Microglial morphology in the somatosensory cortex across lifespan. A quantitative study.

Microglia are long-lived cells that constantly monitor their microenvironment. To accomplish this task, they constantly change their morphology both in the short and long term under physiological conditions. This makes the process of quantifying physiological microglial morphology difficult. By using a semi-manual and a semi-automatic method to assess fine changes in cortical microglia morphology, we were able to quantify microglia changes in number, surveillance and branch tree starting from the fifth postnatal day to 2 years of life. We were able to identify a fluctuating behavior of most analyzed parameters characterized by a rapid cellular maturation, followed by a long period of relative stable morphology during the adult life with a final convergence to an aged phenotype. Detailed cellular arborization analysis revealed age-induced differences in microglia morphology, with mean branch length and the number of terminal processes changing constantly over time. Our study provides insight into microglia morphology changes across lifespan under physiological conditions. We were able to highlight, that due to the dynamic nature of microglia several morphological parameters are needed to establish the physiological state of these cells

Stem cell therapies in preclinical models of stroke. Is the aged brain microenvironment refractory to cell therapy?

© 2017.Stroke is a devastating disease demanding vigorous search for new therapies. Initial enthusiasm to stimulate restorative processes in the ischemic brain by means of cell-based therapies has meanwhile converted into a more balanced view recognizing impediments that may be related to unfavorable age-associated environments. Recent results using a variety of drug, cell therapy or combination thereof suggest that, (i) treatment with Granulocyte-Colony Stimulating Factor (G-CSF) in aged rats has primarily a beneficial effect on functional outcome most likely via supportive cellular processes such as neurogenesis; (ii) the combination therapy, G-CSF with mesenchymal cells (G-CSF + BM-MSC or G-CSF + BM-MNC) did not further improve behavioral indices, neurogenesis or infarct volume as compared to G-CSF alone in aged animals; (iii) better results with regard to integration of transplanted cells in the aged rat environment have been obtained using iPS of human origin; (iv) mesenchymal cells may be used as drug carriers for the aged post-stroke brains. Conclusion: While the middle aged brain does not seem to impair drug and cell therapies, in a real clinical practice involving older post-stroke patients, successful regenerative therapies would have to be carried out for a much longer time

Monomeric C-reactive protein and cerebral hemorrhage: From bench to bedside

© 2018 Di Napoli, Slevin, Popa-Wagner, Singh, Lattanzi and Divani. C-reactive protein (CRP) is an important mediator and a hallmark of the acute-phase response to inflammation. High-sensitivity assays that accurately measure levels of CRP have been recommended for use in risk assessment in ischemic stroke patients. Elevation of CRP during the acute-phase response in intracerebral hemorrhage (ICH) is also associated with the outcomes such as death and vascular complications. However, no association has been found with the increased risk of ICH. The aim of this review is to synthesize the published literature on the associations of CRP with acute ICH both as a risk biomarker and predictor of short- and long-term outcomes as well as its role as a pathogenic determinant. We believe before any clinical utility, a critical appraisal of the strengths and deficiencies of the accumulated evidence is required both to evaluate the current state of knowledge and to improve the design of future clinical studies

Electric Stimulation of Neurogenesis Improves Behavioral Recovery After Focal Ischemia in Aged Rats

