Recent QBI publications

  • Corrigendum to: The epidemiology of alcohol use disorders cross-nationally: findings from the World Mental Health Surveys [Addict. Behav. 102 (2020) 106128] (Addictive Behaviors (2020) 102, (S0306460319304897), (10.1016/j.addbeh.2019.106128))

    The authors regret that the abovementioned article published online September 16, 2019, had an error in the author affiliations. The edited author affiliations are shown above. The authors also regret that the names of the WHO World Mental Health Survey Collaborators were omitted from the end of the article. “The WHO World Mental Health Survey collaborators are Sergio Aguilar-Gaxiola, MD, PhD; Ali Al-Hamzawi, MD; Mohammed Salih Al-Kaisy, MD; Jordi Alonso, MD, PhD; Laura Helena Andrade, MD, PhD; Lukoye Atwoli, MD, PhD; Corina Benjet, PhD; Guilherme Borges, ScD; Evelyn J. Bromet, PhD; Ronny Bruffaerts, PhD; Brendan Bunting, PhD; Jose Miguel Caldas-de-Almeida, MD, PhD; Graça Cardoso, MD, PhD; Somnath Chatterji, MD; Alfredo H. Cia, MD; Louisa Degenhardt, PhD; Koen Demyttenaere, MD, PhD; Silvia Florescu, MD, PhD; Giovanni de Girolamo, MD; Oye Gureje, MD, DSc, FRCPsych; Josep Maria Haro, MD, PhD; Meredith Harris, PhD; Hristo Hinkov, MD, PhD; Chi-yi Hu, MD, PhD; Peter de Jonge, PhD; Aimee Nasser Karam, PhD; Elie G. Karam, MD; Norito Kawakami, MD, DMSc; Ronald C. Kessler, PhD; Andrzej Kiejna, MD, PhD; Viviane Kovess-Masfety, MD, PhD; Sing Lee, MB, BS; Jean-Pierre Lepine, MD; John McGrath, MD, PhD; Maria Elena Medina-Mora, PhD; Zeina Mneimneh, PhD; Jacek Moskalewicz, PhD; Fernando Navarro-Mateu, MD, PhD; Marina Piazza, MPH, ScD; Jose Posada-Villa, MD; Kate M. Scott, PhD; Tim Slade, PhD; Juan Carlos Stagnaro, MD, PhD; Dan J. Stein, FRCPC, PhD; Margreet ten Have, PhD; Yolanda Torres, MPH, Dra.HC; Maria Carmen Viana, MD, PhD; Daniel V. Vigo, MD, DrPH; Harvey Whiteford, MBBS, PhD; David R. Williams, MPH, PhD; and Bogdan Wojtyniak, ScD.” The authors would like to apologise for any inconvenience caused.
  • Educational attainment polygenic scores are associated with cortical total surface area and regions important for language and memory

    It is well established that higher cognitive ability is associated with larger brain size. However, individual variation in intelligence exists despite brain size and recent studies have shown that a simple unifactorial view of the neurobiology underpinning cognitive ability is probably unrealistic. Educational attainment (EA) is often used as a proxy for cognitive ability since it is easily measured, resulting in large sample sizes and, consequently, sufficient statistical power to detect small associations. This study investigates the association between three global (total surface area (TSA), intra-cranial volume (ICV) and average cortical thickness) and 34 regional cortical measures with educational attainment using a polygenic scoring (PGS) approach. Analyses were conducted on two independent target samples of young twin adults with neuroimaging data, from Australia (N ​= ​1097) and the USA (N ​= ​723), and found that higher EA-PGS were significantly associated with larger global brain size measures, ICV and TSA (R ​= ​0.006 and 0.016 respectively, p ​< ​0.001) but not average thickness. At the regional level, we identified seven cortical regions—in the frontal and temporal lobes—that showed variation in surface area and average cortical thickness over-and-above the global effect. These regions have been robustly implicated in language, memory, visual recognition and cognitive processing. Additionally, we demonstrate that these identified brain regions partly mediate the association between EA-PGS and cognitive test performance. Altogether, these findings advance our understanding of the neurobiology that underpins educational attainment and cognitive ability, providing focus points for future research.
  • Radial contractility of actomyosin rings facilitates axonal trafficking and structural stability

    Most mammalian neurons have a narrow axon, which constrains the passage of large cargoes such as autophagosomes that can be larger than the axon diameter. Radial axonal expansion must therefore occur to ensure efficient axonal trafficking. In this study, we reveal that the speed of various large cargoes undergoing axonal transport is significantly slower than that of small ones and that the transit of diverse-sized cargoes causes an acute, albeit transient, axonal radial expansion, which is immediately restored by constitutive axonal contractility. Using live super-resolution microscopy, we demonstrate that actomyosin-II controls axonal radial contractility and local expansion, and that NM-II filaments associate with periodic F-actin rings via their head domains. Pharmacological inhibition of NM-II activity significantly increases axon diameter by detaching the NM-II from F-actin and impacts the trafficking speed, directionality, and overall efficiency of long-range retrograde trafficking. Consequently, prolonged NM-II inactivation leads to disruption of periodic actin rings and formation of focal axonal swellings, a hallmark of axonal degeneration.
  • A prospective population-based study of gestational vitamin D status and brain morphology in preadolescents

    Low vitamin D level during pregnancy has been associated with adverse neurodevelopmental outcomes such as autism spectrum disorders (ASD) in children. However, the underlying neurobiological mechanism remains largely unknown. This study investigated the association between gestational 25-hydroxyvitamin D [25(OH)D] concentration and brain morphology in 2597 children at the age of 10 years in the population-based Generation R Study. We studied both 25(OH)D in maternal venous blood in mid-gestation and in umbilical cord blood at delivery, in relation to brain volumetric measures and surface-based cortical metrics including cortical thickness, surface area, and gyrification using linear regression. We found exposure to higher maternal 25(OH)D concentrations in mid-gestation was associated with a larger cerebellar volume in children (b ​= ​0.02, 95%CI 0.001 to 0.04), however this association did not remain after correction for multiple comparisons. In addition, children exposed to persistently deficient (i.e., <25 ​nmol/L) 25(OH)D concentration from mid-gestation to delivery showed less cerebral gray matter and white matter volumes, as well as smaller surface area and less gyrification at 10 years than those with persistently sufficient (i.e., ≥50 ​nmol/L) 25(OH)D concentration. These results suggest temporal relationships between gestational vitamin D concentration and brain morphological development in children.
  • Draxin-mediated regulation of granule cell progenitor differentiation in the postnatal hippocampal dentate gyrus

