What causes aberrant salience in schizophrenia? A role for impaired short-term habituation and the GRIA1 (GluA1) AMPA receptor subunit.

The GRIA1 locus, encoding the GluA1 (also known as GluRA or GluR1) AMPA glutamate receptor subunit, shows genome-wide association to schizophrenia. As well as extending the evidence that glutamatergic abnormalities have a key role in the disorder, this finding draws attention to the behavioural phenotype of Gria1 knockout mice. These mice show deficits in short-term habituation. Importantly, under some conditions the attention being paid to a recently presented neutral stimulus can actually increase rather than decrease (sensitization). We propose that this mouse phenotype represents a cause of aberrant salience and, in turn, that aberrant salience (and the resulting positive symptoms) in schizophrenia may arise, at least in part, from a glutamatergic genetic predisposition and a deficit in short-term habituation. This proposal links an established risk gene with a psychological process central to psychosis and is supported by findings of comparable deficits in short-term habituation in mice lacking the NMDAR receptor subunit Grin2a (which also shows association to schizophrenia). As aberrant salience is primarily a dopaminergic phenomenon, the model supports the view that the dopaminergic abnormalities can be downstream of a glutamatergic aetiology. Finally, we suggest that, as illustrated here, the real value of genetically modified mice is not as ‘models of schizophrenia’ but as experimental tools that can link genomic discoveries with psychological processes and help elucidate the underlying neural mechanisms

A Transdiagnostic Perspective on Social Anhedonia

Humans are highly social beings, yet people with social anhedonia experience reduced interest in or reward from social situations. Social anhedonia is a key facet of schizotypal personality, an important symptom of schizophrenia, and increasingly recognized as an important feature in a range of other psychological disorders. However, to date, there has been little examination of the similarities and differences in social anhedonia across diagnostic borders. Here, our goal was to conduct a selective review of social anhedonia in different psychological and life course contexts, including the psychosis continuum, depressive disorder, posttraumatic stress disorder, eating disorders, and autism spectrum disorders, along with developmental and neurobiological factors. Current evidence suggests that the nature and expression of social anhedonia vary across psychological disorders with some groups showing deficient learning about, enjoyment from, and anticipation of the pleasurable aspects of social interactions, while for others, some of these components appear to remain intact. However, study designs and methodologies are diverse, the roles of developmental and neurobiological factors are not routinely considered, and direct comparisons between diagnostic groups are rare—which prevents a more nuanced understanding of the underlying mechanisms involved. Future studies, parsing the wanting, liking, and learning components of social reward, will help to fill gaps in the current knowledge base. Consistent across disorders is diminished pleasure from social situations, subsequent withdrawal, and poorer social functioning in those who express social anhedonia. Nonetheless, feelings of loneliness often remain, which suggests the need for social connection is not entirely absent. Adolescence is a particularly important period of social and neural development and may provide a valuable window on the developmental origins of social anhedonia. Adaptive social functioning is key to recovery from mental health disorders; therefore, understanding the intricacies of social anhedonia will help to inform treatment and prevention strategies for a range of diagnostic categories

Loneliness and Schizotypy Are Distinct Constructs, Separate from General Psychopathology

Loneliness is common in youth and associated with a significantly increased risk of psychological disorders. Although loneliness is strongly associated with psychosis, its relationship with psychosis proneness is unclear. Our aim in this paper was to test the hypothesis that loneliness and schizotypal traits, conveying risk for schizophrenia spectrum disorders, are similar but separate constructs. Pooling data from two non-clinical student samples (N = 551) we modeled the structure of the relationship between loneliness and trait schizotypy. Loneliness was assessed with the University of California, Los Angeles Loneliness Scale (UCLA-3), whilst negative (Social Anhedonia) and positive (Perceptual Aberrations) schizotypal traits were assessed with the Wisconsin Schizotypy Scales-Brief (WSS-B). Fit statistics indicated that the best fitting model of UCLA-3 scores comprises three correlated factors (Isolation, Related Connectedness, and Collective Connectedness), consistent with previous reports. Fit statistics for a two factor model of positive and negative schizotypy were excellent. Next, bi-factor analysis was used to model a general psychopatholgy factor (p) across the three loneliness factors and separate negative and positive schizotypy traits. The results showed that all items (except 1) co-loaded on p. However, with the influence of p removed, additional variance remained within separate sub-factors, indicating that loneliness and negative and positive trait schizotypy are distinct and separable constructs. Similarly, once shared variance with p was removed, correlations between sub-factors of loneliness and schizotypal traits were non-significant. These findings have important clinical implications since they suggest that loneliness should not be conflated with the expression of schizotypy. Rather, loneliness needs to be specifically targeted for assessment and treatment in youth at risk for psychosis

