Spreading depolarization (SD) is a slowly propagating wave of profound depolarization that sweeps through cortical tissue. While much emphasis has been placed on the damaging consequences of SD, ...there is uncertainty surrounding the potential activation of beneficial pathways such as cell survival and plasticity. The present study used unbiased assessments of gene expression to evaluate that compensatory and repair mechanisms could be recruited following SD, regardless of the induction method, which prior to this work had not been assessed. We also tested assumptions of appropriate controls and the spatial extent of expression changes that are important for
SD models. SD clusters were induced with either KCl focal application or optogenetic stimulation in healthy mice. Cortical RNA was extracted and sequenced to identify differentially expressed genes (DEGs). SDs using both induction methods significantly upregulated 16 genes (vs. sham animals) that included the cell proliferation-related genes FOS, JUN, and DUSP6, the plasticity-related genes ARC and HOMER1, and the inflammation-related genes PTGS2, EGR2, and NR4A1. The contralateral hemisphere is commonly used as control tissue for DEG studies, but its activity could be modified by near-global disruption of activity in the adjacent brain. We found 21 upregulated genes when comparing SD-involved cortex vs. tissue from the contralateral hemisphere of the same animals. Interestingly, there was almost complete overlap (21/16) with the DEGs identified using sham controls. Neuronal activity also differs in SD initiation zones, where sustained global depolarization is required to initiate propagating events. We found that gene expression varied as a function of the distance from the SD initiation site, with greater expression differences observed in regions further away. Functional and pathway enrichment analyses identified axonogenesis, branching, neuritogenesis, and dendritic growth as significantly enriched in overlapping DEGs. Increased expression of SD-induced genes was also associated with predicted inhibition of pathways associated with cell death, and apoptosis. These results identify novel biological pathways that could be involved in plasticity and/or circuit modification in brain tissue impacted by SD. These results also identify novel functional targets that could be tested to determine potential roles in the recovery and survival of peri-infarct tissues.
Spreading depolarizations (SDs) are profound waves of neuroglial depolarization that can propagate repetitively through injured brain. Recent clinical work has established SD as an important ...contributor to expansion of acute brain injuries and have begun to extend SD studies into other neurological disorders. A critical challenge is to determine how to selectively prevent deleterious consequences of SD. In the present study, we determined whether a wave of profound Zn2+ release is a key contributor to deleterious consequences of SD, and whether this can be targeted pharmacologically. Focal KCl microinjection was used to initiate SD in the CA1 region of the hippocampus in murine brain slices. An extracellular Zn2+ chelator with rapid kinetics (ZX1) increased SD propagation rates and improved recovery of extracellular DC potential shifts. Under conditions of metabolic compromise, tissues showed sustained impairment of functional and structural recovery following a single SD. ZX1 effectively improved recovery of synaptic potentials and intrinsic optical signals in these vulnerable conditions. Fluorescence imaging and genetic deletion of a presynaptic Zn2+ transporter confirmed synaptic release as the primary contributor to extracellular accumulation and deleterious consequences of Zn2+ during SD. These results demonstrate a role for synaptic Zn2+ release in deleterious consequences of SD and show that targeted extracellular chelation could be useful for disorders where repetitive SD enlarges infarcts in injured tissues.
•Spreading depolarization (SD) can contribute to progression of acute brain injury.•We studied recovery from SD in brain slices, combined with metabolic compromise.•Spreading depolarizations release waves of synaptic Zn2+.•Rapid Zn2+ chelation improves functional and structural recovery following SD.•Targeting Zn2+ could complement existing glutamate-focused SD interventions.
Adenovirus infection in red squirrels Shuttleworth, C M; Everest, D J; Stidworthy, M F ...
Veterinary record,
12/2021, Letnik:
189, Številka:
11
Journal Article
Peatlands provide a range of ecosystem services but are sensitive to changes in climate and land-use, and many peatlands globally are degraded. We analyse a large-scale, unique and diverse dataset, ...collected over 15 years, as part of major landscape scale blanket peat restoration projects in the south Pennines, UK. Trajectories of ecosystem change after restoration were assessed by measuring key ecosystem responses including: vegetation cover and indicator species; water table, runoff, and water quality.