    The hippocampus is characterized by the presence of life-long neurogenesis. To elucidate the molecular mechanism regulating hippocampal neurogenesis, we studied the functions of the chemorepellent Draxin in neuronal proliferation and differentiation in the postnatal dentate gyrus. The present in vivo cell labeling and fate tracking analyses revealed enhanced differentiation of hippocampal neural stem and progenitor cells (hNSPCs) in the subgranular zone (SGZ) of Draxin-deficient mice. We observed a reduction in the number of BrdU-pulse labeled or Ki-67 immunopositive SGZ cells in the mutant mice. However, Draxin deficiency did not affect cell cycle duration of SGZ cells. In situ hybridization analysis indicated that the receptor component of the canonical Wnt pathway, Lrp6, is expressed in SGZ cells, including Nestin and Sox2 double-positive hNSPCs. Taken together with the previous finding that Draxin interacts physically with Lrp6, we postulate that Draxin plays a pivotal role in the regulation of Wnt-driven hNSPC differentiation to modulate the rate of neuronal differentiation in the progenitor population.
  • Dissociable effects of tDCS polarity on latent decision processes are associated with individual differences in neurochemical concentrations and cortical morphology

    Applying a weak electrical current to the cortex has the potential to modulate neural functioning and behaviour. The most common stimulation technique, transcranial direct current stimulation (tDCS), has been used for causal investigations of brain and cognitive functioning, and to treat psychiatric conditions such as depression. However, the efficacy of tDCS in modulating behaviour varies across individuals. Moreover, despite being associated with different neural effects, the two polarities of electrical stimulation – anodal and cathodal – can result in similar behavioural outcomes. Here we employed a previously replicated behavioural paradigm that has been associated with polarity non-specific disruption of training effects in a simple decision-making task. We then used the linear ballistic accumulator model to quantify latent components of the decision-making task. In addition, magnetic resonance imaging measures were acquired prior to tDCS sessions to quantify cortical morphology and local neurochemical concentrations. Both anodal and cathodal stimulation disrupted learning-related task improvement relative to sham (placebo) stimulation, but the two polarities of stimulation had distinct effects on latent task components. Whereas anodal stimulation tended to affect decision thresholds for the behavioural task, cathodal stimulation altered evidence accumulation rates. Moreover, performance variability with anodal stimulation was related to cortical thickness of the inferior frontal gyrus, whereas performance variability with cathodal stimulation was related to cortical thickness in the inferior precentral sulcus, as well as to prefrontal neurochemical excitability. Our findings demonstrate that both cortical morphology and local neurochemical balance are important determinants of individual differences in behavioural responses to electrical brain stimulation.
  • A neuroimaging biomarker for striatal dysfunction in schizophrenia

    Mounting evidence suggests that function and connectivity of the striatum is disrupted in schizophrenia. We have developed a new hypothesis-driven neuroimaging biomarker for schizophrenia identification, prognosis and subtyping based on functional striatal abnormalities (FSA). FSA scores provide a personalized index of striatal dysfunction, ranging from normal to highly pathological. Using inter-site cross-validation on functional magnetic resonance images acquired from seven independent scanners (n = 1,100), FSA distinguished individuals with schizophrenia from healthy controls with an accuracy exceeding 80% (sensitivity, 79.3%; specificity, 81.5%). In two longitudinal cohorts, inter-individual variation in baseline FSA scores was significantly associated with antipsychotic treatment response. FSA revealed a spectrum of severity in striatal dysfunction across neuropsychiatric disorders, where dysfunction was most severe in schizophrenia, milder in bipolar disorder, and indistinguishable from healthy individuals in depression, obsessive-compulsive disorder and attention-deficit hyperactivity disorder. Loci of striatal hyperactivity recapitulated the spatial distribution of dopaminergic function and the expression profiles of polygenic risk for schizophrenia. In conclusion, we have developed a new biomarker to index striatal dysfunction and established its utility in predicting antipsychotic treatment response, clinical stratification and elucidating striatal dysfunction in neuropsychiatric disorders.
  • Gamma coherence mediates interhemispheric integration during multiple object tracking

    Our ability to track the paths of multiple visual objects moving between the hemifields requires effective integration of information between the two cerebral hemispheres. Coherent neural oscillations in the gamma band (35-70 Hz) are hypothesised to drive this information transfer. Here we manipulated the need for interhemispheric integration using a novel multiple object tracking (MOT) task in which stimuli either moved between the two visual hemifields-requiring interhemispheric integration-or moved within separate visual hemifields. We used electroencephalography (EEG) to measure interhemispheric coherence during the task. Human observers (21 female; 20 male) were poorer at tracking objects between- versus within-hemifields, reflecting a cost of interhemispheric integration. Critically, gamma coherence was greater in trials requiring interhemispheric integration, particularly between sensors over parieto-occipital areas. In approximately half of the participants, the observed cost of integration was associated with a failure of the cerebral hemispheres to become coherent in the gamma band. Moreover, individual differences in this integration cost correlated with endogenous gamma coherence at these same sensors, though with generally opposing relationships for the real and imaginary part of coherence. The real part (capturing synchronisation with a near-zero phase-lag) benefited between-hemifield tracking; imaginary coherence was detrimental. Finally, instantaneous phase-coherence over the tracking period uniquely predicted between-hemifield tracking performance, suggesting that effective integration benefits from sustained interhemispheric synchronisation. Our results show that gamma coherence mediates interhemispheric integration during MOT, and add to a growing body of work demonstrating that coherence drives communication across cortically distributed neural networks.
  • Association of polygenic score for major depression with response to lithium in patients with bipolar disorder

    Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLiGen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18–2.01) and European sample: OR = 1.75 (95% CI: 1.30–2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61–4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.
  • Author Correction: Understanding the role of bitter taste perception in coffee, tea and alcohol consumption through Mendelian randomization

    An amendment to this paper has been published and can be accessed via a link at the top of the paper. The original version of this Article contained an error in the author name Liang-Dar Hwang, which was incorrectly given as Daniel Liang-Dar Hwang.
  • Opening of smaller toxin pores by lipid micelle formation

  • Analysis of DNA methylation associates the cystine–glutamate antiporter SLC7A11 with risk of Parkinson’s disease

    An improved understanding of etiological mechanisms in Parkinson’s disease (PD) is urgently needed because the number of affected individuals is projected to increase rapidly as populations age. We present results from a blood-based methylome-wide association study of PD involving meta-analysis of 229 K CpG probes in 1,132 cases and 999 controls from two independent cohorts. We identify two previously unreported epigenome-wide significant associations with PD, including cg06690548 on chromosome 4. We demonstrate that cg06690548 hypermethylation in PD is associated with down-regulation of the SLC7A11 gene and show this is consistent with an environmental exposure, as opposed to medications or genetic factors with effects on DNA methylation or gene expression. These findings are notable because SLC7A11 codes for a cysteine-glutamate anti-porter regulating levels of the antioxidant glutathione, and it is a known target of the environmental neurotoxin β-methylamino-L-alanine (BMAA). Our study identifies the SLC7A11 gene as a plausible biological target in PD.
  • Lillies: An R package for the estimation of excess life years lost among patients with a given disease or condition

