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

Evolution of GluN2A/B cytoplasmic domains diversified vertebrate synaptic plasticity and behavior

Two genome duplications early in the vertebrate lineage expanded gene families, including GluN2 subunits of the NMDA receptor. Diversification between the four mammalian GluN2 proteins occurred primarily at their intracellular C−terminal domains (CTDs). To identify shared ancestral functions and diversified subunit−specific functions, we exchanged the exons encoding the GluN2A (also known as Grin2a) and GluN2B (also known as Grin2b) CTDs in two knock−in mice and analyzed the mice's biochemistry, synaptic physiology, and multiple learned and innate behaviors. The eight behaviors were genetically separated into four groups, including one group comprising three types of learning linked to conserved GluN2A/B regions. In contrast, the remaining five behaviors exhibited subunit−specific regulation. GluN2A/B CTD diversification conferred differential binding to cytoplasmic MAGUK proteins and differential forms of long−term potentiation. These data indicate that vertebrate behavior and synaptic signaling acquired increased complexity from the duplication and diversification of ancestral GluN2 gene

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

Searching for cognitive enhancement in the Morris water maze: better and worse performance in D-amino acid oxidase knockout (Dao(-/-) ) mice

A common strategy when searching for cognitive-enhancing drugs has been to target the N-methyl-d-aspartate receptor (NMDAR), given its putative role in synaptic plasticity and learning. Evidence in favour of this approach has come primarily from studies with rodents using behavioural assays like the Morris water maze. D-amino acid oxidase (DAO) degrades neutral D-amino acids such as D-serine, the primary endogenous co-agonist acting at the glycine site of the synaptic NMDAR. Inhibiting DAO could therefore provide an effective and viable means of enhancing cognition, particularly in disorders like schizophrenia, in which NMDAR hypofunction is implicated. Indirect support for this notion comes from the enhanced hippocampal long-term potentiation and facilitated water maze acquisition of ddY/Dao(-) mice, which lack DAO activity due to a point mutation in the gene. Here, in Dao knockout (Dao(-/-) ) mice, we report both better and worse water maze performance, depending on the radial distance of the hidden platform from the side wall of the pool. Dao(-/-) mice displayed an increased innate preference for swimming in the periphery of the maze (possibly due to heightened anxiety), which facilitated the discovery of a peripherally located platform, but delayed the discovery of a centrally located platform. By contrast, Dao(-/-) mice exhibited normal performance in two alternative assays of long-term spatial memory: the appetitive and aversive Y-maze reference memory tasks. Taken together, these results question the proposed relationship between DAO inactivation and enhanced long-term associative spatial memory. They also have generic implications for how Morris water maze studies are performed and interpreted

Knockout of NMDA-receptors from parvalbumin interneurons sensitizes to schizophrenia-related deficits induced by MK-801

It has been suggested that a functional deficit in NMDA-receptors (NMDARs) on parvalbumin (PV)-positive interneurons (PV-NMDARs) is central to the pathophysiology of schizophrenia. Supportive evidence come from examination of genetically modified mice where the obligatory NMDAR-subunit GluN1 (also known as NR1) has been deleted from PV interneurons by Cre-mediated knockout of the corresponding gene Grin1 (Grin1(ΔPV) mice). Notably, such PV-specific GluN1 ablation has been reported to blunt the induction of hyperlocomotion (a surrogate for psychosis) by pharmacological NMDAR blockade with the non-competitive antagonist MK-801. This suggests PV-NMDARs as the site of the psychosis-inducing action of MK-801. In contrast to this hypothesis, we show here that Grin1(ΔPV) mice are not protected against the effects of MK-801, but are in fact sensitized to many of them. Compared with control animals, Grin1(ΔPV)mice injected with MK-801 show increased stereotypy and pronounced catalepsy, which confound the locomotor readout. Furthermore, in Grin1(ΔPV)mice, MK-801 induced medial-prefrontal delta (4 Hz) oscillations, and impaired performance on tests of motor coordination, working memory and sucrose preference, even at lower doses than in wild-type controls. We also found that untreated Grin1(ΔPV)mice are largely normal across a wide range of cognitive functions, including attention, cognitive flexibility and various forms of short-term memory. Taken together these results argue against PV-specific NMDAR hypofunction as a key starting point of schizophrenia pathophysiology, but support a model where NMDAR hypofunction in multiple cell types contribute to the disease

The group II metabotropic glutamate receptor agonist LY354740 and the D2 receptor antagonist haloperidol reduce locomotor hyperactivity but fail to rescue spatial working memory in GluA1 knockout mice.

Group II metabotropic glutamate receptor agonists have been suggested as potential anti-psychotics, at least in part, based on the observation that the agonist LY354740 appeared to rescue the cognitive deficits caused by non-competitive N-methyl-d-aspartate receptor (NMDAR) antagonists, including spatial working memory deficits in rodents. Here, we tested the ability of LY354740 to rescue spatial working memory performance in mice that lack the GluA1 subunit of the AMPA glutamate receptor, encoded by Gria1, a gene recently implicated in schizophrenia by genome-wide association studies. We found that LY354740 failed to rescue the spatial working memory deficit in Gria1(-/-) mice during rewarded alternation performance in the T-maze. In contrast, LY354740 did reduce the locomotor hyperactivity in these animals to a level that was similar to controls. A similar pattern was found with the dopamine receptor antagonist haloperidol, with no amelioration of the spatial working memory deficit in Gria1(-/-) mice, even though the same dose of haloperidol reduced their locomotor hyperactivity. These results with LY354740 contrast with the rescue of spatial working memory in models of glutamatergic hypofunction using non-competitive NMDAR antagonists. Future studies should determine whether group II mGluR agonists can rescue spatial working memory deficits with other NMDAR manipulations, including genetic models and other pharmacological manipulations of NMDAR function

Subclinical psychopathology and affective forecasting: Role of in‐the‐moment feelings

It is important for positive well-being and social engagement to understand how peoplepredict future emotions, an ability known as affective forecasting. However, mechanismsunderpinning the change to affective forecasting are not well understood in peoplewith subclinical psychiatric symptoms. The current study differentiated components that comprise affective forecasting and investigated how non-clinical features relate to these.We recruited 319 participants to complete the social affective forecasting task and respond to questionnaires that captured schizotypal and autistic traits as well as depressive symptoms. Associations between affective forecasting and subclinical features were investigated using correlations, regression, and structure equation modeling. Results showed that interpersonal features of schizotypal traits negatively predicted anticipated emotions in positive social conditions via in-the-moment feelings but not via mental simulation. Findings highlight that in-the-moment feelings may be an intervention target to help people who have difficulties with social interactions to anticipate more pleasure for future social events

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