Search

Identifying therapeutics to delay, and potentially reverse, age-related cognitive decline is critical in light of the increased incidence of dementia-related disorders forecasted in the growing older population1. Here we show that platelet factors transfer the benefits of young blood to the ageing brain. Systemic exposure of aged male mice to a fraction of blood plasma from young mice containing platelets decreased neuroinflammation in the hippocampus at the transcriptional and cellular level and ameliorated hippocampal-dependent cognitive impairments. Circulating levels of the platelet-derived chemokine platelet factor 4 (PF4) (also known as CXCL4) were elevated in blood plasma preparations of young mice and humans relative to older individuals. Systemic administration of exogenous PF4 attenuated age-related hippocampal neuroinflammation, elicited synaptic-plasticity-related molecular changes and improved cognition in aged mice. We implicate decreased levels of circulating pro-ageing immune factors and restoration of the ageing peripheral immune system in the beneficial effects of systemic PF4 on the aged brain. Mechanistically, we identified CXCR3 as a chemokine receptor that, in part, mediates the cellular, molecular and cognitive benefits of systemic PF4 on the aged brain. Together, our data identify platelet-derived factors as potential therapeutic targets to abate inflammation and rescue cognition in old age.

Sensing and acquiring dissolved oxygen is crucial for nearly all aquatic life. This may become even more vital as dissolved oxygen concentrations continue to decline in many aquatic environments. While certain phenotypes that enable fish to live in low oxygen have been characterized, adaptations that arise following sudden, drastic reductions in dissolved oxygen are relatively unknown. Here, we assessed the blind Mexican cavefish, Astyanax mexicanus, for alterations to gill morphology that may be adaptive for life in hypoxic caves. The Astyanax system provides the unique opportunity to compare gill morphology between stereotypical "surface" adapted morphotypes and obligate cave‐dwelling conspecifics. While the surface environment is well‐oxygenated, cavefish must cope with significantly reduced oxygen. We began by quantifying traditional morphological gill traits including filament number and length as well as lamellar density and height in surface fish and two distinct cave populations, Pachón and Tinaja. This enabled us to estimate total lamellar height, a proxy for gill surface area. We then used immunohistochemical staining to label 5‐HT‐positive neuroepithelial cells (NECs), which serve as key oxygen sensors in fish. We discovered an increase in gill surface area for both cavefish populations compared to surface, which may enable a higher capacity of oxygen acquisition. Additionally, we found more NECs in Pachón cavefish compared to both surface fish and Tinaja cavefish, suggesting certain selective pressures may be cave‐specific. Collectively, this work provides evidence that cavefish have adapted to low oxygen conditions via alterations to gill morphology and oxygen sensing, and informs evolutionary mechanisms of rapid adaptation to dramatic, chronic hypoxia. Research Highlights: Astyanax cavefish have significantly greater surface area for oxygen exchange based on increased lamellar height. Certain cavefish have substantially elevated numbers of oxygen sensing cells in gill filaments. [ABSTRACT FROM AUTHOR]

Cave animals, compared to surface-dwelling relatives, tend to have reduced eyes and pigment, longer appendages, and enhanced mechanosensory structures. Pressing questions include how certain cave-related traits are gained and lost, and if they originate through the same or different genetic programs in independent lineages. An excellent system for exploring these questions is the isopod, Asellus aquaticus. This species includes multiple cave and surface populations that have numerous morphological differences between them. A key feature is that hybrids between cave and surface individuals are viable, which enables genetic crosses and linkage analyses. Here, we advance this system by analyzing single animal transcriptomes of Asellus aquaticus. We use high throughput sequencing of non-normalized cDNA derived from the head of a surface-dwelling male, the head of a cave-dwelling male, the head of a hybrid male (produced by crossing a surface individual with a cave individual), and a pooled sample of surface embryos and hatchlings. Assembling reads from surface and cave head RNA pools yielded an integrated transcriptome comprised of 23,984 contigs. Using this integrated assembly as a reference transcriptome, we aligned reads from surface-, cave- and hybrid- head tissue and pooled surface embryos and hatchlings. Our approach identified 742 SNPs and placed four new candidate genes to an existing linkage map for A. aquaticus. In addition, we examined SNPs for allele-specific expression differences in the hybrid individual. All of these resources will facilitate identification of genes and associated changes responsible for cave adaptation in A. aquaticus and, in concert with analyses of other species, will inform our understanding of the evolutionary processes accompanying adaptation to the subterranean environment.

In this study, we report evidence of a novel duplication of Melanocortin receptor 1 (Mc1r) in the cavefish genome. This locus was discovered following the observation of excessive allelic diversity in a ~820 bp fragment of Mc1r amplified via degenerate PCR from a natural population of Astyanax aeneus fish from Guerrero, Mexico. The cavefish genome reveals the presence of two closely related Mc1r open reading frames separated by a 1.46 kb intergenic region. One open reading frame corresponds to the previously reported Mc1r receptor, and the other open reading frame (duplicate copy) is 975 bp in length, encoding a receptor of 325 amino acids. Sequence similarity analyses position both copies in the syntenic region of the single Mc1r locus in 16 representative craniate genomes spanning bony fish (including Astyanax) to mammals, suggesting we discovered tandem duplicates of this important gene. The two Mc1r copies share ~89% sequence similarity and, within Astyanax, are more similar to one another compared to other melanocortin family members. Future studies will inform the precise functional significance of the duplicated Mc1r locus and if this novel copy number variant may have adaptive significance for the Astyanax lineage. Key words: cavefish, brown mutation, Guerrero, copy number variation. Dans ce travail, les auteurs rapportent des evidences pour une duplication inedite du recepteur 1 de la melanocortine (Mc1r) au sein du genome d'un poisson cavernicole. Ce locus a ete decouvert a la suite de l'observation d'une diversite allelique excessive au sein d'un fragment de ~820 pb de Mc1r amplifie au moyen d'amorces degenerees a partir d'une population naturelle de l'Astyanax aeneus provenant de Guerrero au Mexique. Le genome revele la presence de deux cadres de lectures Mc1r tres similaires separes l'un de l'autre par une region intergenique de 1,46 kb. Un cadre de lecture correspond au recepteur Mc1r rapporte anterieurement, tandis que l'autre cadre de lecture (copie dupliquee) mesure 975 pb et code pour un recepteur de 325 acides amines. Une analyse de similarite place les deux copies au sein de la region syntenique de l'unique locus Mc1r present chez 16 genomes representatifs des Craniata allant des poisson osseux (incluant l'Astyanax) jusqu'au mammiferes, ce qui suggere la decouverte d'un premier cas de duplication de ce gene important. Les deux copies de Mc1r sont similaires a ~89% et, au sein des Astyanax, sont plus semblables l'une a l'autre que les autres membres de la famille des melanocortines. De futures etudes pourront determiner l impact fonctionnel precis decoulant de la duplication du locus Mc1r et si ce variant de nombre de copies se veut adaptative au sein des Astyanax. [Traduit par la Redaction] Mots-cles: poisson cavernicoles, mutation brown, Guerrero, variation du nombre de copies., Introduction The gene melanocortin receptor 1 (Mc1r) encodes a seven-transmembrane domain G-protein coupled receptor expressed in melanin-producing cells (Tsatmali et al. 2002). This protein receptor binds [alpha]-melanophore stimulating hormone, resulting [...]