Microcircuits of excitatory and inhibitory neurons in layer 2/3 of mouse barrel cortex

Avermann M, Tomm C, Mateo C, Gerstner W, Petersen CC. Microcircuits of excitatory and inhibitory neurons in layer 2/3 of mouse barrel cortex. J Neurophysiol 107: 3116-3134, 2012. First published March 7, 2012; doi:10.1152/jn.00917.2011.-Synaptic interactions between nearby excitatory and inhibitory neurons in the neocortex are thought to play fundamental roles in sensory processing. Here, we have combined optogenetic stimulation, whole cell recordings, and computational modeling to define key functional microcircuits within layer 2/3 of mouse primary somatosensory barrel cortex. In vitro optogenetic stimulation of excitatory layer 2/3 neurons expressing channelrhodopsin-2 evoked a rapid sequence of excitation followed by inhibition. Fast-spiking (FS) GABAergic neurons received large-amplitude, fast-rising depolarizing postsynaptic potentials, often driving action potentials. In contrast, the same optogenetic stimulus evoked small-amplitude, subthreshold postsynaptic potentials in excitatory and non-fast-spiking (NFS) GABAergic neurons. To understand the synaptic mechanisms underlying this network activity, we investigated unitary synaptic connectivity through multiple simultaneous whole cell recordings. FS GABAergic neurons received unitary excitatory postsynaptic potentials with higher probability, larger amplitudes, and faster kinetics compared with NFS GABAergic neurons and other excitatory neurons. Both FS and NFS GABAergic neurons evoked robust inhibition on postsynaptic layer 2/3 neurons. A simple computational model based on the experimentally determined electrophysiological properties of the different classes of layer 2/3 neurons and their unitary synaptic connectivity accounted for key aspects of the network activity evoked by optogenetic stimulation, including the strong recruitment of FS GABAergic neurons acting to suppress firing of excitatory neurons. We conclude that FS GABAergic neurons play an important role in neocortical microcircuit function through their strong local synaptic connectivity, which might contribute to driving sparse coding in excitatory layer 2/3 neurons of mouse barrel cortex in vivo

Do Damped and Sub-damped Lyman-alpha Absorbers Arise in Galaxies of Different Masses?

We consider the questions of whether the damped Lyman-alpha (DLA) and sub-DLA absorbers in quasar spectra differ intrinsically in metallicity, and whether they could arise in galaxies of different masses. Using the recent measurements of the robust metallicity indicators Zn and S in DLAs and sub-DLAs, we confirm that sub-DLAs have higher mean metallicities than DLAs, especially at $z \lesssim 2$. We find that the intercept of the metallicity-redshift relation derived from Zn and S is higher than that derived from Fe by 0.5-0.6 dex. We also show that, while there is a correlation between the metallicity and the rest equivalent width of Mg II $\lambda 2796$ or Fe II $\lambda 2599$ for DLAs, no correlation is seen for sub-DLAs. Given this, and the similar Mg II or Fe II selection criteria employed in the discovery of both types of systems at lower redshifts, the difference between metallicities of DLAs and sub-DLAs appears to be real and not an artefact of selection. This conclusion is supported by our simulations of Mg II $\lambda 2796$ and Fe II $\lambda 2599$ lines for a wide range of physical conditions. On examining the velocity spreads of the absorbers, we find that sub-DLAs show somewhat higher mean and median velocity spreads ($\Delta v$), and an excess of systems with $\Delta v > 150$ km s$^{-1}$, than DLAs. Compared to DLAs, the [Mn/Fe] vs. [Zn/H] trend for sub-DLAs appears to be steeper and closer to the trend for Galactic bulge and thick disk stars, possibly suggesting different stellar populations. The absorber data appear to be consistent with galaxy down-sizing. The data are also consistent with the relative number densities of low-mass and high-mass galaxies. It is thus plausible that sub-DLAs arise in more massive galaxies on average than DLAs.Comment: 27 pages, 5 figures, 4 tables. Accepted for publication in New Astronom

