher win-stay behaviour than females, indicating greater exploitation of previously rewarded actions, an effect that was modest in size but highly significant. Power analyses revealed that >30 mice per sex were needed to detect these modest but significant sex differences with 80% power. No consistent sex differences were observed in pellet intake, suggesting that differences in exploitation did not reflect differences in hunger drive or demand for pellets. Exploitation is a more efficient strategy when environmental parameters are fixed, while exploration can be more advantageous when parameters such as reward locations are changing and uncertain. We tested this idea by re-running our mice in a probabilistic foraging task, where actions led to uncertain probabilities of reward. While males continued to show higher levels of win-stay behaviour on this task, this no longer led to increases in accuracy. Behavioural modelling also supported this framework, demonstrating that stronger win-stay behaviour was most advantageous in deterministic models, and less advantageous in probabilistic models. Together, our findings demonstrate that male and female mice have small but significant differences in their exploration-exploitation balance, which leads to more accurate foraging in certain, but not uncertain, environments.

neuroscience↗

A single binge ethanol exposure is apoptotic within hours across neurodevelopment and partially regulated by the Myt1l gene.

Ethanol rapidly produces widespread neuronal apoptosis during early development, but this susceptibility declines as the brain matures. In previous research, we found Myt1l (a proneuronal transcription factor) mutations can cause precocious differentiation, neuronal immaturity, and transcriptomic alterations, including many in apoptotic regulators. Therefore, we used a recently developed Myt1l haploinsufficient mouse model to examine this genes effects on ethanol-induced apoptosis across different developmental stages. We discovered that haploinsufficiency can moderately influence vulnerability to ethanol in a complex, age- and cell type-specific manner: apoptosis was reduced on P7, increased P21, but unaffected on P60. Remarkably, we also discovered the previously unrecognized ability of a single binge of ethanol to rapidly increase apoptosis within six hours in early adolescent and adult wild-type mice occurring in microglia and the newborn granule neurons in the hippocampus. This suggests apoptosis is an underappreciated contributor to ethanols neuropathology at older ages and, translated to human use, occurs far more frequently than previously recognized.

neuroscience↗

A survey of hypothalamic phenotypes identifies molecular and behavioral consequences of MYT1L haploinsufficiency in male and female mice.

The transcription factor MYT1L supports proper neuronal differentiation and maturation during brain development. MYT1L haploinsufficiency results in a neurodevelopmental disorder characterized by intellectual disability, developmental delay, autism, behavioral disruptions, aggression, obesity and epilepsy. While MYT1L is expressed throughout the brain, how it supports proper neuronal function in distinct regions has not been assessed. Some features of MYT1L Neurodevelopmental Syndrome suggest disruption of hypothalamic function, such as obesity and endocrine issues, and previous research showed changes in hypothalamic neuropeptide expression following knockdown in zebrafish. Here, we leveraged our heterozygous Myt1l mutant, previously shown to recapitulate aspects of the human syndrome such as hyperactivity, social challenges, and obesity, to examine the impact of MYT1L loss on hypothalamic function. Examining the molecular profile of the MYT1L haploinsufficient hypothalamus revealed a similar scale of disruption to previously studied brain regions, yet with region-specific roles for MYT1L, including regulation of neuropeptide systems. Alterations in oxytocin and arginine vasopressin cell numbers were also found. Behaviors studied included maternal care, social group hierarchies, and aggression, all of which were unchanged. Feeding and metabolic markers were also largely unchanged in MYT1L haploinsufficient mice, yet an interaction was observed between diet and MYT1L genotype on weight gain. Our findings here suggest that gross endocrine function was not altered by MYT1L haploinsufficiency, and that key sex-specific behaviors related to proper hypothalamic function remain intact. Further study is needed to understand the functional impact of the altered hypothalamic molecular profile and changes in neuropeptide cell numbers that result from MYT1L haploinsufficiency.

animal behavior and cognition↗

Painting the diversity of a world's favourite fruit: A next generation catalogue of cultivated bananas

Societal impact statementBananas are nutritious fruits of major importance in the tropics and subtropics. Characterizing their diversity is essential to ensure their conservation and use. A catalogue showcasing cultivated bananas genomic diversity was compiled and is to be used as a tool to support the classification of banana cultivars. This research revealed that cultivated banana groups are not all made of identical clones. Materials from recent collecting missions indicated that more banana diversity is expected to be found as the exploration of the banana gene pool continues. These discoveries will drive dynamic conservation strategies for banana genetic resources and will increase their use. SummaryO_LIBanana is an important food crop cultivated in many tropical and subtropical regions around the world. Due to their low fertility, banana landraces are clonally propagated. However, different factors, such as synonymy and the effects of environment, make their assignment to described sets of clones, or cultivar groups, difficult. Consequently, passport data of accessions in genebanks is often uncomplete and sometimes inaccurate. C_LIO_LIWith the recent advances in genomics, a new powerful tool was developed enabling the fine-scale characterization of bananas ancestry along chromosomes, i.e. in silico chromosome painting. We applied this method to a high-throughput genotyping data set obtained from 317 banana accessions spanning most of the known cultivar groups. This set included both genebank and new uncharacterized materials. C_LIO_LIBy comparing curated morphological assignation to the genomic patterns resulting from in silico chromosome painting, we were able to compile a catalogue referencing the chromosome painting patterns of most of the described cultivar groups. C_LIO_LIExamining the genomic patterns obtained, we discovered intra-cultivar group variability. In some cultivar groups, mitotic recombination or deletions were clonally accumulated in cultivars. In addition, we identified at least 4 cultivar groups in which cultivars likely resulting from distinct sexual events co-existed, notably Pisang Awak in which 5 distinct genomic patterns of two ploidy levels were identified. New patterns were also discovered in the newest materials of the set, showing that a wider diversity of clones still exist on farm. C_LI

genomics↗

Vitamin D constrains inflammation by modulating the expression of key genes on Chr17q12-21.1