Efficient 1 GHz Ti:sapphire laser with improved broadband continuum in the infrared

We demonstrate a 1 GHz prismless femtosecond Ti:sapphire ring laser which emits 890 mW for 7.6W of pump power over a continuum extending from 585 to 1200 nm at -20 dB below the maximum. A broadband continuum is obtained without careful mirror dispersion compensation, with the net cavity group-delay-dispersion having -50 to +100 fs2 oscillations from 700 to 900 nm. Further broadening is obtained by use of a slightly convex cavity mirror that increases self-phase modulation. 17% (75%) of the intracavity (output) power is generated in single-pass through the crystal, outside the cavity bandwidth and concentrated in the low gain infrared region from 960 to 1200 nm. This laser seems well suited for optical frequency metrology, possibly allowing easier stabilization of the carrier-to-envelope offset frequency without use of photonic fibers

Refinements to rodent head fixation and fluid/food control for neuroscience

The use of head fixation in mice is increasingly common in research, its use having initially been restricted to the field of sensory neuroscience. Head restraint has often been combined with fluid control, rather than food restriction, to motivate behaviour, but this too is now in use for both restrained and non-restrained animals. Despite this, there is little guidance on how best to employ these techniques to optimise both scientific outcomes and animal welfare. This article summarises current practices and provides recommendations to improve animal wellbeing and data quality, based on a survey of the community, literature reviews, and the expert opinion and practical experience of an international working group convened by the UK's National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs). Topics covered include head fixation surgery and post-operative care, habituation to restraint, and the use of fluid/food control to motivate performance. We also discuss some recent developments that may offer alternative ways to collect data from large numbers of behavioural trials without the need for restraint. The aim is to provide support for researchers at all levels, animal care staff, and ethics committees to refine procedures and practices in line with the refinement principle of the 3Rs

Neural processing of criticism and positive comments from relatives in individuals with schizotypal personality traits

Objectives. High negative expressed emotion by family members towards schizophrenia patients increases the risk of subsequent relapse. The study aimed to determine whether individuals with high schizotypy (HS) and low schizotypy (LS) would differ in activation of brain areas involved in cognitive control when listening to relative criticism

Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APP

Down syndrome, caused by trisomy of chromosome 21, is the single most common risk factor for early-onset Alzheimer's disease. Worldwide approximately 6 million people have Down syndrome, and all these individuals will develop the hallmark amyloid plaques and neurofibrillary tangles of Alzheimer's disease by the age of 40 and the vast majority will go on to develop dementia. Triplication of APP, a gene on chromosome 21, is sufficient to cause early-onset Alzheimer's disease in the absence of Down syndrome. However, whether triplication of other chromosome 21 genes influences disease pathogenesis in the context of Down syndrome is unclear. Here we show, in a mouse model, that triplication of chromosome 21 genes other than APP increases amyloid-β aggregation, deposition of amyloid-β plaques and worsens associated cognitive deficits. This indicates that triplication of chromosome 21 genes other than APP is likely to have an important role to play in Alzheimer's disease pathogenesis in individuals who have Down syndrome. We go on to show that the effect of trisomy of chromosome 21 on amyloid-β aggregation correlates with an unexpected shift in soluble amyloid-β 40/42 ratio. This alteration in amyloid-β isoform ratio occurs independently of a change in the carboxypeptidase activity of the γ-secretase complex, which cleaves the peptide from APP, or the rate of extracellular clearance of amyloid-β. These new mechanistic insights into the role of triplication of genes on chromosome 21, other than APP, in the development of Alzheimer's disease in individuals who have Down syndrome may have implications for the treatment of this common cause of neurodegeneration

Hippocampal Gene Expression Analysis Highlights Ly6a/Sca-1 as Candidate Gene for Previously Mapped Novelty Induced Behaviors in Mice

In this study, we show that the covariance between behavior and gene expression in the brain can help further unravel the determinants of neurobehavioral traits. Previously, a QTL for novelty induced motor activity levels was identified on murine chromosome 15 using consomic strains. With the goal of narrowing down the linked region and possibly identifying the gene underlying the quantitative trait, gene expression data from this F2-population was collected and used for expression QTL analysis. While genetic variation in these mice was limited to chromosome 15, eQTL analysis of gene expression showed strong cis-effects as well as trans-effects elsewhere in the genome. Using weighted gene co-expression network analysis, we were able to identify modules of co-expressed genes related to novelty induced motor activity levels. In eQTL analyses, the expression of Ly6a (a.k.a. Sca-1) was found to be cis-regulated by chromosome 15. Ly6a also surfaced in a group of genes resulting from the network analysis that was correlated with behavior. Behavioral analysis of Ly6a knock-out mice revealed reduced novelty induced motor activity levels when compared to wild type controls, confirming functional importance of Ly6a in this behavior, possibly through regulating other genes in a pathway. This study shows that gene expression profiling can be used to narrow down a previously identified behavioral QTL in mice, providing support for Ly6a as a candidate gene for functional involvement in novelty responsiveness

A population of galaxy-scale jets discovered using LOFAR

The effects of feedback from high luminosity radio-loud AGN have been extensively discussed in the literature, but feedback from low-luminosity radio-loud AGN is less well understood. The advent of high sensitivity, high angular resolution, large field of view telescopes such as LOFAR is now allowing wide-area studies of such faint sources for the first time. Using the first data release of the LOFAR Two Metre Sky Survey (LoTSS) we report on our discovery of a population of 195 radio galaxies with 150 MHz luminosities between 3 × 1022 and 1.5 × 1025WHz−1 and total radio emission no larger than 80 kpc. These objects, which we term galaxy-scale jets (GSJ), are small enough to be directly influencing the evolution of the host on galaxy scales. We report upon the typical host properties of our sample, finding that 9 per cent are hosted by spirals with the remainder being hosted by elliptical galaxies. Two of the spiral-hosted GSJ are highly unusual with low radio luminosities and FRII-like morphology. The host properties of our GSJ show that they are ordinary AGN observed at a stage in their life shortly after the radio emission has expanded beyond the central regions of the host. Based on our estimates, we find that about half of our GSJ have internal radio lobe energy within an order of magnitude of the ISM energy so that, even ignoring any possible shocks, GSJ are energetically capable of affecting the evolution of the host. The current sample of GSJ will grow in size with future releases of LoTSS and can also form the basis for further studies of feedback from low-luminosity radio sources

The LOFAR Two-Metre Sky Survey (LoTSS): VI. Optical identifications for the second data release

The second data release of the LOFAR Two-Metre Sky Survey (LoTSS) covers 27% of the northern sky, with a total area of $\sim 5,700$ deg$^2$. The high angular resolution of LOFAR with Dutch baselines (6 arcsec) allows us to carry out optical identifications of a large fraction of the detected radio sources without further radio followup; however, the process is made more challenging by the many extended radio sources found in LOFAR images as a result of its excellent sensitivity to extended structure. In this paper we present source associations and identifications for sources in the second data release based on optical and near-infrared data, using a combination of a likelihood-ratio cross-match method developed for our first data release, our citizen science project Radio Galaxy Zoo: LOFAR, and new approaches to algorithmic optical identification, together with extensive visual inspection by astronomers. We also present spectroscopic or photometric redshifts for a large fraction of the optical identifications. In total 4,116,934 radio sources lie in the area with good optical data, of which 85% have an optical or infrared identification and 58% have a good redshift estimate. We demonstrate the quality of the dataset by comparing it with earlier optically identified radio surveys. This is by far the largest ever optically identified radio catalogue, and will permit robust statistical studies of star-forming and radio-loud active galaxies.Comment: 29 pages. Accepted by A&A; data products available at https://lofar-surveys.org/dr2_release.htm