© Copyright © 2020 Balseanu, Grigore, Pinosanu, Slevin, Hermann, Glavan and Popa-Wagner. The major aim of stroke therapies is to stimulate brain repair and to improve behavioral recuperation after cerebral ischemia. Despite remarkable advances in cell therapy for stroke, stem cell-based tissue replacement has not been achieved yet stimulating the search for alternative strategies for brain self-repair using the neurogenic zones of the brain, the dentate gyrus and the subventricular zone (SVZ). However, during aging, the potential of the hippocampus and the SVZ to generate new neuronal precursors, declines. We hypothesized that electrically stimulation of endogenous neurogenesis in aged rats could increase the odds of brain self-repair and improve behavioral recuperation after focal ischemia. Following stroke in aged animals, the rats were subjected to two sessions of electrical non-convulsive stimulation using ear-clip electrodes, at 7- and 24 days after MCAO. Animal were sacrificed after 48 days. We report that electrical stimulation (ES) stimulation of post-stroke aged rats led to an improved functional recovery of spatial long-term memory (T-maze) but not on the rotating pole or the inclined plane, both tests requiring complex sensorimotor skills. Surprisingly, ES had a detrimental effect on the asymmetric sensorimotor deficit. Histologically, there was a robust increase in the number of doublecortin-positive cells in the dentate gyrus and SVZ of the infarcted hemisphere and the presence of a considerable number of neurons expressing tubulin beta III in the infarcted area. Among the gene that were unique to ES, we noted increases in the expression of seizure related 6 homolog like which is one of the physiological substrate of the β-secretase BACE1 involved in the pathophysiology of the Alzheimer’s disease and Igfbp3 and BDNF receptor mRNAs which has been shown to have a neuroprotective effect after cerebral ischemia. However, ES was associated with a long-term down regulation of cortical gene expression after stroke in aged rats suggesting that gene expression in the peri-infarcted cortical area may not be related to electrical stimulation induced-neurogenesis in the subventricular zone and hippocampus

Repeated PTZ Treatment at 25-Day Intervals Leads to a Highly Efficient Accumulation of Doublecortin in the Dorsal Hippocampus of Rats

BACKGROUND: Neurogenesis persists throughout life in the adult mammalian brain. Because neurogenesis can only be assessed in postmortem tissue, its functional significance remains undetermined, and identifying an in vivo correlate of neurogenesis has become an important goal. By studying pentylenetetrazole-induced brain stimulation in a rat model of kindling we accidentally discovered that 25±1 days periodic stimulation of Sprague-Dawley rats led to a highly efficient increase in seizure susceptibility. METHODOLOGY/PRINCIPAL FINDINGS: By EEG, RT-PCR, western blotting and immunohistochemistry, we show that repeated convulsive seizures with a periodicity of 25±1 days led to an enrichment of newly generated neurons, that were BrdU-positive in the dentate gyrus at day 25±1 post-seizure. At the same time, there was a massive increase in the number of neurons expressing the migratory marker, doublecortin, at the boundary between the granule cell layer and the polymorphic layer in the dorsal hippocampus. Some of these migrating neurons were also positive for NeuN, a marker for adult neurons. CONCLUSION/SIGNIFICANCE: Our results suggest that the increased susceptibility to seizure at day 25±1 post-treatment is coincident with a critical time required for newborn neurons to differentiate and integrate into the existing hippocampal network, and outlines the importance of the dorsal hippocampus for seizure-related neurogenesis. This model can be used as an in vivo correlate of neurogenesis to study basic questions related to neurogenesis and to the neurogenic mechanisms that contribute to the development of epilepsy

HIV-associated neurocognitive disorders.

Currently, neuropsychological impairment among HIV+ patients on antiretroviral therapy leads to a reduction in the quality of life and it is an important challenge due to the high prevalence of HIV-associated neurocognitive disorders and its concomitant consequences in relation to morbidity and mortality- including those HIV+ patients with adequate immunological and virological status. The fact that the virus is established in CNS in the early stages and its persistence within the CNS can help us to understand HIV-related brain injury even when highly active antiretroviral therapy is effective. The rising interest in HIV associated neurocognitive disorders has let to development new diagnostic tools, improvement of the neuropsychological tests, and the use of new biomarkers and new neuroimaging techniques that can help the diagnosis. Standardization and homogenization of neurocognitive tests as well as normalizing and simplification of easily accessible tools that can identify patients with increased risk of cognitive impairment represent an urgent requirement. Future efforts should also focus on diagnostic keys and searching for useful strategies in order to decrease HIV neurotoxicity within the CNS

Search for muon-neutrino emission from GeV and TeV gamma-ray flaring blazars using five years of data of the ANTARES telescope