Search for 511 keV Emission in Satellite Galaxies of the Milky Way with INTEGRAL/SPI

Reproduced with permission from Astronomy & Astrophysics. © 2018 ESO.The positron annihilation gamma-ray signal in the Milky Way (MW) shows a puzzling morphology: a very bright bulge and a very low surface-brightness disk. A coherent explanation of the positron origin, propagation through the Galaxy and subsequent annihilation in the interstellar medium has not yet been found. Tentative explanations involve positrons from radioactivity, X-ray binaries, and dark matter (DM). Dwarf satellite galaxies (DSGs) are believed to be DM-dominated and hence promising candidates in the search for 511 keV emission as a result of DM annihilation into electron-positron pairs. The goal of this study is to constrain possible 511 keV gamma-ray signals from 39 DSGs of the MW and to test the annihilating DM scenario. We use the spectrometer SPI on INTEGRAL to extract individual spectra for the studied objects. As the diffuse galactic emission dominates the signal, the large scale morphology of the MW has been modelled accordingly and was included in a maximum likelihood analysis. Alternatively, a distance-weighted stacked spectrum has been determined. Only Reticulum II (Ret II) shows a 3.1 sigma signal. Five other sources show tentative 2 sigma signals. The mass-to-511-keV-luminosity-ratio shows a marginal trend towards higher values for intrinsically brighter objects, opposite to the V band mass-to-light-ratio, which is generally used to uncover DM in DSGs. All derived flux values are above the level implied by a DM interpretation of the MW bulge signal. The signal from Ret II is unlikely to be related to a DM origin alone, otherwise, the MW bulge would be about 100 times brighter than what is seen. Ret II is exceptional considering the DSG sample, and rather points to enhanced recent star formation activity, if its origins are similar to processes in the MW. Understanding this emission may provide further clues regarding the origin of the annihilation emission in the MW.Peer reviewe

Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background Global development goals increasingly rely on country-specific estimates for benchmarking a nation's progress. To meet this need, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 estimated global, regional, national, and, for selected locations, subnational cause-specific mortality beginning in the year 1980. Here we report an update to that study, making use of newly available data and improved methods. GBD 2017 provides a comprehensive assessment of cause-specific mortality for 282 causes in 195 countries and territories from 1980 to 2017. Methods The causes of death database is composed of vital registration (VR), verbal autopsy (VA), registry, survey, police, and surveillance data. GBD 2017 added ten VA studies, 127 country-years of VR data, 502 cancer-registry country-years, and an additional surveillance country-year. Expansions of the GBD cause of death hierarchy resulted in 18 additional causes estimated for GBD 2017. Newly available data led to subnational estimates for five additional countries Ethiopia, Iran, New Zealand, Norway, and Russia. Deaths assigned International Classification of Diseases (ICD) codes for non-specific, implausible, or intermediate causes of death were reassigned to underlying causes by redistribution algorithms that were incorporated into uncertainty estimation. We used statistical modelling tools developed for GBD, including the Cause of Death Ensemble model (CODErn), to generate cause fractions and cause specific death rates for each location, year, age, and sex. Instead of using UN estimates as in previous versions, GBD 2017 independently estimated population size and fertility rate for all locations. Years of life lost (YLLs) were then calculated as the sum of each death multiplied by the standard life expectancy at each age. All rates reported here are age-standardised. Findings At the broadest grouping of causes of death (Level 1), non-communicable diseases (NC Ds) comprised the greatest fraction of deaths, contributing to 73.4% (95% uncertainty interval [UI] 72.5-74.1) of total deaths in 2017, while communicable, maternal, neonatal, and nutritional (CMNN) causes accounted for 186% (17.9-19.6), and injuries 8.0% (7.7-8.2). Total numbers of deaths from NCD causes increased from 2007 to 2017 by 22.7% (21.5-23.9), representing an additional 7.61 million (7. 20-8.01) deaths estimated in 2017 versus 2007. The death rate from NCDs decreased globally by 7.9% (7.08.8). The number of deaths for CMNN causes decreased by 222% (20.0-24.0) and the death rate by 31.8% (30.1-33.3). Total deaths from injuries increased by 2.3% (0-5-4-0) between 2007 and 2017, and the death rate from injuries decreased by 13.7% (12.2-15.1) to 57.9 deaths (55.9-59.2) per 100 000 in 2017. Deaths from substance use disorders also increased, rising from 284 000 deaths (268 000-289 000) globally in 2007 to 352 000 (334 000-363 000) in 2017. Between 2007 and 2017, total deaths from conflict and terrorism increased by 118.0% (88.8-148.6). A greater reduction in total deaths and death rates was observed for some CMNN causes among children younger than 5 years than for older adults, such as a 36.4% (32.2-40.6) reduction in deaths from lower respiratory infections for children younger than 5 years compared with a 33.6% (31.2-36.1) increase in adults older than 70 years. Globally, the number of deaths was greater for men than for women at most ages in 2017, except at ages older than 85 years. Trends in global YLLs reflect an epidemiological transition, with decreases in total YLLs from enteric infections, respirator}, infections and tuberculosis, and maternal and neonatal disorders between 1990 and 2017; these were generally greater in magnitude at the lowest levels of the Socio-demographic Index (SDI). At the same time, there were large increases in YLLs from neoplasms and cardiovascular diseases. YLL rates decreased across the five leading Level 2 causes in all SDI quintiles. The leading causes of YLLs in 1990 neonatal disorders, lower respiratory infections, and diarrhoeal diseases were ranked second, fourth, and fifth, in 2017. Meanwhile, estimated YLLs increased for ischaemic heart disease (ranked first in 2017) and stroke (ranked third), even though YLL rates decreased. Population growth contributed to increased total deaths across the 20 leading Level 2 causes of mortality between 2007 and 2017. Decreases in the cause-specific mortality rate reduced the effect of population growth for all but three causes: substance use disorders, neurological disorders, and skin and subcutaneous diseases. Interpretation Improvements in global health have been unevenly distributed among populations. Deaths due to injuries, substance use disorders, armed conflict and terrorism, neoplasms, and cardiovascular disease are expanding threats to global health. For causes of death such as lower respiratory and enteric infections, more rapid progress occurred for children than for the oldest adults, and there is continuing disparity in mortality rates by sex across age groups. Reductions in the death rate of some common diseases are themselves slowing or have ceased, primarily for NCDs, and the death rate for selected causes has increased in the past decade. Copyright (C) 2018 The Author(s). Published by Elsevier Ltd.Peer reviewe

Measuring progress from 1990 to 2017 and projecting attainment to 2030 of the health-related Sustainable Development Goals for 195 countries and territories: a systematic analysis for the Global Burden of Disease Study 2017

