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Studies by Bruce Ransom and colleagues have made a major contribution to show that white matter is susceptible to ischemia/hypoxia. White matter contains axons and the glia that support them, notably myelinating oligodendrocytes, which are highly vulnerable to ischemic-hypoxic damage. Previous studies have shown that metabotropic GluRs (mGluRs) are cytoprotective for oligodendrocyte precursor cells and immature oligodendrocytes, but their potential role in adult white matter was unresolved. Here, we report that group 1 mGluR1/5 and group 2 mGluR3 subunits are expressed in optic nerves from mice aged postnatal day (P)8–12 and P30–35. We demonstrate that activation of group 1 mGluR protects oligodendrocytes against oxygen-glucose deprivation (OGD) in developing and young adult optic nerves. In contrast, group 2 mGluR are shown to be protective for oligodendrocytes against OGD in postnatal but not young adult optic nerves. The cytoprotective effect of group 1 mGluR requires activation of PKC, whilst group 2 mGluR are dependent on negatively regulating adenylyl cyclase and cAMP. Our results identify a role for mGluR in limiting injury of oligodendrocytes in developing and young adult white matter, which may be useful for protecting oligodendrocytes in neuropathologies involving excitoxicity and ischemia/hypoxia.

Cerebral blood flow is highly sensitive to changes in CO2/H+ where an increase in CO2/H+ causes vasodilation and increased blood flow. Tissue CO2/H+ also functions as the main stimulus for breathing by activating chemosensitive neurons that control respiratory output. Considering that CO2/H+-induced vasodilation would accelerate removal of CO2/H+ and potentially counteract the drive to breathe, we hypothesize that chemosensitive brain regions have adapted a means of preventing vascular CO2/H+-reactivity. Here, we show in rat that purinergic signaling, possibly through P2Y2/4 receptors, in the retrotrapezoid nucleus (RTN) maintains arteriole tone during high CO2/H+ and disruption of this mechanism decreases the CO2ventilatory response. Our discovery that CO2/H+-dependent regulation of vascular tone in the RTN is the opposite to the rest of the cerebral vascular tree is novel and fundamentally important for understanding how regulation of vascular tone is tailored to support neural function and behavior, in this case the drive to breathe. We breathe to help us take oxygen into the body and remove carbon dioxide. Our cells use the oxygen to break down food to release energy, and as they do so they produce carbon dioxide as a waste product. Cells release this carbon dioxide back into the bloodstream so that it can be transported to the lungs to be breathed out. Carbon dioxide also makes the blood more acidic; if the blood becomes too acidic, tissues and organs may not work properly. The brain uses roughly 25% of the oxygen consumed by the body and is particularly sensitive to the levels of gases and acidity in the blood. It has been known for more than a century that increased carbon dioxide causes blood vessels in the brain to widen, allowing the excess carbon dioxide to be carried away quickly. More recent work has shown that increased carbon dioxide also activates neurons called respiratory chemoreceptors. These in turn activate the brain centers that drive breathing, causing us to breathe more rapidly to help us remove surplus carbon dioxide. But this scenario contains a paradox. If high levels of carbon dioxide cause widening of the blood vessels in the brain regions that contain respiratory chemoreceptors, this should, in theory, wash out that important stimulus, reducing the drive to breathe. So how does the brain prevent this unhelpful response? By studying the brains of adult rats, Hawkins et al. show that different rules apply to the brain centers that control breathing compared to other areas of the brain. In one such region, if the blood becomes too acidic, support cells called astrocytes release chemical signals called purines. This counteracts the tendency of high carbon dioxide levels to widen blood vessels in this region, and instead causes these vessels to become narrower. This mechanism ensures that local levels of carbon dioxide in respiratory brain centers remain in tune with the demands of local networks, thereby maintaining the drive to breathe. The next challenges are to identify the molecular mechanisms that control the diameter of blood vessels in brain regions containing respiratory chemoreceptors, and to find out whether drugs that modulate these mechanisms have the potential to treat some respiratory conditions.