The reactions of these metrics vary in their behaviour, both in the timing of first response and the rate of change towards a new stable state. Re-establishment of vegetation is a key driver in rapidly reducing particulate carbon loss and attenuating stormflow, while over time biodiversity is improved by the return of native species, and water tables gradually rise. The phasing of these ecosystem service responses indicates that there are different characteristic timescales for the improvement of peatland functions, driven by both surface and subsurface processes. The rapid establishment of vegetation cover over two years, and its importance in improving a broad range of functions, signify it as a key milestone for reporting project success within typical funding timeframes.
This study supports the adoption of Lime-Fertiliser-Seed-Mulch restoration on eroding blanket peatlands globally. The trajectories developed are important to help guide practitioners of ecological restoration. Better understanding of the dynamics underpinning the slower response times of subsurface hydrological and biogeochemical function is identified as a key knowledge gap. An understanding of the limits of ecosystems recovery is important when target setting for restoration projects, especially where attaining pristine conditions is unachievable.
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•Ecosystem services show phased recovery following restoration in eroded peatlands.•Re-vegetation is key to reporting project success over short funding timeframes.•Results support wide-scale adoption of Lime-Seed-Fertiliser-Mulch restoration.
Spreading depolarization (SD), a pathologic feature of migraine, stroke and traumatic brain injury, is a propagating depolarization of neurons and glia causing profound metabolic demand. Adenosine, ...the low-energy metabolite of ATP, has been shown to be elevated after SD in brain slices and under conditions likely to trigger SD in vivo. The relationship between metabolic status and adenosine accumulation after SD was tested here, in brain slices and in vivo. In brain slices, metabolic impairment (assessed by nicotinamide adenine dinucleotide (phosphate) autofluorescence and O2 availability) was associated with prolonged extracellular direct current (DC) shifts indicating delayed repolarization, and increased adenosine accumulation. In vivo, adenosine accumulation was observed after SD even in otherwise healthy mice. As in brain slices, in vivo adenosine accumulation correlated with DC shift duration and increased when DC shifts were prolonged by metabolic impairment (i.e., hypoglycemia or middle cerebral artery occlusion). A striking pattern of adenosine dynamics was observed during focal ischemic stroke, with nearly all the observed adenosine signals in the periinfarct region occurring in association with SDs. These findings suggest that adenosine accumulation could serve as a biomarker of SD incidence and severity, in a range of clinical conditions.
Spreading depolarizations (SDs) are profound disruptions of cellular homeostasis that slowly propagate through gray matter and present an extraordinary metabolic challenge to brain tissue. Recent ...work has shown that SDs occur commonly in human patients in the neurointensive care setting and have established a compelling case for their importance in the pathophysiology of acute brain injury. The International Conference on Spreading Depolarizations (iCSD) held in Boca Raton, Florida, in September of 2018 included a discussion session focused on the question of “Which SDs are deleterious to brain tissue?” iCSD is attended by investigators studying various animal species including invertebrates, in vivo and in vitro preparations, diseases of acute brain injury and migraine, computational modeling, and clinical brain injury, among other topics. The discussion included general agreement on many key issues, but also revealed divergent views on some topics that are relevant to the design of clinical interventions targeting SDs. A draft summary of viewpoints offered was then written by a multidisciplinary writing group of iCSD members, based on a transcript of the session. Feedback of all discussants was then formally collated, reviewed and incorporated into the final document. It is hoped that this report will stimulate collection of data that are needed to develop a more nuanced understanding of SD in different pathophysiological states, as the field continues to move toward effective clinical interventions.
Peatlands are wetland ecosystems with great significance as natural habitats and as major global carbon stores. They have been subject to widespread exploitation and degradation with resulting losses ...in characteristic biota and ecosystem functions such as climate regulation. More recently, large-scale programmes have been established to restore peatland ecosystems and the various services they provide to society. Despite significant progress in peatland science and restoration practice, we lack a process-based understanding of how soil microbiota influence peatland functioning and mediate the resilience and recovery of ecosystem services, to perturbations associated with land use and climate change.