The ANTARES telescope is well-suited for detecting astrophysical transient neutrino sources as it can observe a full hemisphere of the sky at all times with a high duty cycle. The background due to atmospheric particles can be drastically reduced, and the point-source sensitivity improved, by selecting a narrow time window around possible neutrino production periods. Blazars, being radio-loud active galactic nuclei with their jets pointing almost directly towards the observer, are particularly attractive potential neutrino point sources, since they are among the most likely sources of the very high-energy cosmic rays. Neutrinos and gamma rays may be produced in hadronic interactions with the surrounding medium. Moreover, blazars generally show high time variability in their light curves at different wavelengths and on various time scales. This paper presents a time-dependent analysis applied to a selection of flaring gamma-ray blazars observed by the FERMI/LAT experiment and by TeV Cherenkov telescopes using five years of ANTARES data taken from 2008 to 2012. The results are compatible with fluctuations of the background. Upper limits on the neutrino fluence have been produced and compared to the measured gamma-ray spectral energy distribution.Comment: 27 pages, 16 figure

The Antares Collaboration : Contributions to the 34th International Cosmic Ray Conference (ICRC 2015, The Hague)

The ANTARES detector, completed in 2008, is the largest neutrino telescope in the Northern hemisphere. Located at a depth of 2.5 km in the Mediterranean Sea, 40 km off the Toulon shore, its main goal is the search for astrophysical high energy neutrinos. In this paper we collect the 21 contributions of the ANTARES collaboration to the 34th International Cosmic Ray Conference (ICRC 2015). The scientific output is very rich and the contributions included in these proceedings cover the main physics results, ranging from steady point sources, diffuse searches, multi-messenger analyses to exotic physics

Status and Recent Results of the Acoustic Neutrino Detection Test System AMADEUS

The AMADEUS system is an integral part of the ANTARES neutrino telescope in the Mediterranean Sea. The project aims at the investigation of techniques for acoustic neutrino detection in the deep sea. Installed at a depth of more than 2000m, the acoustic sensors of AMADEUS are based on piezo-ceramics elements for the broad-band recording of signals with frequencies ranging up to 125kHz. AMADEUS was completed in May 2008 and comprises six "acoustic clusters", each one holding six acoustic sensors that are arranged at distances of roughly 1m from each other. The clusters are installed with inter-spacings ranging from 15m to 340m. Acoustic data are continuously acquired and processed at a computer cluster where online filter algorithms are applied to select a high-purity sample of neutrino-like signals. 1.6 TB of data were recorded in 2008 and 3.2 TB in 2009. In order to assess the background of neutrino-like signals in the deep sea, the characteristics of ambient noise and transient signals have been investigated. In this article, the AMADEUS system will be described and recent results will be presented.Comment: 7 pages, 8 figures. Proceedings of ARENA 2010, the 4th International Workshop on Acoustic and Radio EeV Neutrino Detection Activitie

Attenuated Inflammatory Response in Aged Mice Brains following Stroke

Background: Increased age is a major risk factor for stroke incidence, post-ischemic mortality, and severe and long-term disability. Stroke outcome is considerably influenced by post-ischemic mechanisms. We hypothesized that the inflammatory response following an ischemic injury is altered in aged organisms. Methods and Results: To that end, we analyzed the expression pattern of pro-inflammatory cytokines (TNF, IL-1a, IL-1b, IL-6), anti-inflammatory cytokines (IL-10, TGFb1), and chemokines (Mip-1a, MCP-1, RANTES) of adult (2 months) and aged (24 months) mice brains at different reperfusion times (6 h, 12 h, 24 h, 2 d, 7 d) following transient occlusion of the middle cerebral artery. The infarct size was assessed to monitor possible consequences of an altered inflammatory response in aged mice. Our data revealed an increased neuro-inflammation with age. Above all, we found profound age-related alterations in the reaction to stroke. The response of pro-inflammatory cytokines (TNF, and IL-1b) and the level of chemokines (Mip-1a, and MCP-1) were strongly diminished in the aged post-ischemic brain tissue. IL-6 showed the strongest age-dependent decrease in its post-ischemic expression profile. Anti-inflammatory cytokines (TGFb1, and IL-10) revealed no significant age dependency after ischemia. Aged mice brains tend to develop smaller infarcts. Conclusion: The attenuated inflammatory response to stroke in aged animals may contribute to their smaller infarcts. The results presented here highlight the importance of using aged animals to investigate age-associated diseases like stroke