The spectrum of Ischemia-induced white matter injury varies with age

Stroke is a neurological condition that targets the whole range of the human population, from the pre-term infant to the elderly and is a major cause of death worldwide (Ingall 2004). During its lifespan, the brain's vulnerability to hypoxia-ischemia varies. Term infants who suffer this insult usually exhibit widespread neuronal injury in the cerebral cortex with a stroke-like distribution of damage (Deng 2008), whereas in pre-term infants immature oligodendrocytes and subplate neurons below the neocortex are most vulnerable and result in Periventricular Leukomalacia (PVL) (Back et al. 2007; McQuillen et al. 2005). The incidence of stroke decreases in young adulthood, but peaks again in the elderly. Moreover, the underlying pathological mechanisms that occur following ischemia are different at each stage. Experimental stroke research on stroke has traditionally focused on grey matter injury, but recent evidence indicates that white matter injury is a critical part of its pathophysiology. In this debilitating condition the mechanisms of ischemia-induced damage differ with age and all cellular components of white matter (axons, oligodendrocytes and astrocytes) are affected. This review paper focuses on the relative vulnerability to ischemia of white matter during the course of development and on our recent findings of how individual cellular components are affected during each stage.peer-reviewe

L-lactate reduces ischemic white matter injury and modulates HCA1 oligodendrocyte expression in an in vivo mouse model of focal ischemia

L-lactate is a metabolite that is oxidized preferentially to glucose under conditions of high metabolic stress. The discovery and localization of the lactate receptor HCA1 in various brain regions suggests that lactate is additionally an important signaling molecule in the brain. Lactate is neuroprotective in various ischemia paradigms, reduces axonal injury in vitro and is avidly utilized by oligodendrocytes (OLs). The protective potential of L-lactate to reduce white matter (WM) injury in a mouse stroke model was investigated.N/

Two-photon microscopy : sequential imaging studies in vivo

Microscopists have always desired to look inside various organ tissues to study structure, function and dysfunction of their cellular constituents. In the past, this has frequently required tissue extraction and histological preparation to gain access. Traditional optical microscopy techniques, which use linear (one-photon) absorption processes for contrast generation, are limited to use near the tissue surface (< 80 µm) because at greater depths strong and multiple light scattering blurs the images. Scattering particularly strongly affects signal strength in confocal microscopy, which achieves three-dimensional resolution and optical sectioning with a detection pinhole that rejects all light that appears not to originate from the focus. New optical microscopy techniques have been developed that use nonlinear light-matter interactions to generate signal contrast only within a thin raster-scanned plane. Since its first demonstration over a decade ago, two-photon microscopy has been applied to a variety of imaging tasks and has now become the technique of choice for fluorescence microscopy in thick tissue preparations and in live animals. The gain in resolution over conventional in vivo imaging techniques has been several orders of magnitude. Neuroscientists have used it to measure calcium dynamics deep in brain slices and in live animals, blood flow measurement, neuronal plasticity and to monitor neurodegenerative disease models in brain slices and in live rodents. These types of applications define the most important niche for two-photon microscopy - high-resolution imaging of physiology, morphology and cell-cell interactions in intact tissue. Clearly the biggest advantage of two-photon microscopy is in longitudinal monitoring of rodent models of disease or plasticity over days to weeks. The aim of this article is to discuss some methodological principles, and show some applications of this technique obtained from our laboratory in the area of acute experimental stroke research.peer-reviewe

Vulnerability of white matter to ischemia varies during development

Stroke is the one of the leading causes of mortality and morbidity in developed countries. The central role of injury to white matter in the pathophysiology of stroke has been recognised over the recent years. Stroke can affect a wide range of the population (from the premature infant to the elderly) and therefore the mechanism of injury of central white matter may vary with age. The main aim of this review paper is to shed some light on the difference in maturation of injury to the axon-oligodendrocyte unit following an ischemic insult between different developmental stages. Both components of this unit exhibit varying degrees of susceptibility to ischemia throughout their development. Axons are particularly resistant to ischemia in the neonatal stage. However, they show a marked decreased in tolerance to ischemia during the period of myelination. Late oligodendrocyte progenitor cells (OPC) are the most sensitive type of oligodendrocyte, and their role in periventricular leukomalacia (PVL) is well known. On the other hand, early OPC are particularly resistant to ischemia. Studying the effect of ischemia on white matter in the brain during the different developmental stages will lead to a better understanding of the pathophysiology of white matter injury and hopefully, in the future, to the development of new therapeutic strategies of the various white matter diseases.peer-reviewe

Lateral Habenula contribution in Nicotine addiction : focus on Dopamine, GABA and Serotonin Interactions

Compelling evidence has shown a pivotal role of dopaminergic function in drug addiction. Recently, the Habenula (Hb) has attracted a great deal of attention as another target for nicotine in the brain because of its role in regulating dopamine (DA), gamma-aminobutyric acid (GABA) and serotonin (5-HT) systems. Nicotine acts binding to acetylcholine receptors that are widely distributed in the brain. Interestingly, the receptor subtypes that mediate nicotine withdrawal responses are highly expressed in the Hb. Moreover, the block of habenular nicotinic receptors in animals chronically treated with nicotine enhances withdrawal responses once nicotine is discontinued. Furthermore, it has been shown how a high dose of nicotine can cause massive degeneration almost exclusively in the medial habenula (MHb) and its output tract, the fasciculus retroflexus. Thus, symptoms associated with nicotine withdrawal may be caused by dysfunctions of the Hb output. Therefore, Hb might be of fundamental importance in the expression of nicotine reinforcing properties and withdrawal. Here, we will focus on the role of the lateral habenula (LHb) on nicotine modulation of DA function and we will evaluate LHb interaction with the rostromedial tegmental nucleus (RMTg), a GABAergic area, and the serotonergic raphé nuclei. Furthermore, as LHb has high density expression of 5-HT2C receptors, these subtypes might be important in the control of its neuronal activity and output to the midbrain monoaminergic and GABAergic systems.peer-reviewe