    Life expectancy at a given age is a summary measure of mortality rates present in a population (estimated as the area under the survival curve), and represents the average number of years an individual at that age is expected to live if current age-specific mortality rates apply now and in the future. A complementary metric is the number of Life Years Lost, which is used to measure the reduction in life expectancy for a specific group of persons, for example those diagnosed with a specific disease or condition (e.g. smoking). However, calculation of life expectancy among those with a specific disease is not straightforward for diseases that are not present at birth, and previous studies have considered a fixed age at onset of the disease, e.g. at age 15 or 20 years. In this paper, we present the R package lillies (freely available through the Comprehensive R Archive Network; CRAN) to guide the reader on how to implement a recently-introduced method to estimate excess Life Years Lost associated with a disease or condition that overcomes these limitations. In addition, we show how to decompose the total number of Life Years Lost into specific causes of death through a competing risks model, and how to calculate confidence intervals for the estimates using non-parametric bootstrap. We provide a description on how to use the method when the researcher has access to individual-level data (e.g. electronic healthcare and mortality records) and when only aggregated-level data are available.
  • Repopulating Microglia Promote Brain Repair in an IL-6-Dependent Manner

    Cognitive dysfunction and reactive microglia are hallmarks of traumatic brain injury (TBI), yet whether these cells contribute to cognitive deficits and secondary inflammatory pathology remains poorly understood. Here, we show that removal of microglia from the mouse brain has little effect on the outcome of TBI, but inducing the turnover of these cells through either pharmacologic or genetic approaches can yield a neuroprotective microglial phenotype that profoundly aids recovery. The beneficial effects of these repopulating microglia are critically dependent on interleukin-6 (IL-6) trans-signaling via the soluble IL-6 receptor (IL-6R) and robustly support adult neurogenesis, specifically by augmenting the survival of newborn neurons that directly support cognitive function. We conclude that microglia in the mammalian brain can be manipulated to adopt a neuroprotective and pro-regenerative phenotype that can aid repair and alleviate the cognitive deficits arising from brain injury.Microglia in the mammalian brain can be manipulated to adopt a neuroprotective and pro-regenerative phenotype that can aid repair and alleviate the cognitive deficits arising from brain injury.
  • Erratum: Correction: Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia (Molecular psychiatry (2020) 25 3 (584-602))

    Prior to and following the publication of this article the authors noted that the complete list of authors was not included in the main article and was only present in Supplementary Table 1. The author list in the original article has now been updated to include all authors, and Supplementary Table 1 has been removed. All other supplementary files have now been updated accordingly. Furthermore, in Table 1 of this Article, the replication cohort for the row Close relative in data set, n (%) was incorrect. All values have now been corrected to 0(0%). The publishers would like to apologise for this error and the inconvenience it may have caused.
  • Bayesian population receptive field modeling in human somatosensory cortex

    Somatosensation is fundamental to our ability to sense our body and interact with the world. Our body is continuously sampling the environment using a variety of receptors tuned to different features, and this information is routed up to primary somatosensory cortex. Strikingly, the spatial organization of the peripheral receptors in the body are well maintained, with the resulting representation of the body in the brain being referred to as the somatosensory homunculus. Recent years have seen considerable advancements in the field of high-resolution fMRI, which have enabled an increasingly detailed examination of the organization and properties of this homunculus. Here we combined advanced imaging techniques at ultra-high field (7T) with a recently developed Bayesian population receptive field (pRF) modeling framework to examine pRF properties in primary somatosensory cortex. In each subject, vibrotactile stimulation of the fingertips (i.e., the peripheral mechanoreceptors) modulated the fMRI response along the post-central gyrus and these signals were used to estimate pRFs. We found the pRF center location estimates to be in accord with previous work as well as evidence of other properties in line with the underlying neurobiology. Specifically, as expected from the known properties of cortical magnification, we find a larger representation of the index finger compared to the other stimulated digits (middle, index, little). We also show evidence that the little finger is marked by the largest pRF sizes, and that pRF size increases from anterior to posterior regions of S1. The ability to estimate somatosensory pRFs in humans provides an unprecedented opportunity to examine the neural mechanisms underlying somatosensation and is critical for studying how the brain, body, and environment interact to inform perception and action.
  • The epidemiology of alcohol use disorders cross-nationally: findings from the World Mental Health Surveys

    Background: Prevalences of Alcohol Use Disorders (AUDs) and Mental Health Disorders (MHDs) in many individual countries have been reported but there are few cross-national studies. The WHO World Mental Health (WMH) Survey Initiative standardizes methodological factors facilitating comparison of the prevalences and associated factors of AUDs in a large number of countries to identify differences and commonalities. Methods: Lifetime and 12-month prevalence estimates of DSM-IV AUDs, MHDs, and associations were assessed in the 29 WMH surveys using the WHO CIDI 3.0. Results: Prevalence estimates of alcohol use and AUD across countries and WHO regions varied widely. Mean lifetime prevalence of alcohol use in all countries combined was 80%, ranging from 3.8% to 97.1%. Combined average population lifetime and 12-month prevalence of AUDs were 8.6% and 2.2% respectively and 10.7% and 4.4% among non-abstainers. Of individuals with a lifetime AUD, 43.9% had at least one lifetime MHD and 17.9% of respondents with a lifetime MHD had a lifetime AUD. For most comorbidity combinations, the MHD preceded the onset of the AUD. AUD prevalence was much higher for men than women. 15% of all lifetime AUD cases developed before age 18. Higher household income and being older at time of interview, married, and more educated, were associated with a lower risk for lifetime AUD and AUD persistence. Conclusions: Prevalence of alcohol use and AUD is high overall, with large variation worldwide. The WMH surveys corroborate the wide geographic consistency of a number of well-documented clinical and epidemiological findings and patterns.
  • A new frequency domain passive acoustic mapping method using passive Hilbert beamforming to reduce the computational complexity of fast Fourier transform

    Passive acoustic mapping (PAM) is the current state-of-the-art imaging tool for monitoring cavitation activity during focused ultrasound therapy such as blood-brain barrier opening. However, PAM incurs huge computational complexity. To address this issue, frequency-domain PAM (FD-PAM) was proposed. Nevertheless, FD-PAM still requires a large number of fast Fourier transforms (FFTs) to produce the frequency components utilized for cavitation monitoring with PAM. Hence, in this paper, we proposes a frequency domain PAM method using passive Hilbert beamforming (PHB-PAM), which can significantly reduce the number of input samples for FFT by down-sampling the analytic signal of the received RF samples at each channel at a rate equal to the bandwidth of the frequency components of interest. The experimental results show that the proposed PHB-PAM provides comparable image quality to that of FD-PAM (correlation coefficient > 0.98). Additionally, the study experimentally verifies that the pre-processing block for generating the decimated analytic signal and FFT in PHB-PAM can be realized using lesser logic resources than FFT in FD-PAM when implemented in an FPGA. Especially, with 128-fold decimation, PHB-PAM reduces the amount of LUTs and DSP slices to implement the pre-processing block by 72.16% and 53.4%, respectively, compared to those of FD-PAM, which allows the 64-channel implementation of the pre-processing block in a low-cost single FPGA. Finally, a hardware-efficient architecture for the pre-processing block of PHB-PAM is described, which can be implemented by replacing the two lowpass filters of an off-the-shelf analog front-end component for ultrasound imaging with a pair of band-pass filters. If PHB-PAM is realized using such a component, it can truly minimize the computational complexity of FD-PAM.
  • Overcoming challenges and dogmas to understand the functions of pseudogenes

