Repeated parallel differentiation of social learning differences in benthic and limnetic threespine stickleback fish.

Individuals can reduce sampling costs and increase foraging efficiency by using information provided by others. One simple form of social information use is delayed local enhancement or increased interest in a location because of the past presence of others. We tested for delayed local enhancement in two ecomorphs of stickleback fish, benthic and limnetic, from three different lakes with putative independent evolutionary origins. Two of these lakes have reproductively isolated ecomorphs (species-pairs), whereas in the third, a previously intact species-pair recently collapsed into a hybrid swarm. Benthic fish in both intact species-pair lakes were more likely to exhibit delayed local enhancement despite being more solitary than limnetic fish. Their behaviour and morphology suggest their current perceived risk and past evolutionary pressure from predation did not drive this difference. In the hybrid swarm lake, we found a reversal in patterns of social information use, with limnetic-looking fish showing delayed local enhancement rather than benthic-looking fish. Together, our results strongly support parallel differentiation of social learning differences in recently evolved fish species, although hybridization can apparently erode and possibly even reverse these differences.

Triplication of the interferon receptor locus contributes to hallmarks of Down syndrome in a mouse model.

Down syndrome (DS), the genetic condition caused by trisomy 21, is characterized by variable cognitive impairment, immune dysregulation, dysmorphogenesis and increased prevalence of diverse co-occurring conditions. The mechanisms by which trisomy 21 causes these effects remain largely unknown. We demonstrate that triplication of the interferon receptor (IFNR) gene cluster on chromosome 21 is necessary for multiple phenotypes in a mouse model of DS. Whole-blood transcriptome analysis demonstrated that IFNR overexpression associates with chronic interferon hyperactivity and inflammation in people with DS. To define the contribution of this locus to DS phenotypes, we used genome editing to correct its copy number in a mouse model of DS, which normalized antiviral responses, prevented heart malformations, ameliorated developmental delays, improved cognition and attenuated craniofacial anomalies. Triplication of the Ifnr locus modulates hallmarks of DS in mice, suggesting that trisomy 21 elicits an interferonopathy potentially amenable to therapeutic intervention.

Trisomy of Human Chromosome 21 Orthologs Mapping to Mouse Chromosome 10 Cause Age and Sex-Specific Learning Differences: Relevance to Down Syndrome.

Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), is the most common genetic cause of intellectual disability. The Dp10(1)Yey (Dp10) is a mouse model of DS that is trisomic for orthologs of 25% of the Hsa21 protein-coding genes, the entirety of the Hsa21 syntenic region on mouse chromosome 10. Trisomic genes include several involved in brain development and function, two that modify and regulate the activities of sex hormones, and two that produce sex-specific phenotypes as null mutants. These last four are the only Hsa21 genes with known sexually dimorphic properties. Relatively little is known about the potential contributions to the DS phenotype of segmental trisomy of Mmu10 orthologs. Here, we have tested separate cohorts of female and male Dp10 mice, at 3 and 9 months of age, in an open field elevated zero maze, rotarod, and balance beam, plus the learning and memory tasks, spontaneous alternation, puzzle box, double-H maze, context fear conditioning, and acoustic startle/prepulse inhibition, that depend upon the function of the prefrontal cortex, striatum, hippocampus, and cerebellum. We show that there are age and sex-specific differences in strengths and weaknesses, suggesting that genes within the telomere proximal region of Hsa21 influence the DS phenotype.

JAK1 Inhibition Blocks Lethal Immune Hypersensitivity in a Mouse Model of Down Syndrome.

Individuals with Down syndrome (DS; trisomy 21) display hyperactivation of interferon (IFN) signaling and chronic inflammation, which could potentially be explained by the extra copy of four IFN receptor (IFNR) genes encoded on chromosome 21. However, the clinical effects of IFN hyperactivity in DS remain undefined. Here, we report that a commonly used mouse model of DS overexpresses IFNR genes and shows hypersensitivity to IFN ligands in diverse immune cell types. When treated repeatedly with a TLR3 agonist to induce chronic inflammation, these animals overexpress key IFN-stimulated genes, induce cytokine production, exhibit liver pathology, and undergo rapid weight loss. Importantly, the lethal immune hypersensitivity and cytokine production and the ensuing pathology are ameliorated by JAK1 inhibition. These results indicate that individuals with DS may experience harmful hyperinflammation upon IFN-inducing immune stimuli, as observed during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, pointing to JAK1 inhibition as a strategy to restore immune homeostasis in DS.

Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity.

Trisomy 21 (T21) causes Down syndrome (DS), a condition characterized by high prevalence of autoimmune disorders. However, the molecular and cellular mechanisms driving this phenotype remain unclear. Building upon our previous finding that T cells from people with DS show increased expression of interferon (IFN)-stimulated genes, we have completed a comprehensive characterization of the peripheral T cell compartment in adults with DS with and without autoimmune conditions. CD8+ T cells from adults with DS are depleted of naïve subsets and enriched for differentiated subsets, express higher levels of markers of activation and senescence (e.g., IFN-γ, Granzyme B, PD-1, KLRG1), and overproduce cytokines tied to autoimmunity (e.g., TNF-α). Conventional CD4+ T cells display increased differentiation, polarization toward the Th1 and Th1/17 states, and overproduction of the autoimmunity-related cytokines IL-17A and IL-22. Plasma cytokine analysis confirms elevation of multiple autoimmunity-related cytokines (e.g., TNF-α, IL17A-D, IL-22) in people with DS, independent of diagnosis of autoimmunity. Although Tregs are more abundant in DS, functional assays show that CD8+ and CD4+ effector T cells with T21 are resistant to Treg-mediated suppression, regardless of Treg karyotype. Transcriptome analysis of white blood cells and T cells reveals strong signatures of T cell differentiation and activation that correlate positively with IFN hyperactivity. Finally, mass cytometry analysis of 8 IFN-inducible phosphoepitopes demonstrates that T cell subsets with T21 show elevated levels of basal IFN signaling and hypersensitivity to IFN-α stimulation. Therefore, these results point to T cell dysregulation associated with IFN hyperactivity as a contributor to autoimmunity in DS.

