Recent QBI publications

  • 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.
  • 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.
  • 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”.
  • 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.
  • Cell-specific non-canonical amino acid labelling identifies changes in the de novo proteome during memory formation

    The formation of spatial long-term memory (LTM) requires the de novo synthesis of distinct sets of proteins; however, a non-biased examination of the de novo proteome in this process is lacking. Here, we generated a novel mouse strain, which enables cell-type-specific labelling of newly synthesised proteins with non-canonical amino acids (NCAAs) by genetically restricting the expression of the mutant tRNA synthetase, NLL-MetRS, to hippocampal neurons. By combining this labelling technique with an accelerated version of the active place avoidance task and bio-orthogonal non-canonical amino acid tagging (BONCAT) followed by SWATH quantitative mass spectrometry, we identified 156 proteins that were altered in synthesis in hippocampal neurons during spatial memory formation. In addition to observing increased synthesis of known proteins important in memory-related processes, such as glutamate receptor recycling, we also identified altered synthesis of proteins associated with mRNA splicing as a potential mechanism involved in spatial LTM formation.
  • White matter microstructural differences across major depressive disorder, bipolar disorder and schizophrenia: a tract-based spatial statistics study

    Background: White matter abnormalities have been implicated in mental disorders including major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ); however, the shared and distinct white matter integrity across mental disorders is still unclear. Methods: A total of 290 participants (MDD = 85, BD = 42, SZ = 68, and healthy controls = 95) were included in the present study. Tract-based spatial statistics were performed to measure fractional anisotropy (FA) and characterize shared and distinguishing white matter changes across mental disorders. Results: We found that decreased FA converged across MDD, BD and SZ in the body and genu of the corpus callosum, bilateral anterior and posterior corona radiata, and right superior corona radiata. By contrast, diagnosis-specific effect was only found in MDD in the anterior portion of anterior corona radiata. Limitations: The small and imbalanced sample size, and possible confounding effects of medication. Conclusions: Our findings suggest that abnormally reduced white matter integrity in the interhemispheric and thalamocortical circuit could be consistently involved in the pathogenesis of MDD, BD and SZ.
  • Functional maintenance in the multiple demand network characterizes superior fluid intelligence in aging

    The multiple demand network (MDN) is conceptualized as the core processing system for multitasking. Increasing evidence also provides strong support for the involvement of the MDN in fluid intelligence (gF), that is, the ability to solve new problems. However, the underlying neural mechanisms of declining intelligence in old age are poorly explored, particularly whether maintenance of the functional architecture of the MDN can characterize superior intelligence in successful aging. Here, we used eigenvector centrality (EC) to explore the resting-state functional architecture of the MDN in terms of its communication across the entire brain. We found gF to be negatively associated with age and that the MDN EC competitively mediated age-related decline in gF over the aging lifespan, suggesting that excessive cross-talk from the MDN is deleterious for intelligence. