Reduced inhibitory gate in the barrel cortex of Neuroligin3R451C knock-in mice, an animal model of Autism Spectrum Disorders

Neuroligins are postsynaptic adhesion molecules that interacting with presynaptic neurexins ensure the cross-talk between pre-and postsynaptic specializations. Rare mutations in neurexin-neuroligin genes have been linked to autism spectrum disorders (ASDs). One of these, the R451C mutation of the gene encoding for Neuroligin3 (Nlgn3), has been found in patients with familial forms of ASDs. Animals carrying this mutation (NL3R451C knock-in mice) exhibit impaired social behaviors, reminiscent of those observed in ASD patients, associated with major alterations in both GABAergic and glutamatergic transmission, which vary among different brain regions and at different developmental stages. Here, pair recordings from parvalbumin-(PV) expressing basket cells and spiny neurons were used to study GABAergic synaptic signaling in layer IV barrel cortex of NL3R451C mutant mice. We found that the R451C mutation severely affects the probability of GABA release from PV-expressing basket cells, responsible for controlling via thalamo-cortical inputs the feed-forward inhibition. No changes in excitatory inputs to parvalbumin-positive basket cells or spiny neurons were detected. These data clearly show that primary targets of the NL3 mutation are PV-expressing basket cells, independently of the brain region where they are localized. Changes in the inhibitory gate of layer IV somatosensory cortex may alter sensory processing in ASD patients leading to misleading sensory representations with difficulties to combine pieces of information into a unified perceptual whole. \ua9 2014 The Authors

The ADAR RNA editing enzyme controls neuronal excitability in Drosophila melanogaster

RNA editing by deamination of specific adenosine bases to inosines during pre-mRNA processing gen-erates edited isoforms of proteins. Recoding RNA editing is more widespread in Drosophila than in vertebrates. Editing levels rise strongly at metamor-phosis, and Adar5G1 null mutant flies lack editing events in hundreds of CNS transcripts; mutant flies have reduced viability, severely defective locomo-tion and age-dependent neurodegeneration. On the other hand, overexpressing an adult dADAR isoform with high enzymatic activity ubiquitously during larval and pupal stages is lethal. Advantage was taken of this to screen for genetic modifiers; Adar overexpression lethality is rescued by reduced dosage of the Rdl (Resistant to dieldrin), gene encoding a subunit of inhibitory GABA receptors. Reduced dosage of the Gad1 gene encoding the GABA synthetase also rescues Adar overexpression lethality. Drosophila Adar5G1 mutant phenotypes are ameliorated by feeding GABA modulators. We demonstrate that neuronal excitability is linked to dADAR expression levels in individual neurons; Adar-overexpressing larval motor neurons show reduced excitability whereas Adar5G1 null mutant or targeted Adar knockdown motor neurons exhibit increased excitability. GABA inhibitory signalling is impaired in human epileptic and autistic conditions, and vertebrate ADARs may have a relevant evolutionarily conserved control over neuronal excitability

Neural Computation via Neural Geometry: A Place Code for Inter-whisker Timing in the Barrel Cortex?

The place theory proposed by Jeffress (1948) is still the dominant model of how the brain represents the movement of sensory stimuli between sensory receptors. According to the place theory, delays in signalling between neurons, dependent on the distances between them, compensate for time differences in the stimulation of sensory receptors. Hence the location of neurons, activated by the coincident arrival of multiple signals, reports the stimulus movement velocity. Despite its generality, most evidence for the place theory has been provided by studies of the auditory system of auditory specialists like the barn owl, but in the study of mammalian auditory systems the evidence is inconclusive. We ask to what extent the somatosensory systems of tactile specialists like rats and mice use distance dependent delays between neurons to compute the motion of tactile stimuli between the facial whiskers (or ‘vibrissae’). We present a model in which synaptic inputs evoked by whisker deflections arrive at neurons in layer 2/3 (L2/3) somatosensory ‘barrel’ cortex at different times. The timing of synaptic inputs to each neuron depends on its location relative to sources of input in layer 4 (L4) that represent stimulation of each whisker. Constrained by the geometry and timing of projections from L4 to L2/3, the model can account for a range of experimentally measured responses to two-whisker stimuli. Consistent with that data, responses of model neurons located between the barrels to paired stimulation of two whiskers are greater than the sum of the responses to either whisker input alone. The model predicts that for neurons located closer to either barrel these supralinear responses are tuned for longer inter-whisker stimulation intervals, yielding a topographic map for the inter-whisker deflection interval across the surface of L2/3. This map constitutes a neural place code for the relative timing of sensory stimuli

Neocortical Axon Arbors Trade-off Material and Conduction Delay Conservation

The brain contains a complex network of axons rapidly communicating information between billions of synaptically connected neurons. The morphology of individual axons, therefore, defines the course of information flow within the brain. More than a century ago, Ramón y Cajal proposed that conservation laws to save material (wire) length and limit conduction delay regulate the design of individual axon arbors in cerebral cortex. Yet the spatial and temporal communication costs of single neocortical axons remain undefined. Here, using reconstructions of in vivo labelled excitatory spiny cell and inhibitory basket cell intracortical axons combined with a variety of graph optimization algorithms, we empirically investigated Cajal's conservation laws in cerebral cortex for whole three-dimensional (3D) axon arbors, to our knowledge the first study of its kind. We found intracortical axons were significantly longer than optimal. The temporal cost of cortical axons was also suboptimal though far superior to wire-minimized arbors. We discovered that cortical axon branching appears to promote a low temporal dispersion of axonal latencies and a tight relationship between cortical distance and axonal latency. In addition, inhibitory basket cell axonal latencies may occur within a much narrower temporal window than excitatory spiny cell axons, which may help boost signal detection. Thus, to optimize neuronal network communication we find that a modest excess of axonal wire is traded-off to enhance arbor temporal economy and precision. Our results offer insight into the principles of brain organization and communication in and development of grey matter, where temporal precision is a crucial prerequisite for coincidence detection, synchronization and rapid network oscillations

Segregation and Violence: Comparing the Effects of Residential Segregation on Latino and Black Violence

Racial/ethnic residential segregation has been shown to contribute to violence and have harmful consequences for minority groups. However, research examining the segregation–crime relationship has focused almost exclusively on blacks and whites while largely ignoring Latinos and other race/ethnic groups and has rarely considered potential mediators (e.g., concentrated disadvantage) in segregation–violence relationships. This study uses year 2000 arrest data for California and New York census places to extend segregation–crime research by comparing the effects of racial/ethnic residential segregation from whites on black and Latino homicide. Results indicate that (1) racial/ethnic segregation contributes to both Latino and black homicide, and (2) the effects for both groups are mediated by concentrated disadvantage. Implications for segregation–violence relationships, the racial-invariance position, and the Latino paradox are discussed

Racial/Ethnic Threat and Federal Sentencing

This study examines whether federal sentencing decisions are influenced by the racial/ethnic composition of federal court districts. Multilevel models of individual cases within federal judicial districts show that black defendants receive moderately longer sentences than whites, and that Hispanics and whites receive similar sentences. These race/ethnicity effects on sentence length are found to vary across federal districts, but not as predicted by racial threat theory. In contrast to racial threat predictions, black sentence lengths are not significantly conditioned by the district black population. Contrary to racial threat predictions, Hispanic defendants receive the harshest sentences when they account for the smallest share of the population (1-3 percent) and the most lenient sentences when they make up more sizable shares of district populations (more than 27 percent). Our results indicate that racial threat theory provides an inadequate explanation of how social contexts influence the federal sentencing of blacks and Hispanics

Economic Competition and Racial/Ethnic Disparities in Sentencing: A Test of Economic Threat Perspective

Economic threat arguments within the broader racial/ethnic threat theory suggest that economic competition between minorities and Whites encourages the majority group to apply formal social controls on minorities to maintain their advantaged positions. Prior sentencing research has given limited attention to economic threat and has only done so using cross-sectional measures, which does not capture changing economic circumstances (a key element of racial/ethnic threat). The goal of this study is to provide a test of economic threat—and racial/ethnic threat more broadly—utilizing time variant measures. To achieve this goal, we use case-level data from the Minnesota Sentencing Guidelines Commission (N = 122,666) and county-level data from the United States Census Bureau. Multilevel regression models reveal partial but limited support for economic threat. Specifically, counties with a growing portion of minorities living above the poverty line between 2000 and 2010 had larger minority disadvantages (in comparison to Whites) at incarceration. However, economic threat measures do not significantly contextualize minority–White sentence length differences, while the broader racial/ethnic threat measures do not significantly influence minority–White outcomes at the incarceration or sentencing length decision. The results suggest that economic threat may explain a small but limited portion of the racial disparities identified