    Pseudogenes are defined as regions of the genome that contain defective copies of genes. They exist across almost all forms of life, and in mammalian genomes are annotated in similar numbers to recognized protein-coding genes. Although often presumed to lack function, growing numbers of pseudogenes are being found to play important biological roles. In consideration of their evolutionary origins and inherent limitations in genome annotation practices, we posit that pseudogenes have been classified on a scientifically unsubstantiated basis. We reflect that a broad misunderstanding of pseudogenes, perpetuated in part by the pejorative inference of the 'pseudogene' label, has led to their frequent dismissal from functional assessment and exclusion from genomic analyses. With the advent of technologies that simplify the study of pseudogenes, we propose that an objective reassessment of these genomic elements will reveal valuable insights into genome function and evolution.
  • Significant out-of-sample classification from methylation profile scoring for amyotrophic lateral sclerosis

    We conducted DNA methylation association analyses using Illumina 450K data from whole blood for an Australian amyotrophic lateral sclerosis (ALS) case–control cohort (782 cases and 613 controls). Analyses used mixed linear models as implemented in the OSCA software. We found a significantly higher proportion of neutrophils in cases compared to controls which replicated in an independent cohort from the Netherlands (1159 cases and 637 controls). The OSCA MOMENT linear mixed model has been shown in simulations to best account for confounders. When combined in a methylation profile score, the 25 most-associated probes identified by MOMENT significantly classified case–control status in the Netherlands sample (area under the curve, AUC = 0.65, CI = [0.62–0.68], p = 8.3 × 10). The maximum AUC achieved was 0.69 (CI = [0.66–0.71], p = 4.3 × 10) when cell-type proportion was included in the predictor.
  • Mapping interactions among cell-free expressed Zirka virus proteins

    The rapid spread of arthropod-borne Zika virus poses a serious public health threat that calls for effective ways of controlling and treating viral infection. This in turn necessitates better understanding of the mechanisms of virus assembly and its interaction with the host cells. In order to facilitate such efforts, we developed a new multihost expression vector pmCellFree that allows rapid and multiplexed production of ZIKV proteins in any in vitro translation system as well as in mammalian cells. Using a combination of in vitro expression in Leishmania cell-free system and AlphaLISA interaction assay, pairwise protein interactions of all ZIKV proteins were systematically tested. We identified thirty-three intraviral binary protein interactions, of which 13 interactions are novel. These findings were further validated by expressing selected protein pairs in mammalian HEK293T cell line and assessing their interactions in the cellular lysate. The results of these interaction assays were identical to those obtained with in vitro expressed proteins. The observed novel protein–protein interactions were further validated using a pulldown assay. The unrevealed novel protein interactions may point to the previously unappreciated complexity of the ZIKV assembly process and may play an important role in the infection process. These interactions may represent new targets for antiviral drug development.
  • Microhabitat partitioning correlates with opsin gene expression in coral reef cardinalfishes (Apogonidae)

    Fish are the most diverse vertebrate group, and they have evolved equally diverse visual systems, varying in terms of eye morphology, number and distribution of spectrally distinct photoreceptor types, visual opsin genes and opsin gene expression levels. This variation is mainly due to adaptations driven by two factors: differences in the light environments and behavioural tasks. However, while the effects of large-scale habitat differences are well described, it is less clear whether visual systems also adapt to differences in environmental light at the microhabitat level. To address this, we assessed the relationship between microhabitat use and visual system features in fishes inhabiting coral reefs, where habitat partitioning is particularly common. We suggest that differences in microhabitat use by cardinalfishes (Apogonidae) drive morphological and molecular adaptations in their visual systems. To test this, we investigated diurnal microhabitat use in 17 cardinalfish species and assessed whether this correlated with differences in visual opsin gene expression and eye morphology. We found that cardinalfishes display six types of microhabitat partitioning behaviours during the day, ranging from specialists found exclusively in the water column to species that are always hidden inside the reef matrix. Species predominantly found in exposed microhabitats had higher expression of the short-wavelength-sensitive violet opsin (SWS2B) and lower expression of the dim-light active rod opsin (RH1). Species of intermediate exposure, on the other hand, expressed opsins that are mostly sensitive to the blue-green central part of the light spectrum (SWS2As and RH2s), while fishes entirely hidden in the reef substrate had a higher expression of the long-wavelength-sensitive red opsin. We also found that eye size relative to body size differed between cardinalfish species, and relative eye size decreased with an increase in habitat exposure. Retinal topography did not show co-adaptation with microhabitat use, but data suggested co-adaptation with feeding mode. We suggest that, although most cardinalfishes are nocturnal foragers, their visual systems—and possibly those of other (reef) fishes—have also adapted to the light intensity and the light spectrum of their preferred diurnal microhabitats. A free Plain language summary can be found within the Supporting Information of this article.
  • Polygenic risk score for bipolar disorder and school grades

  • Effects of unilateral cortical resection of the visual cortex on bilateral human white matter

    Children with unilateral resections of ventral occipito-temporal cortex (VOTC) typically do not evince visual perceptual impairments, even when relatively large swathes of VOTC are resected. In search of possible explanations for this behavioral competence, we evaluated white matter microstructure and connectivity in eight pediatric epilepsy patients following unilateral cortical resection and 15 age-matched controls. To uncover both local and broader resection-induced effects, we analyzed tractography data using two complementary approaches. First, the microstructural properties were measured in the inferior longitudinal and the inferior fronto-occipital fasciculi, the major VOTC association tracts. Group differences were only evident in the ipsilesional, and not in the contralesional, hemisphere, and single-subject analyses revealed that these differences were limited to the site of the resection. Second, graph theory was used to characterize the connectivity of the contralesional occipito-temporal regions. There were no changes to the network properties in patients with left VOTC resections nor in patients with resections outside the VOTC, but altered network efficiency was observed in two cases with right VOTC resections. These results suggest that, in many, although perhaps not all, cases of unilateral VOTC resections in childhood, the white matter profile in the preserved contralesional hemisphere along with residual neural activity might be sufficient for normal visual perception.
  • Monocytes and neutrophils are associated with clinical features in amyotrophic lateral sclerosis