Astrocytes in the retrotrapezoid nucleus (RTN) stimulate breathing in response to CO 2 /H + , however, it is not clear how these cells detect changes in CO 2 /H + . Considering Kir4.1/5.1 channels are CO 2 /H + -sensitive and important for several astrocyte-dependent processes, we consider Kir4.1/5.1 a leading candidate CO 2 /H + sensor in RTN astrocytes. To address this, we show that RTN astrocytes express Kir4.1 and Kir5.1 transcripts. We also characterized respiratory function in astrocyte-specific inducible Kir4.1 knockout mice (Kir4.1 cKO); these mice breathe normally under room air conditions but show a blunted ventilatory response to high levels of CO 2 , which could be partly rescued by viral mediated re-expression of Kir4.1 in RTN astrocytes. At the cellular level, astrocytes in slices from astrocyte-specific inducible Kir4.1 knockout mice are less responsive to CO 2 /H + and show a diminished capacity for paracrine modulation of respiratory neurons. These results suggest Kir4.1/5.1 channels in RTN astrocytes contribute to respiratory behavior. Inducible deletion of Kir4.1 channels from astrocytes blunts the CO2/H + -dependent drive to breathe at the cellular and whole animal level in mice

Background: Obstructive sleep apnea (OSA) is highly prevalent in the early stages of Alzheimer’s disease (AD), and its hallmark, sleep fragmentation, may accelerate cognitive decline. Continuous positive airway pressure (CPAP) improves OSA-related hypoxia during slow-wave sleep, but its cognitive benefits in AD remain unclear. Methods: We performed a 12-month sub-analysis of a prospective, longitudinal pilot study that enrolled 21 adults (median age = 77 yr; 71% women) with Mild Cognitive Impairment (MCI) with AD confirmed biomarkers and polysomnography-diagnosed OSA. All participants underwent baseline overnight polysomnography (PSG) and neuropsychological testing (Clinical Dementia Rating (CDR), Mini-Mental State Examination (MMSE), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)) that were repeated after 12 months. Twelve participants were CPAP-compliant (moderate/severe OSA) and nine were non-users (mild OSA/intolerance). Cognitive change scores (Δ = 12 months -baseline) were compared with Generalized Linear Models (GLM) adjusted for baseline cognition and Apnea–Hypopnea Index (AHI); associations between baseline sleep parameters and cognitive trajectories were examined. And the association of sleep variables with the use of CPAP was also evaluated. Results: Compared with non-users, CPAP users showed significantly slower global decline (Δ MMSE: p = 0.016) and improvements in overall cognition (Δ RBANS Total: p = 0.028) and RBANS sub-domains (Δ RBANS FC: p = 0.010; Δ RBANS SF: p = 0.045). Longer baseline non-rapid eye movement (NREM) stage 3 and rapid eye movement (REM) sleep, greater total sleep time and sleep efficiency, and right-side sleeping were each linked to better cognitive outcomes, whereas extended NREM stage 2, wakefulness, and supine sleeping were associated with poorer trajectories. Conclusions: Twelve months of CPAP use was associated with attenuated cognitive decline and domain-specific gains in AD-related MCI with OSA. Sleep architecture and body position during sleep predicted cognitive outcomes, underscoring the therapeutic relevance of optimizing breathing and sleep quality. Larger, longer-term trials are warranted to confirm CPAP’s disease-modifying potential and to clarify the mechanistic role of sleep in AD progression.