Background: Efforts to establish the 2015 baseline and monitor early implementation of the UN Sustainable Development Goals (SDGs) highlight both great potential for and threats to improving health by 2030. To fully deliver on the SDG aim of “leaving no one behind”, it is increasingly important to examine the health-related SDGs beyond national-level estimates. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017), we measured progress on 41 of 52 health-related SDG indicators and estimated the health-related SDG index for 195 countries and territories for the period 1990–2017, projected indicators to 2030, and analysed global attainment. Methods: We measured progress on 41 health-related SDG indicators from 1990 to 2017, an increase of four indicators since GBD 2016 (new indicators were health worker density, sexual violence by non-intimate partners, population census status, and prevalence of physical and sexual violence [reported separately]). We also improved the measurement of several previously reported indicators. We constructed national-level estimates and, for a subset of health-related SDGs, examined indicator-level differences by sex and Socio-demographic Index (SDI) quintile. We also did subnational assessments of performance for selected countries. To construct the health-related SDG index, we transformed the value for each indicator on a scale of 0–100, with 0 as the 2\ub75th percentile and 100 as the 97\ub75th percentile of 1000 draws calculated from 1990 to 2030, and took the geometric mean of the scaled indicators by target. To generate projections through 2030, we used a forecasting framework that drew estimates from the broader GBD study and used weighted averages of indicator-specific and country-specific annualised rates of change from 1990 to 2017 to inform future estimates. We assessed attainment of indicators with defined targets in two ways: first, using mean values projected for 2030, and then using the probability of attainment in 2030 calculated from 1000 draws. We also did a global attainment analysis of the feasibility of attaining SDG targets on the basis of past trends. Using 2015 global averages of indicators with defined SDG targets, we calculated the global annualised rates of change required from 2015 to 2030 to meet these targets, and then identified in what percentiles the required global annualised rates of change fell in the distribution of country-level rates of change from 1990 to 2015. We took the mean of these global percentile values across indicators and applied the past rate of change at this mean global percentile to all health-related SDG indicators, irrespective of target definition, to estimate the equivalent 2030 global average value and percentage change from 2015 to 2030 for each indicator. Findings: The global median health-related SDG index in 2017 was 59\ub74 (IQR 35\ub74–67\ub73), ranging from a low of 11\ub76 (95% uncertainty interval 9\ub76–14\ub70) to a high of 84\ub79 (83\ub71–86\ub77). SDG index values in countries assessed at the subnational level varied substantially, particularly in China and India, although scores in Japan and the UK were more homogeneous. Indicators also varied by SDI quintile and sex, with males having worse outcomes than females for non-communicable disease (NCD) mortality, alcohol use, and smoking, among others. Most countries were projected to have a higher health-related SDG index in 2030 than in 2017, while country-level probabilities of attainment by 2030 varied widely by indicator. Under-5 mortality, neonatal mortality, maternal mortality ratio, and malaria indicators had the most countries with at least 95% probability of target attainment. Other indicators, including NCD mortality and suicide mortality, had no countries projected to meet corresponding SDG targets on the basis of projected mean values for 2030 but showed some probability of attainment by 2030. For some indicators, including child malnutrition, several infectious diseases, and most violence measures, the annualised rates of change required to meet SDG targets far exceeded the pace of progress achieved by any country in the recent past. We found that applying the mean global annualised rate of change to indicators without defined targets would equate to about 19% and 22% reductions in global smoking and alcohol consumption, respectively; a 47% decline in adolescent birth rates; and a more than 85% increase in health worker density per 1000 population by 2030. Interpretation: The GBD study offers a unique, robust platform for monitoring the health-related SDGs across demographic and geographic dimensions. Our findings underscore the importance of increased collection and analysis of disaggregated data and highlight where more deliberate design or targeting of interventions could accelerate progress in attaining the SDGs. Current projections show that many health-related SDG indicators, NCDs, NCD-related risks, and violence-related indicators will require a concerted shift away from what might have driven past gains—curative interventions in the case of NCDs—towards multisectoral, prevention-oriented policy action and investments to achieve SDG aims. Notably, several targets, if they are to be met by 2030, demand a pace of progress that no country has achieved in the recent past. The future is fundamentally uncertain, and no model can fully predict what breakthroughs or events might alter the course of the SDGs. What is clear is that our actions—or inaction—today will ultimately dictate how close the world, collectively, can get to leaving no one behind by 2030

Measuring progress from 1990 to 2017 and projecting attainment to 2030 of the health-related Sustainable Development Goals for 195 countries and territories: a systematic analysis for the Global Burden of Disease Study 2017.