    Immunity has emerged as a key player in neurodegenerative diseases such as amyotrophic lateral sclerosis, with recent studies documenting aberrant immune changes in patients and animal models. A challenging aspect of amyotrophic lateral sclerosis research is the heterogeneous nature of the disease. Here, we investigate the associations between peripheral blood myeloid cell populations and clinical features characteristic of amyotrophic lateral sclerosis. Peripheral blood leukocytes from 23 healthy controls and 48 patients with amyotrophic lateral sclerosis were analysed to measure myeloid cell alterations. The proportion of monocytes (classical, intermediates and non-classical subpopulations) and neutrophils, as well as the expression of select surface markers, were quantitated using flow cytometry. Given the heterogeneous nature of amyotrophic lateral sclerosis, multivariable linear analyses were performed to investigate associations between patients’ myeloid profile and clinical features, such as the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, Bulbar subscore of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale over disease duration and respiratory function. We demonstrate a shift in monocyte subpopulations in patients with amyotrophic lateral sclerosis, with the ratio of classical to non-classical monocytes increased compared to healthy controls. In line with this, patients with a greater disease severity, as determined by a lower Revised Amyotrophic Lateral Sclerosis Functional Rating Scale score, had reduced non-classical monocytes. Interestingly, patients with greater bulbar involvement had a reduction in the proportions of classical, intermediate and non-classical monocyte populations. We also revealed several notable associations between myeloid marker expression and clinical features in amyotrophic lateral sclerosis. CD16 expression on neutrophils was increased in patients with greater disease severity and a faster rate of disease progression, whereas HLA-DR expression on all monocyte populations was elevated in patients with greater respiratory impairment. This study demonstrates that patients with amyotrophic lateral sclerosis with distinct clinical features have differential myeloid cell signatures. Identified cell populations and markers may be candidates for targeted mechanistic studies and immunomodulation therapies in amyotrophic lateral sclerosis.
  • Subunit-specific augmentation of AMPA receptor ubiquitination by phorbol ester

    Excitatory neurotransmission relies on the precise targeting of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors to the neuronal plasma membrane. Activity-dependent ubiquitination of AMPA receptor (AMPAR) subunits sorts internalised receptors to late endosomes for degradation, which ultimately determines the number of AMPARs on neuronal membrane. Our recent study has demonstrated a functional cross-talk between the phosphorylation and ubiquitination of the GluA1 subunit in mammalian central neurons. However, the existence of such a cross modulation for the GluA2 subunit remains unknown. Here, we have shown that bicuculline induced GluA2 ubiquitination on the same lysine residues (Lys-870 and Lys-882) in the C-terminal as those elicited by the AMPA treatment. Interestingly, bicuculline-induced ubiquitination was markedly enhanced by the phospho-mimetic GluA2 S880E mutant. Pharmacological activation of protein kinase C (PKC) by phorbol ester, which mediates the phosphorylation of GluA2 at Ser-880, augmented bicuculline-induced ubiquitination of GluA2 in cultured neurons. This effect was specific for the GluA2 subunit because phorbol ester did not alter the level of GluA1 ubiquitination. However, phorbol ester-induced enhancement of GluA2 ubiquitination did not require Ser-880 phosphorylation. This suggests that pseudo-phosphorylation of Ser-880 is sufficient but is not necessary for the augmentation of bicuculline-induced GluA2 ubiquitination. Collectively, these data provide the first demonstration of subunit-specific modulation of AMPAR ubiquitination by the PKC-dependent signalling pathway in mammalian central neurons.
  • Genome-wide association study of dietary intake in the UK biobank study and its associations with schizophrenia and other traits

    Motivated by observational studies that report associations between schizophrenia and traits, such as poor diet, increased body mass index and metabolic disease, we investigated the genetic contribution to dietary intake in a sample of 335,576 individuals from the UK Biobank study. A principal component analysis applied to diet question item responses generated two components: Diet Component 1 (DC1) represented a meat-related diet and Diet Component 2 (DC2) a fish and plant-related diet. Genome-wide association analysis identified 29 independent single-nucleotide polymorphisms (SNPs) associated with DC1 and 63 SNPs with DC2. Estimated from over 35,000 3rd-degree relative pairs that are unlikely to share close family environments, heritabilities for both DC1 and DC2 were 0.16 (standard error (s.e.) = 0.05). SNP-based heritability was 0.06 (s.e. = 0.003) for DC1 and 0.08 (s.e = 0.004) for DC2. We estimated significant genetic correlations between both DCs and schizophrenia, and several other traits. Mendelian randomisation analyses indicated a negative uni-directional relationship between liability to schizophrenia and tendency towards selecting a meat-based diet (which could be direct or via unidentified correlated variables), but a bi-directional relationship between liability to schizophrenia and tendency towards selecting a fish and plant-based diet consistent with genetic pleiotropy.
  • Contrast sensitivity and visual acuity of Queensland fruit flies (Bactrocera tryoni)

    This study examines the visual acuity of Queensland fruit flies (Bactrocera tryoni) by analysing their turning responses to an immersive visual stimulus consisting of a pattern of vertical stripes presented at various angular periods and rotational rates. The results infer that these flies possess an interommatidial angle of approximately 2∘ , and an ommatidial acceptance angle of approximately 1.72∘ . This suggests that the visual acuity of Queensland fruit flies is substantially better than that of the classical vinegar fly (Drosophila melanogaster), and is comparable to those of the housefly (Musca domestica) and the honeybee (Apis mellifera). The contrast sensitivity of Queensland fruit flies is comparable to that of the housefly.
  • RICOPILI: Rapid Imputation for COnsortias PIpeLIne

    SUMMARY: Genome-wide association study (GWAS) analyses, at sufficient sample sizes and power, have successfully revealed biological insights for several complex traits. RICOPILI, an open-sourced Perl-based pipeline was developed to address the challenges of rapidly processing large-scale multi-cohort GWAS studies including quality control (QC), imputation and downstream analyses. The pipeline is computationally efficient with portability to a wide range of high-performance computing environments. RICOPILI was created as the Psychiatric Genomics Consortium pipeline for GWAS and adopted by other users. The pipeline features (i) technical and genomic QC in case-control and trio cohorts, (ii) genome-wide phasing and imputation, (iv) association analysis, (v) meta-analysis, (vi) polygenic risk scoring and (vii) replication analysis. Notably, a major differentiator from other GWAS pipelines, RICOPILI leverages on automated parallelization and cluster job management approaches for rapid production of imputed genome-wide data. A comprehensive meta-analysis of simulated GWAS data has been incorporated demonstrating each step of the pipeline. This includes all the associated visualization plots, to allow ease of data interpretation and manuscript preparation. Simulated GWAS datasets are also packaged with the pipeline for user training tutorials and developer work. AVAILABILITY AND IMPLEMENTATION: RICOPILI has a flexible architecture to allow for ongoing development and incorporation of newer available algorithms and is adaptable to various HPC environments (QSUB, BSUB, SLURM and others). Specific links for genomic resources are either directly provided in this paper or via tutorials and external links. The central location hosting scripts and tutorials is found at this URL: https://sites.google.com/a/broadinstitute.org/RICOPILI/home. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
  • Idea formulation for spoken language production: the interface of cognition and language

    Language and communication are fundamental to the human experience, and, traditionally, spoken language is studied as an isolated skill. However, before propositional language (i.e., spontaneous, voluntary, novel speech) can be produced, propositional content or 'ideas' must be formulated.