IntroductionIschaemic stroke, and subsequent reperfusion injury is a multicellular process, with limited treatment options. The successful translation of novel therapies is currently hampered by the lack of existing cellular models that reflect human disease and consider the multicellular nature of ischaemic stroke. In this project we developed a simple, cost effective and adaptable model of the human neurovascular unit, that is compatible with flow to enable the pathological basis of ischaemic stroke and neuroinflammation to be investigated. The model also offers a novel non-animal-based platform to identify and test novel therapeutic strategies for the treatment and prevention of ischaemic stroke and reperfusion injury.AimsTo characterise the role of activated platelets and inflammatory mediators on cells of the neurovascular unit to assess their involvement in ischemic reperfusion injury.MethodMonocultures of human microglia (HMC-3), astrocyte-like glioma (U87) and microvascular endothelial cells (hCMECs/D3) were treated with activated platelet releasate, and cell activation, proliferation, migration, and survival were monitored. Human washed platelet releasate was prepared by centrifugation.Quantitative PCR (qPCR) in the presence of SYBR Green I was performed using CFX PCR system.High resolution 3D imagingHMC-3 (Red), U87 (green) and HMEC/D3 (Blue) were incubated with cell tracker in serum free media for 30 minutes. HMC-3 and U87 were seeded within a 1.5 mg.ml collagen rat tail matrix in a microfluidic chamber. HMEC/D3 cell line was seeded on top of the collagen matrix within the fluid chamber. 3D Z stack images taken with Stellaris 5 Confocal microscope.Results/ConclusionTreatment of the different neurovascular cell types with hypoxia, TNFα and platelet releasate were also found to alter expression of key mediators of neuroinflammation (IL-1B, IL-6) and thrombosis (vWF and CD39) alongside targets of interest for the research team (LXRα, LXRβ, Pim-1, Pim-2, Pim-3 and SIRT1, P2Y2), identifying potential roles for these mediators in the regulation of neuroinflammation following ischaemic stroke and reperfusion injury.Conflict of InterestAbstract from work I did in previous PDRA. I have approval to submit

Astrocytes in the retrotrapezoid nucleus (RTN) stimulate breathing in response to CO /H , however, it is not clear how these cells detect changes in CO /H . Considering Kir4.1/5.1 channels are CO /H -sensitive and important for several astrocyte-dependent processes, we consider Kir4.1/5.1 a leading candidate CO /H sensor in RTN astrocytes. To address this, we show that RTN astrocytes express Kir4.1 and Kir5.1 transcripts. We also characterized respiratory function in astrocyte-specific inducible Kir4.1 knockout mice (Kir4.1 cKO); these mice breathe normally under room air conditions but show a blunted ventilatory response to high levels of CO , which could be partly rescued by viral mediated re-expression of Kir4.1 in RTN astrocytes. At the cellular level, astrocytes in slices from astrocyte-specific inducible Kir4.1 knockout mice are less responsive to CO /H and show a diminished capacity for paracrine modulation of respiratory neurons. These results suggest Kir4.1/5.1 channels in RTN astrocytes contribute to respiratory behavior.

Landscape ecology is recognised as a valuable basis for landscape planning in many countries. It has, hitherto, remained largely unknown to British planners. The increasing emphasis on the importance of planning for the 'wider countryside' and the move away from site based nature conservation in this country has lead to the recognition that there are a lack of tools for integrated land use planning currently available to British planners. This study aims to explore the nature of landscape ecology, its principles and application, to assess the transferability of existing approaches to the application of the discipline and evaluate its potential for landscape planning in this country. The first stage of the research involved the systematic analysis of international landscape ecological literature to determine the main principles and approaches to the application of the discipline. Discrete approaches to application were identified from the literature and three were selected for application in a case study area in Britain.The results of the indicative plans produced by application of the approaches to the Sherwood Forest Study Area were then evaluated by two expert panels; one comprising land use planners local to the study area, the second comprising national scientific experts. The research has found that distinct and different approaches to the application of landscape ecology can be identified and are potentially transferable, with some modifications, to other contexts. No one approach provided an optimum plan, but all had some degree of validity, indicating the possibility of developing 'off the shelf' solutions to landscape planning problems. Landscape ecology was perceived not only as having the potential to provide a toolkit for land use planners for planning in the 'wider countryside' but also as having a potentially important role in developing a dialogue between planning and science. Ongoing research into the scientific principles of the discipline and its applications and the education of politicians and planners are now required to firmly establish landscape ecology as an effective tool for landscape planning.

Virginia Hawkins of the Somerset section of Franklin is a member of the Sisters Network of Central New Jersey, a support group for African-American breast cancer survivors.\\n

I spend 40 hours a week working within the system to help men and women with HIV/AIDS find a safe place to live.