BACKGROUND: Efforts to establish the 2015 baseline and monitor early implementation of the UN Sustainable Development Goals (SDGs) highlight both great potential for and threats to improving health by 2030. To fully deliver on the SDG aim of 'leaving no one behind', it is increasingly important to examine the health-related SDGs beyond national-level estimates. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017), we measured progress on 41 of 52 health-related SDG indicators and estimated the health-related SDG index for 195 countries and territories for the period 1990-2017, projected indicators to 2030, and analysed global attainment. METHODS: We measured progress on 41 health-related SDG indicators from 1990 to 2017, an increase of four indicators since GBD 2016 (new indicators were health worker density, sexual violence by non-intimate partners, population census status, and prevalence of physical and sexual violence [reported separately]). We also improved the measurement of several previously reported indicators. We constructed national-level estimates and, for a subset of health-related SDGs, examined indicator-level differences by sex and Socio-demographic Index (SDI) quintile. We also did subnational assessments of performance for selected countries. To construct the health-related SDG index, we transformed the value for each indicator on a scale of 0-100, with 0 as the 2·5th percentile and 100 as the 97·5th percentile of 1000 draws calculated from 1990 to 2030, and took the geometric mean of the scaled indicators by target. To generate projections through 2030, we used a forecasting framework that drew estimates from the broader GBD study and used weighted averages of indicator-specific and country-specific annualised rates of change from 1990 to 2017 to inform future estimates. We assessed attainment of indicators with defined targets in two ways: first, using mean values projected for 2030, and then using the probability of attainment in 2030 calculated from 1000 draws. We also did a global attainment analysis of the feasibility of attaining SDG targets on the basis of past trends. Using 2015 global averages of indicators with defined SDG targets, we calculated the global annualised rates of change required from 2015 to 2030 to meet these targets, and then identified in what percentiles the required global annualised rates of change fell in the distribution of country-level rates of change from 1990 to 2015. We took the mean of these global percentile values across indicators and applied the past rate of change at this mean global percentile to all health-related SDG indicators, irrespective of target definition, to estimate the equivalent 2030 global average value and percentage change from 2015 to 2030 for each indicator

Oral acute toxicity of imidacloprid, thiamethoxam and clothianidin in eared doves: a contribution for the risk assessment of neonicotinoids in birds

Neonicotinoids have recently been demonstrated to cause direct negative impacts on birds from North America and Europe. To further understand the impact of these compounds on bird species and to improve risk assessment capacities, the current study determined the acute toxicities of imidacloprid, clothianidin, and thiamethoxam formulations on South American eared doves (Zenaida auriculata). Insecticides were administered by gavage to adult doves to determine median lethal doses (LD50) according to a standardized sequential procedure. The acute toxicity of formulated imidacloprid (LD50=59mgactive ingredient, a.i./kg bodyweight, b. w.) was much higher than that of the tested formulations of clothianidin (LD50 = 4248 mg a.i./kg b.w.) and thiamethoxam (LD50 = 4366 mg a.i./kg b.w.). Imidacloprid also differed from the other two neonicotinoids in terms of the onset and intensity of intoxication signs and the times of death and recovery. All three insecticides induced a reduction in food consumption that led to body weight loss. An average weight dove of 127 g would obtain a dose equivalent to the LD50 of imidacloprid by consuming 1.7 g of treated sorghum seeds. As eared doves offered non-treated sorghum seeds 5 h per day consumed on average 6.4±1.8 g (mean±S.D.), it is concluded that these doves could feasibly be exposed to lethal doses in the field. Thiswork is the first to describe intoxication signs and report oral neonicotinoid LD50s in a wild South-American bird species.EEA ParanáFil: Addy Orduna, Laura. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Paraná; ArgentinaFil: Brodeur, Celine Marie Julie. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Recursos Bilológicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Mateo Soria, Rafael. Instituto de Investigación en Recursos Cinegéticos; Españ

Oral acute toxicity of imidacloprid, thiamethoxam and clothianidin in eared doves: A contribution for the risk assessment of neonicotinoids in birds