    This review highlights the role of broader cognitive processes, particularly 'executive attention', in the formulation of propositional content (i.e., 'ideas') for propositional language production.

    Several key lines of evidence converge to suggest that the formulation of ideas for propositional language production draws on executive attentional processes. Larger-scale clinical research has demonstrated a link between attentional processes and language, while detailed case studies of neurological patients have elucidated specific idea formulation mechanisms relating to the generation, selection and sequencing of ideas for expression. Furthermore, executive attentional processes have been implicated in the generation of ideas for propositional language production. Finally, neuroimaging studies suggest that a widely distributed network of brain regions, including parts of the prefrontal and parietal cortices, supports propositional language production.

    Theoretically driven experimental research studies investigating mechanisms involved in the formulation of ideas are lacking. We suggest that novel experimental approaches are needed to define the contribution of executive attentional processes to idea formulation, from which comprehensive models of spoken language production can be developed. Clinically, propositional language impairments should be considered in the context of broader executive attentional deficits.
  • Modulating brain activity and behaviour with tDCS: Rumours of its death have been greatly exaggerated

    Transcranial electrical brain stimulation (tES) techniques have shown substantial promise in research and applied settings. However, over the last few years the technique has courted significant controversy, resulting in scepticism regarding its reported beneficial effects and future potential. In this opinion article, we examine the key points of criticism raised to date, including whether tES has any meaningful effect on the cortex, issues of replicability, and the variability in its efficacy across individuals. For each point, we assess the strength of the evidence for and against the argument and, where relevant, suggest how the field can improve. We conclude that while some of the highlighted shortcomings of research using electrical brain stimulation are justified, on balance the arguments against using such techniques in cognitive neuroscience are often overstated and elevate the risk of the field “throwing the baby out with the bath water”.
  • Paternal-age-related de novo mutations and risk for five disorders

    Epidemiologic associations have been made between advanced paternal age and increased offspring risk of autism spectrum disorder (ASD), schizophrenia (SCZ), congenital heart disease (CHD), epilepsy (EPI), and intellectual disability (ID). This association have been often attributed to de novo single nucleotide variants (dnSNVs) that occur 3 to 4 times more often in paternal compared with maternal germ cells.
  • Exposure to air pollution during childhood and risk of developing schizophrenia: a national cohort study

    Background: Ambient air pollution affects neurological function, but its association with schizophrenia risk is unclear. We investigated exposure to nitrogen oxides (NO) as a whole and nitrogen dioxide (NO) specifically, as well as PM, and PM, during childhood and subsequent schizophrenia risk. Methods: People born in Denmark from 1980 to 1984 (N=230 844), who were residing in the country on their tenth birthday, and who had two Danish-born parents were followed-up from their tenth birthday until schizophrenia diagnosis or Dec 31, 2016. Mean daily exposure to each pollutant (NO, NO, PM, and PM) at all of an individual's residential addresses from birth to their tenth birthday was modelled. Incidence rate ratios, cumulative incidence, and population attributable risks were calculated using survival analysis techniques. Findings: We analysed data between Aug 1, 2018, and Nov 15, 2019. Of 230 844 individuals included, 2189 cohort members were diagnosed with schizophrenia during follow-up. Higher concentrations of residential NO and NO exposure during childhood were associated with subsequent elevated schizophrenia risk. People exposed to daily mean concentrations of more than 26·5 μg/m NO had a 1·62 (95% CI 1·41–1·87) times increased risk compared with people exposed to a mean daily concentration of less than 14·5 μg/m. The absolute risks of developing schizophrenia by the age of 37 years when exposed to daily mean concentrations of more than 26·5 μg/m NO between birth and 10 years were 1·45% (95% CI 1·30–1·62%) for men and 1·03% (0·90–1·17) for women, whereas when exposed to a mean daily concentration of less than 14·5 μg/m, the risk was 0·80% (95% CI 0·69–0·92%) for men and 0·67% (0·57–0·79) for women. Associations between exposure to PM or PM and schizophrenia risk were less consistent. Interpretation: If the association between air pollution and schizophrenia is causal, reducing ambient air pollution including NO and NO could have a potentially considerable effect on lowering schizophrenia incidence at the population level. Further investigations are necessary to establish a causal relationship. Funding: Lundbeck Foundation, Stanley Medical Research Institute, European Research Council, NordForsk, Novo Nordisk Foundation, National Health and Medical Research Council, Danish National Research Foundation.
  • Adherens junctions: guardians of cortical development

    Apical radial glia comprise the pseudostratified neuroepithelium lining the embryonic lateral ventricles and give rise to the extensive repertoire of pyramidal neuronal subtypes of the neocortex. The establishment of a highly apicobasally polarized radial glial morphology is a mandatory prerequisite for cortical development as it governs neurogenesis, neural migration and the integrity of the ventricular wall. As in all epithelia, cadherin-based adherens junctions (AJs) play an obligate role in the maintenance of radial glial apicobasal polarity and neuroepithelial cohesion. In addition, the assembly of resilient AJs is critical to the integrity of the neuroepithelium which must resist the tensile forces arising from increasing CSF volume and other mechanical stresses associated with the expansion of the ventricles in the embryo and neonate. Junctional instability leads to the collapse of radial glial morphology, disruption of the ventricular surface and cortical lamination defects due to failed neuronal migration. The fidelity of cortical development is therefore dependent on AJ assembly and stability. Mutations in genes known to control radial glial junction formation are causative for a subset of inherited cortical malformations (neuronal heterotopias) as well as perinatal hydrocephalus, reinforcing the concept that radial glial junctions are pivotal determinants of successful corticogenesis. In this review we explore the key animal studies that have revealed important insights into the role of AJs in maintaining apical radial glial morphology and function, and as such, have provided a deeper understanding of the aberrant molecular and cellular processes contributing to debilitating cortical malformations. We highlight the reciprocal interactions between AJs and the epithelial polarity complexes that impose radial glial apicobasal polarity. We also discuss the critical molecular networks promoting AJ assembly in apical radial glia and emphasize the role of the actin cytoskeleton in the stabilization of cadherin adhesion – a crucial factor in buffering the mechanical forces exerted as a consequence of cortical expansion.
  • Fear conditioning and the basolateral amygdala

    Fear is a response to impending threat that prepares a subject to make appropriate defensive responses, whether to freeze, fight, or flee to safety. The neural circuits that underpin how subjects learn about cues that signal threat, and make defensive responses, have been studied using Pavlovian fear conditioning in laboratory rodents as well as humans. These studies have established the amygdala as a key player in the circuits that process fear and led to a model where fear learning results from long-term potentiation of inputs that convey information about the conditioned stimulus to the amygdala. In this review, we describe the circuits in the basolateral amygdala that mediate fear learning and its expression as the conditioned response. We argue that while the evidence linking synaptic plasticity in the basolateral amygdala to fear learning is strong, there is still no mechanism that fully explains the changes that underpin fear conditioning.
  • Differences in signal contrast and camouflage among different colour variations of a stomatopod crustacean, Neogonodactylus oerstedii