We argue that there is a need to: in the short-term, characterise peatland microbial communities across a range of spatial and temporal scales and develop an improved understanding of the links between peatland habitat, ecological functions and microbial processes; in the medium term, define what a successfully restored ‘target’ peatland microbiome looks like for key carbon cycle related ecosystem services and develop microbial-based monitoring tools for assessing restoration needs; and in the longer term, to use this knowledge to influence restoration practices and assess progress on the trajectory towards ‘intact’ peatland status.
Rapid advances in genetic characterisation of the structure and functions of microbial communities offer the potential for transformative progress in these areas, but the scale and speed of methodological and conceptual advances in studying ecosystem functions is a challenge for peatland scientists. Advances in this area require multidisciplinary collaborations between peatland scientists, data scientists and microbiologists and ultimately, collaboration with the modelling community.
Developing a process-based understanding of the resilience and recovery of peatlands to perturbations, such as climate extremes, fires, and drainage, will be key to meeting climate targets and delivering ecosystem services cost effectively.
•Although microbes are key to peatland function the underpinning processes are unclear.•Microbial characterisation is needed across a range of sites, depths and conditions.•Temporal and spatial changes in microbial communities need to be linked to functions.•Potential to use microbiome as a monitoring tool for peatland restoration progress•Enhancing microbial communities could improve peatland resilience.
Six new species of Fusarium associated with soil and plant hosts from ecosystems of minimal anthropogenic disturbance in Australia are described. Fusarium coicis from Coix gasteenii, F. goolgardi ...from Xanthorrhoea glauca, F. mundagurra from soil and Mangifera indica, F. newnesense from soil, F. tjaetaba from Sorghum interjectum and F. tjaynera from soil, Triodia microstachya, Sorghum interjectum and Sorghum intrans. Morphology and phylogenetic analysis of EF-1α, RPB1 and RPB2 sequence data were used to delineate species boundaries. The new species were phylogenetically distributed in the Fusarium sambucinum, F. fujikuroi, and F. chlamydosporum species complexes, and two novel species complexes. These six new species have particular phylogeographic significance as not only do they provide further insight into the geographic patterns of Fusarium evolution but also challenge current phylogeographic hypotheses.
Spermatogonial stem cells (SSCs) are at the foundation of mammalian spermatogenesis. Whereas rare A(single) spermatogonia comprise the rodent SSC pool, primate spermatogenesis arises from more ...abundant A(dark) and A(pale) spermatogonia, and the identity of the stem cell is subject to debate. The fundamental differences between these models highlight the need to investigate the biology of primate SSCs, which have greater relevance to human physiology. The alkylating chemotherapeutic agent, busulfan, ablates spermatogenesis in rodents and causes infertility in humans. We treated adult rhesus macaques with busulfan to gain insights about its effects on SSCs and spermatogenesis. Busulfan treatment caused acute declines in testis volume and sperm counts, indicating a disruption of spermatogenesis. One year following high-dose busulfan treatment, sperm counts remained undetectable, and testes were depleted of germ cells. Similar to rodents, rhesus spermatogonia expressed markers of germ cells (VASA, DAZL) and stem/progenitor spermatogonia (PLZF and GFRalpha1), and cells expressing these markers were depleted following high-dose busulfan treatment. Furthermore, fresh or cryopreserved germ cells from normal rhesus testes produced colonies of spermatogonia, which persisted as chains on the basement membrane of mouse seminiferous tubules in the primate to nude mouse xenotransplant assay. In contrast, testis cells from animals that received high-dose busulfan produced no colonies. These studies provide basic information about rhesus SSC activity and the impact of busulfan on the stem cell pool. In addition, the germ cell-depleted testis model will enable autologous/homologous transplantation to study stem cell/niche interactions in nonhuman primate testes.
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