Neonicotinoids have recently been demonstrated to cause direct negative impacts on birds from North America and Europe. To further understand the impact of these compounds on bird species and to improve risk assessment capacities, the current study determined the acute toxicities of imidacloprid, clothianidin, and thiamethoxam formulations on South American eared doves (Zenaida auriculata). Insecticides were administered by gavage to adult doves to determine median lethal doses (LD50) according to a standardized sequential procedure. The acute toxicity of formulated imidacloprid (LD50 = 59 mg active ingredient, a.i./kg body weight, b.w.) was much higher than that of the tested formulations of clothianidin (LD50 = 4248 mg a.i./kg b.w.) and thiamethoxam (LD50 = 4366 mg a.i./kg b.w.). Imidacloprid also differed from the other two neonicotinoids in terms of the onset and intensity of intoxication signs and the times of death and recovery. All three insecticides induced a reduction in food consumption that led to body weight loss. An average weight dove of 127 g would obtain a dose equivalent to the LD50 of imidacloprid by consuming 1.7 g of treated sorghum seeds. As eared doves offered non-treated sorghum seeds 5 h per day consumed on average 6.4 ± 1.8 g (mean ± S.D.), it is concluded that these doves could feasibly be exposed to lethal doses in the field. This work is the first to describe intoxication signs and report oral neonicotinoid LD50s in a wild South-American bird species.Fil: Addy Orduna, Laura. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Entre Ríos. Estación Experimental Agropecuaria Paraná; ArgentinaFil: Brodeur, Celine Marie Julie. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación de Recursos Naturales. Instituto de Recursos Biológicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pezzi, Juan Rafael Mateo. Consejo Superior de Investigaciones Científicas; Españ

Parallel pathways from whisker and visual sensory cortices to distinct frontal regions of mouse neocortex

The spatial organization of mouse frontal cortex is poorly understood. Here, we used voltage-sensitive dye to image electrical activity in the dorsal cortex of awake head-restrained mice. Whisker-deflection evoked the earliest sensory response in a localized region of primary somatosensory cortex and visual stimulation evoked the earliest responses in a localized region of primary visual cortex. Over the next milliseconds, the initial sensory response spread within the respective primary sensory cortex and into the surrounding higher order sensory cortices. In addition, secondary hotspots in the frontal cortex were evoked by whisker and visual stimulation, with the frontal hotspot for whisker deflection being more anterior and lateral compared to the frontal hotspot evoked by visual stimulation. Investigating axonal projections, we found that the somatosensory whisker cortex and the visual cortex directly innervated frontal cortex, with visual cortex axons innervating a region medial and posterior to the innervation from somatosensory cortex, consistent with the location of sensory responses in frontal cortex. In turn, the axonal outputs of these two frontal cortical areas innervate distinct regions of striatum, superior colliculus, and brainstem. Sensory input, therefore, appears to map onto modality-specific regions of frontal cortex, perhaps participating in distinct sensorimotor transformations, and directing distinct motor outputs. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License

Long-range connectivity of mouse primary somatosensory barrel cortex

The primary somatosensory barrel cortex processes tactile vibrissae information, allowing rodents to actively perceive spatial and textural features of their immediate surroundings. Each whisker on the snout is individually represented in the neocortex by an anatomically identifiable 'barrel' specified by the segregated termination zones of thalamocortical axons of the ventroposterior medial nucleus, which provide the primary sensory input to the neocortex. The sensory information is subsequently processed within local synaptically connected neocortical microcircuits, which have begun to be investigated in quantitative detail. In addition to these local synaptic microcircuits, the excitatory pyramidal neurons of the barrel cortex send and receive long-range glutamatergic axonal projections to and from a wide variety of specific brain regions. Much less is known about these long-range connections and their contribution to sensory processing. Here, we review current knowledge of the long-range axonal input and output of the mouse primary somatosensory barrel cortex. Prominent reciprocal projections are found between primary somatosensory cortex and secondary somatosensory cortex, motor cortex, perirhinal cortex and thalamus. Primary somatosensory barrel cortex also projects strongly to striatum, thalamic reticular nucleus, zona incerta, anterior pretectal nucleus, superior colliculus, pons, red nucleus and spinal trigeminal brain stem nuclei. These long-range connections of the barrel cortex with other specific cortical and subcortical brain regions are likely to play a crucial role in sensorimotor integration, sensory perception and associative learning