    Animal colouration is often a trade-off between background matching for camouflage from predators, and conspicuousness for communication with con- or heterospecifics. Stomatopods are marine crustaceans known to use colour signals during courtship and contests, while their overall body colouration may provide camouflage. However, we have little understanding of how stomatopods perceive these signals in their environment or whether overall body coloration does provide camouflage from predators. Neogonodactylus oerstedii assess meral spot colour during contests, and meral spot colour varies depending on local habitat. By calculating quantum catch for N. oerstedii’s 12 photoreceptors associated with chromatic vision, we found that variation in meral spot total reflectance does not function to increase signal contrast in the local habitat. Neogonodactylus oerstedii also show between-habitat variation in dorsal body colouration. We used visual models to predict a trichromatic fish predator’s perception of these colour variations. Our results suggest that sandy and green stomatopods are camouflaged from a typical fish predator in rubble fields and seagrass beds, respectively. To our knowledge, this is the first study to investigate signal contrast and camouflage in a stomatopod. These results provide new insight into the function and evolution of colouration in a species with a complex visual system.
  • Regulation of NMDA glutamate receptor functions by the GluN2 subunits

    The N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors that mediate the flux of calcium (Ca ) into the postsynaptic compartment. Calcium influx subsequently triggers the activation of various intracellular signaling cascades that underpin multiple forms of synaptic plasticity. Functional NMDARs are assembled as heterotetramers composed of two obligatory GluN1 subunits and two GluN2 or GluN3 subunits. Four different GluN2 subunits (GluN2A-D) are present throughout the central nervous system; however, they are differentially expressed, both developmentally and spatially, in a cell- and synapse-specific manner. Each GluN2 subunit confers NMDARs with distinct ion channel properties and intracellular trafficking pathways. Regulated membrane trafficking of NMDARs is a dynamic process that ultimately determines the number of NMDARs at synapses, and is controlled by subunit-specific interactions with various intracellular regulatory proteins. Here we review recent progress made towards understanding the molecular mechanisms that regulate the trafficking of GluN2-containing NMDARs, focusing on the roles of several key synaptic proteins that interact with NMDARs via their carboxyl termini.
  • Toward an MRI-based mesoscale connectome of the squid brain

    Using high-resolution diffusion magnetic resonance imaging (dMRI) and a suite of old and new staining techniques, the beginnings of a multi-scale connectome map of the squid brain is erected. The first of its kind for a cephalopod, this includes the confirmation of 281 known connections with the addition of 145 previously undescribed pathways. These and other features suggest a suite of functional attributes, including (1) retinotopic organization through the optic lobes and into other brain areas well beyond that previously recognized, (2) a level of complexity and sub-division in the basal lobe supporting ideas of convergence with the vertebrate basal ganglia, and (3) differential lobe-dependent growth rates that mirror complexity and transitions in ontogeny.
  • Neural dynamics of the attentional blink revealed by encoding orientation selectivity during rapid visual presentation

    The human brain is inherently limited in the information it can make consciously accessible. When people monitor a rapid stream of visual items for two targets, they typically fail to see the second target if it occurs within 200-500 ms of the first, a phenomenon called the attentional blink (AB). The neural basis for the AB is poorly understood, partly because conventional neuroimaging techniques cannot resolve visual events displayed close together in time. Here we introduce an approach that characterises the precise effect of the AB on behaviour and neural activity. We employ multivariate encoding analyses to extract feature-selective information carried by randomly-oriented gratings. We show that feature selectivity is enhanced for correctly reported targets and suppressed when the same items are missed, whereas irrelevant distractor items are unaffected. The findings suggest that the AB involves both short- and long-range neural interactions between visual representations competing for access to consciousness.
  • The ubiquitin system: a regulatory hub for intellectual disability and autism spectrum disorder

    Intellectual disability (ID) and autism spectrum disorder (ASD) are two of the most common neurodevelopmental disorders. Both disorders are extremely heterogenous, and only ~ 40% of reported cases have so far been attributed to genetic mutations. Of the many cellular processes that are affected, the ubiquitin system (UbS) is of particular relevance in that it can rapidly regulate multiple signaling cascades simultaneously. The UbS is a post-translational modification process that revolves around the covalent attachment of a ubiquitin moiety to a substrate, thereby influencing different elements of protein biology, including trafficking, signal transduction, and degradation. Importantly, the UbS has been implicated in regulating multiple pathophysiological pathways related to ASD and ID. This review will discuss how the UbS acts as major signaling hub in the pathogenesis of ASD and ID, raising the prospect of treating broader patient cohorts by targeting the UbS as a common point of convergence of various mutations.
  • Genome-wide gene-environment analyses of major depressive disorder and reported lifetime traumatic experiences in UK Biobank

    Depression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of genetic risk factors, is complex and poorly understood. When modelling trauma exposure as an environmental influence on depression, both gene-environment correlations and gene-environment interactions have been observed. The UK Biobank concurrently assessed Major Depressive Disorder (MDD) and self-reported lifetime exposure to traumatic events in 126,522 genotyped individuals of European ancestry. We contrasted genetic influences on MDD stratified by reported trauma exposure (final sample size range: 24,094-92,957). The SNP-based heritability of MDD with reported trauma exposure (24%) was greater than MDD without reported trauma exposure (12%). Simulations showed that this is not confounded by the strong, positive genetic correlation observed between MDD and reported trauma exposure. We also observed that the genetic correlation between MDD and waist circumference was only significant in individuals reporting trauma exposure (r = 0.24, p = 1.8 × 10 versus r = -0.05, p = 0.39 in individuals not reporting trauma exposure, difference p = 2.3 × 10). Our results suggest that the genetic contribution to MDD is greater when reported trauma is present, and that a complex relationship exists between reported trauma exposure, body composition, and MDD.
  • 7T MR neurography-ultrasound fusion for peripheral nerve imaging

    Background We present one patient with an initial diagnosis of Guillain-Barre syndrome (GBS) and one with Charcot-Marie-Tooth disease (CMT) type 1A. Methods Both patients underwent ankle tibial nerve fusion-imaging of high-resolution ultrasound (HRUS) with 7T MR neurography (MRN). Results In GBS, the nerve was enlarged, T2-hyperintense, and showed increased vascularization 21 months after symptom onset. In CMT1A, the enlarged nerve was T2-isointense with normal endoneurial blood flow. Conclusions We demonstrate the utility of 7T-MRN-HRUS-fusion-imaging. In GBS, there was evidence of ongoing inflammation resulting in a changed diagnosis to acute-onset chronic demyelinating polyradiculoneuropathy and maintenance of immunotherapy. By MRN-HRUS-fusion, patients with presumed peripheral axonal degeneration could be shown to display imaging markers associated with peripheral nervous system inflammation. Thus, more accurate identification of a treatable inflammatory component may become possible.
  • Cortisol and major depressive disorder-translating findings from humans to animal models and back