Mass Cytometry Reveals Global Immune Remodeling with Multi-lineage Hypersensitivity to Type I Interferon in Down Syndrome.

People with Down syndrome (DS; trisomy 21) display a different disease spectrum relative to the general population, including lower rates of solid malignancies and higher incidence of neurological and autoimmune conditions. However, the mechanisms driving this unique clinical profile await elucidation. We completed a deep mapping of the immune system in adults with DS using mass cytometry to evaluate 100 immune cell types, which revealed global immune dysregulation consistent with chronic inflammation, including key changes in the myeloid and lymphoid cell compartments. Furthermore, measurement of interferon-inducible phosphorylation events revealed widespread hypersensitivity to interferon-α in DS, with cell-type-specific variations in downstream intracellular signaling. Mechanistically, this could be explained by overexpression of the interferon receptors encoded on chromosome 21, as demonstrated by increased IFNAR1 surface expression in all immune lineages tested. These results point to interferon-driven immune dysregulation as a likely contributor to the developmental and clinical hallmarks of DS.

Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors.

Trisomy 21 (T21) causes Down syndrome (DS), affecting immune and neurological function by ill-defined mechanisms. Here we report a large metabolomics study of plasma and cerebrospinal fluid, showing in independent cohorts that people with DS produce elevated levels of kynurenine and quinolinic acid, two tryptophan catabolites with potent immunosuppressive and neurotoxic properties, respectively. Immune cells of people with DS overexpress IDO1, the rate-limiting enzyme in the kynurenine pathway (KP) and a known interferon (IFN)-stimulated gene. Furthermore, the levels of IFN-inducible cytokines positively correlate with KP dysregulation. Using metabolic tracing assays, we show that overexpression of IFN receptors encoded on chromosome 21 contribute to enhanced IFN stimulation, thereby causing IDO1 overexpression and kynurenine overproduction in cells with T21. Finally, a mouse model of DS carrying triplication of IFN receptors exhibits KP dysregulation. Together, our results reveal a mechanism by which T21 could drive immunosuppression and neurotoxicity in DS.

Sex differences in cognition and their relationship to male mate choice.

Male cognition has gained recognition as an important potential player in sexual selection. A number of studies have found positive correlations between male sexual signals and cognitive performance and/or female preferences for males with better cognitive performance, although other studies have not found these relationships. Sex roles can differ dramatically, and sex differences in selection on cognition likely follow from the different tasks associated with these sex roles. Here, using threespine stickleback Gasterosteus aculeatus, a species with clearly divergent sex roles and mutual mate choice, we focus on the cognitive trait inhibitory control because males must differentially respond to reproductive females versus other sticklebacks while defending territories and refrain from eating eggs and fry while performing paternal care. We presented fish with a detour task four times over a period of 7 days, allowing us to assess initial inhibitory control and improvement over time. We ask 1) whether there are sex differences in inhibitory control and 2) whether male mate choice is associated with female inhibitory control. Although males outperformed females on three different measures of detour task performance across four trials, these differences were largely explained by males being less neophobic than females. Females took more trials to successfully solve the detour task, even after accounting for sex differences in neophobia. Female cognitive abilities, however, were unrelated to the vigor with which males courted them. The equivocal results regarding sex differences in cognitive ability suggest further study given the very different selection pressures each sex experiences.

The relationship between male sexual signals, cognitive performance, and mating success in stickleback fish.

Cognitive ability varies dramatically among individuals, yet the manner in which this variation correlates with reproduction has rarely been investigated. Here, we ask (1) do male sexual signals reflect their cognitive ability, and (2) is cognitive ability associated with male mating success? Specifically, we presented threespine sticklebacks (Gasterosteus aculeatus) with a detour-reaching task to assess initial inhibitory control. Fish that performed better were those who solved the detour-reaching task, solved it faster, and required fewer attempts to solve. We then reexamined males' performance on this task over several days to assess learning ability in this context. We next measured sexual signals (coloration, nest area, and courtship vigor) and asked whether they reveal information about these male cognitive abilities. Finally, we examined whether success at attracting a female is associated with male cognition. After controlling for the strong effect of neophobia, we found that no measured sexual signals were associated with initial inhibitory control. Sexual signals were also not associated with change in performance on the detour-reaching task over time (learning). However, females preferred mating with males who had better initial inhibitory control. We speculate that inhibitory control is a critical trait for male sticklebacks. In this system, males perform all parental care, but must avoid eating their own fry which closely resemble their prey items. Therefore, males with better inhibitory control may be more likely to successfully raise their offspring to independence. Our research adds to a growing list of mating systems and taxa in which cognition is important for measures related to fitness.