The central role of aquaporins in the pathophysiology of ischemic stroke

Stroke is a complex and devastating neurological condition with limited treatment options. Brain edema is a serious complication of stroke. Early edema formation can significantly contribute to infarct formation and thus represents a promising target. Aquaporin (AQP) water channels contribute to water homeostasis by regulating water transport and are implicated in several disease pathways. At least 7 AQP subtypes have been identified in the rodent brain and the use of transgenic mice has greatly aided our understanding of their functions. AQP4, the most abundant channel in the brain, is up-regulated around the peri-infarct border in transient cerebral ischemia and AQP4 knockout mice demonstrate significantly reduced cerebral edema and improved neurological outcome. In models of vasogenic edema, brain swelling is more pronounced in AQP4-null mice than wild-type providing strong evidence of the dual role of AQP4 in the formation and resolution of both vasogenic and cytotoxic edema. AQP4 is co-localized with inwardly rectifying K+-channels (Kir4.1) and glial K+ uptake is attenuated in AQP4 knockout mice compared to wild-type, indicating some form of functional interaction. AQP4-null mice also exhibit a reduction in calcium signaling, suggesting that this channel may also be involved in triggering pathological downstream signaling events. Associations with the gap junction protein Cx43 possibly recapitulate its role in edema dissipation within the astroglial syncytium. Other roles ascribed to AQP4 include facilitation of astrocyte migration, glial scar formation, modulation of inflammation and signaling functions. Treatment of ischemic cerebral edema is based on the various mechanisms in which fluid content in different brain compartments can be modified. The identification of modulators and inhibitors of AQP4 offer new therapeutic avenues in the hope of reducing the extent of morbidity and mortality in stroke.peer-reviewe

A Comparison of Agricultural and Urban influences on Water Quality in South West WA

In Western Australia, a number of coastal rivers and estuaries have suffered from eutrophication since the 1960’s. Often the focus of the threat to water quality in these areas has been agriculture because of its extensive nature and widespread use of highly soluble fertilisers. Over recent years a focus on nutrient inputs, outputs and nutrient balance in a number of projects provides an opportunity to compare the relative nutrient threats from the agricultural and urban sectors, placed in the context of increasing urbanisation and development. These disparate data sets also allow a comparison of nutrient inputs in each sector in the form of fertiliser and non-fertiliser sources, and show how these translate into whole of catchment nutrient inputs, transformations and exports to waterways. These sets of data also provide some insight into the adoption of management practices in each sector, and the relative threats to water quality from each sector on the basis of its location in a catchment

Remote learning and examination based on augmented reality

Remote Learning and Examination based on Augmented Reality (RELAR) is a European Erasmus+ project (2020-1-NL01-KA226-VET-083043) that aims to create a crisis-proof resilient education environment, enabling remote coaching and digital skills training based on AR. RELAR integrates seven European partners –Vocational Training Institutions and Higher Education Institutions– all linked to the maritime industry. The industry itself is also represented. With the help of a reference group, a set of learning outcomes has been defined to develop three demo scenarios to test and demonstrate the RELAR system, which is based on the RealWear HMT-1 assisted reality hands-free computer. All scenarios are scaffolded on the same framework that integrates active learning pedagogy, curriculum requirements and technological integration. This digital active learning process pedagogy incorporates two processes for instruction: a remote instruction process called ‘Expert Coaching’ that gives the students the possibility of receiving instant feedback while taking actions and decisions; and a remote assessment process named ‘Digital Workflow’ that incorporates formative assessment to consolidate learning. The curricular aspect focuses on the professional competencies students will acquire, the expected learning outcomes, the required knowledge, and the transferable skills required by students to perform professionally. Finally, technological integration describes how and when the assisted reality system should be incorporated to add value to the learning process. This paper describes the work in the learning spaces currently under development by the partnership based on the same methodological and pedagogical foundations

Two-step closure of the Miocene Indian Ocean Gateway to the Mediterranean

The Tethys Ocean was compartmentalized into the Mediterranean Sea and Indian Ocean during the early Miocene, yet the exact nature and timing of this disconnection are not well understood. Here we present two new neodymium isotope records from isolated carbonate platforms on both sides of the closing seaway, Malta (outcrop sampling) and the Maldives (IODP Site U1468), to constrain the evolution of past water mass exchange between the present day Mediterranean Sea and Indian Ocean via the Mesopotamian Seaway. Combining these data with box modeling results indicates that water mass exchange was reduced by similar to 90% in a first step at ca. 20 Ma. The terminal closure of the seaway then coincided with the sea level drop caused by the onset of permanent glaciation of Antarctica at ca. 13.8 Ma. The termination of meridional water mass exchange through the Tethyan Seaway resulted in a global reorganization of currents, paved the way to the development of upwelling in the Arabian Sea and possibly led to a strengthening of South Asian Monsoon