Staying under the Radar? Immigration Effects on Overdose Deaths and the Impact of Sanctuary Jurisdictions

Growing political and public rhetoric claim that immigration has contributed to drug crime and the overdose crisis of the 21st century. However, research to date has given little attention to immigration–overdose relationships, and almost no work has examined the ways that the sanctuary status of locales influences these connections. The current study draws on the immigrant revitalization perspective and Brayne’s (2014) systems avoidance theory to examine the connections between immigrant concentration, sanctuary status, and overdose mortality across MSAs for the 2015 period, overall and across races/ethnicities. The analysis uses data on overdose deaths drawn from the CDC’s Restricted Access Multiple Cause of Death Mortality files, combined with data on characteristics of MSAs drawn from the U.S. Census and other macro-level data sources. Findings reveal that the percent Latinx foreign-born is related to lower levels of overdose deaths overall and for White and Black populations but higher levels of Latinx overdose mortality. Contrary to expectations, sanctuary status has little effect on overdose deaths across most groups, and it does not significantly condition immigration–overdose relationships

Religious Contexts and Violence in Emerging and Traditional Immigrant Destinations

Amidst both a resurgent interest in the impact of religion on social problems like crime, including its contextual effects, as well as scholarship directed toward the immigration-crime intersection, the current study examines how different religious traditions impact known violent offending uniquely in traditional versus emerging immigrant destinations. To do so, we employ negative binomial models regressing homicides, robberies, and aggravated assaults on adherence to three major religious traditions (mainline Protestant, evangelical Protestant, and Catholic), as well as immigration and other key macro-structural controls. We disaggregate our analysis for three types of United States counties in 2010: emerging, traditional, and other immigrant destinations. We find that religious traditions vary in their relationship with known violence across destination types: Catholic adherence is protective against crime (net of controls) only in established immigrant destinations, but evangelical Protestant adherence is associated with higher levels of robbery and aggravated assault in the same locales. Religious adherence has no links to violence in emerging immigrant destinations. Broadly, our findings reveal that the religious context is an important part of the evolving story of immigration, though it is multifaceted and context-dependent

Exploring Pandora's Box: potential and pitfalls of low coverage genome surveys for evolutionary biology

High throughput sequencing technologies are revolutionizing genetic research. With this ‘‘rise of the machines’’, genomic sequences can be obtained even for unknown genomes within a short time and for reasonable costs. This has enabled evolutionary biologists studying genetically unexplored species to identify molecular markers or genomic regions of interest (e.g. micro- and minisatellites, mitochondrial and nuclear genes) by sequencing only a fraction of the genome. However, when using such datasets from non-model species, it is possible that DNA from non-target contaminant species such as bacteria, viruses, fungi, or other eukaryotic organisms may complicate the interpretation of the results. In this study we analysed 14 genomic pyrosequencing libraries of aquatic non-model taxa from four major evolutionary lineages. We quantified the amount of suitable micro- and minisatellites, mitochondrial genomes, known nuclear genes and transposable elements and searched for contamination from various sources using bioinformatic approaches. Our results show that in all sequence libraries with estimated coverage of about 0.02–25%, many appropriate micro- and minisatellites, mitochondrial gene sequences and nuclear genes from different KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways could be identified and characterized. These can serve as markers for phylogenetic and population genetic analyses. A central finding of our study is that several genomic libraries suffered from different biases owing to non-target DNA or mobile elements. In particular, viruses, bacteria or eukaryote endosymbionts contributed significantly (up to 10%) to some of the libraries analysed. If not identified as such, genetic markers developed from high-throughput sequencing data for non-model organisms may bias evolutionary studies or fail completely in experimental tests. In conclusion, our study demonstrates the enormous potential of low-coverage genome survey sequences and suggests bioinformatic analysis workflows. The results also advise a more sophisticated filtering for problematic sequences and non-target genome sequences prior to developing markers