    Major depressive disorder (MDD) is a global problem for which current pharmacotherapies are not completely effective. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has long been associated with MDD; however, the value of assessing cortisol as a biological benchmark of the pathophysiology or treatment of MDD is still debated. In this review, we critically evaluate the relationship between HPA axis dysfunction and cortisol level in relation to MDD subtype, stress, gender and treatment regime, as well as in rodent models. We find that an elevated cortisol response to stress is associated with acute and severe, but not mild or atypical, forms of MDD. Furthermore, the increased incidence of MDD in females is associated with greater cortisol response variability rather than higher baseline levels of cortisol. Despite almost all current MDD treatments influencing cortisol levels, we could find no convincing relationship between cortisol level and therapeutic response in either a clinical or preclinical setting. Thus, we argue that the absolute level of cortisol is unreliable for predicting the efficacy of antidepressant treatment. We propose that future preclinical models should reliably produce exaggerated HPA axis responses to acute or chronic stress a priori, which may, or may not, alter baseline cortisol levels, while also modelling the core symptoms of MDD that can be targeted for reversal. Combining genetic and environmental risk factors in such a model, together with the interrogation of the resultant molecular, cellular, and behavioral changes, promises a new mechanistic understanding of MDD and focused therapeutic strategies.
  • A multi-contrast MRI approach to thalamus segmentation

    Thalamic alterations occur in many neurological disorders including Alzheimer's disease, Parkinson's disease and multiple sclerosis. Routine interventions to improve symptom severity in movement disorders, for example, often consist of surgery or deep brain stimulation to diencephalic nuclei. Therefore, accurate delineation of grey matter thalamic subregions is of the upmost clinical importance. MRI is highly appropriate for structural segmentation as it provides different views of the anatomy from a single scanning session. Though with several contrasts potentially available, it is also of increasing importance to develop new image segmentation techniques that can operate multi-spectrally. We hereby propose a new segmentation method for use with multi-modality data, which we evaluated for automated segmentation of major thalamic subnuclear groups using T-1-weighted, T2*-weighted and quantitative susceptibility mapping (QSM) information. The proposed method consists of four steps: Highly iterative image co-registration, manual segmentation on the average training-data template, supervised learning for pattern recognition, and a final convex optimisation step imposing further spatial constraints to refine the solution. This led to solutions in greater agreement with manual segmentation than the standard Morel atlas based approach. Furthermore, we show that the multi-contrast approach boosts segmentation performances. We then investigated whether prior knowledge using the training-template contours could further improve convex segmentation accuracy and robustness, which led to highly precise multi-contrast segmentations in single subjects. This approach can be extended to most 3D imaging data types and any region of interest discernible in single scans or multi-subject templates.
  • Sleep restores place learning to the adenylyl cyclase mutant rutabaga

    Sleep plays an important role in regulating plasticity. In Drosophila, the relationship between sleep and learning and memory has primarily focused on mushroom body dependent operant-learning assays such as aversive phototaxic suppression and courtship conditioning. In this study, sleep was increased in the classic mutant rutabaga (rut) and dunce (dnc) by feeding them the GABA-A agonist gaboxadol (Gab). Performance was evaluated in each mutant in response to social enrichment and place learning, tasks that do not require the mushroom body. Gab-induced sleep did not restore behavioral plasticity to either rut or dnc mutants following social enrichment. However, increased sleep restored place learning to rut mutants. These data extend the positive effects of enhanced sleep to place learning and highlight the utility of Gab for elucidating the beneficial effects of sleep on brain functioning.
  • Partial loss of USP9X function leads to a male neurodevelopmental and behavioural disorder converging on TGFβ signalling

    The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.

    We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.

    Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory.

    Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function.
  • What are neurotransmitter release sites and do they interact?

    It has long been known that each neuron in both the central and peripheral nervous system has a large number of active zones. Nonetheless, how active zones are regulated to maintain a homeostatic release state and response to the constantly changing environment remains poorly understood. Due to its relatively simple structure and easy accessibility, the neuromuscular synapse (NM-synapse) continues to be used as a model synapse to examine the basic nature of synaptic neurotransmission. In the NM-synapse, quantal neurotransmitter release can occur spontaneously or triggered by invading nerve impulses. Past research has indicated that some active zones tend to be involved more with spontaneous quantal release than evoked quantal release. Furthermore, evoked quantal release has been shown to be highly non-uniform between active zones along nerve terminal branches. How these large numbers of active zones along the same nerve terminal are functionally correlated remains unclear. This review starts with the basic features of quantal neurotransmitter release, then progresses to the current knowledge on how the active zones interact with each other along the same nerve terminal.
  • Common functional networks in the mouse brain revealed by multi-centre resting-state fMRI analysis

    Preclinical applications of resting-state functional magnetic resonance imaging (rsfMRI) offer the possibility to non-invasively probe whole-brain network dynamics and to investigate the determinants of altered network signatures observed in human studies. Mouse rsfMRI has been increasingly adopted by numerous laboratories worldwide. Here we describe a multi-centre comparison of 17 mouse rsfMRI datasets via a common image processing and analysis pipeline. Despite prominent cross-laboratory differences in equipment and imaging procedures, we report the reproducible identification of several large-scale resting-state networks (RSN), including a mouse default-mode network, in the majority of datasets. A combination of factors was associated with enhanced reproducibility in functional connectivity parameter estimation, including animal handling procedures and equipment performance. RSN spatial specificity was enhanced in datasets acquired at higher field strength, with cryoprobes, in ventilated animals, and under medetomidine-isoflurane combination sedation. Our work describes a set of representative RSNs in the mouse brain and highlights key experimental parameters that can critically guide the design and analysis of future rodent rsfMRI investigations.
  • Blockade of TrkB but not p75 NTR activates a subpopulation of quiescent neural precursor cells and enhances neurogenesis in the adult mouse hippocampus

    Brain-derived neurotrophic factor signaling plays a major role in the regulation of hippocampal neurogenesis in the adult brain. While the majority of studies suggest that this is due to its effect on the survival and differentiation of newborn neurons, it remains unclear whether this signaling directly regulates neural precursor cell (NPC) activity and which of its two receptors, TrkB or the p75 neurotrophin receptor (p75 ) mediates this effect. Here, we examined both the RNA and protein expression of these receptors and found that TrkB but not p75 receptors are expressed by hippocampal NPCs in the adult mouse brain. Using a clonal neurosphere assay, we demonstrate that pharmacological blockade of TrkB receptors directly activates a distinct subpopulation of NPCs. Moreover, we show that administration of ANA-12, a TrkB-selective antagonist, in vivo either by systemic intraperitoneal injection or by direct infusion within the hippocampus leads to an increase in the production of new neurons. In contrast, we found that NPC-specific knockout of p75 had no effect on the proliferation of NPCs and did not alter neurogenesis in the adult hippocampus. Collectively, these results demonstrate a novel role of TrkB receptors in directly regulating the activity of a subset of hippocampal NPCs and suggest that the transient blockade of these receptors could be used to enhance adult hippocampal neurogenesis.
  • Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

    Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.