Vitamin D possesses immunomodulatory functions and vitamin D deficiency has been associated with the rise in chronic inflammatory diseases, including asthma (1). Vitamin D supplementation studies do not provide insight into the molecular genetic mechanisms of vitamin D mediated immunoregulation. Here we provide evidence for vitamin D regulation of two human chromosomal loci, Chr17q12-21.1 and Chr17q21.2, reliably associated with autoimmune and chronic inflammatory diseases (2-4). We demonstrate increased vitamin D receptor (VDR) expression in mouse lung CD4+ Th2 cells, differential expression of Chr17q12-21.1 and Chr17q21.2 genes in Th2 cells based on vitamin D status and identify the IL-2/Stat5 pathway as a target of vitamin D signaling. Vitamin D deficiency caused severe lung inflammation after allergen challenge in mice that was prevented by long term prenatal vitamin D supplementation. Mechanistically, vitamin D induced the expression of the Ikzf3 encoded protein Aiolos to suppress IL-2-signaling and ameliorate cytokine production in Th2 cells. These translational findings demonstrate mechanisms for the immune protective effect of vitamin D in allergic lung inflammation with a strong molecular genetic link to the regulation of both Chr17q12-21.1 and Chr17q21.2 genes and suggest further functional studies and interventional strategies for long-term prevention of asthma and other autoimmune disorders. One Sentence SummaryVitamin D regulates two human chromosomal loci, Chr17q12-21.1 and Chr17q21.2, that are associated with autoimmune and chronic inflammatory diseases.

systems biology↗

Genomic signatures of the unjamming transition in compressed human bronchial epithelial cells

Epithelial tissue has the capacity to switch from a collective phase that is quiescent, solidlike and non-migratory to one that is dynamic, fluid-like and migratory. In certain physiological and pathophysiological contexts this phenotypic switch has been attributed not to the well-known epithelial-to-mesenchymal transition, EMT, but rather to the recently discovered unjamming transition, UJT. UJT has been characterized thus far mainly at functional and morphological levels whereas underlying genome-wide molecular events remain largely unexplored. Using primary human bronchial epithelial cells and one well-defined trigger of UJT -mechanical compression- here we combine temporal RNA-Seq data and Protein-Protein Interaction networks to provide the first genome-wide analysis of UJT. Our results show that compression induces a multiphasic transcriptional response characterized by an early activation of genes regulating the membrane and actomyosin structure, and a delayed activation of genes regulating the extracellular matrix and cellmatrix interactions. This biphasic response is mediated by a cascade of signaling processes that promotes actin polymerization through the recruitment of integrin-ECM adhesive complexes and promotes increased cellular motility through activation of AP-1 transcription factors via ERK and JNK pathways. These findings, taken together, show that the UJT program is not the result of any single signaling pathway but rather comprises a coordinated interplay of downstream pathways including development, fate selection, energy metabolism, cytoskeletal reorganization, and adhesive interaction with extracellular matrix.

genomics↗

Integrative genomics analysis identifies ACVR1B as a candidate causal gene of emphysema distribution in non-alpha 1-antitrypsin deficient smokers

BackgroundSeveral genetic risk loci associated with emphysema apico-basal distribution (EABD) have been identified through genome-wide association studies (GWAS), but the biological functions of these variants are unknown. To characterize gene regulatory functions of EABD-associated variants, we integrated EABD GWAS results with 1) a multi-tissue panel of expression quantitative trait loci (eQTL) from subjects with COPD and the GTEx project and 2) epigenomic marks from 127 cell types in the Roadmap Epigenomics project. Functional validation was performed for a variant near ACVR1B.\n\nResultsSNPs from 168 loci with P-values<5x10-5 in the largest GWAS meta-analysis of EABD (Boueiz A. et al, AJRCCM 2017) were analyzed. 54 loci overlapped eQTL regions from our multi-tissue panel, and 7 of these loci showed a high probability of harboring a single, shared GWAS and eQTL causal variant (colocalization posterior probability[&ge;]0.9). 17 cell types exhibited greater than expected overlap between EABD loci and DNase-I hypersensitive peaks, DNaseI hotspots, enhancer marks, or digital DNaseI footprints (permutation P-value < 0.05), with the strongest enrichment observed in CD4+, CD8+, and regulatory T cells. A region near ACVR1B demonstrated significant colocalization with a lung eQTL and overlapped DNase-I hypersensitive regions in multiple cell types, and reporter assays in human bronchial epithelial cells confirmed allele-specific regulatory activity for the lead variant, rs7962469.\n\nConclusionsIntegrative analysis highlights candidate causal genes, regulatory variants, and cell types that may contribute to the pathogenesis of emphysema distribution. These findings will enable more accurate functional validation studies and better understanding of emphysema distribution biology.

genomics↗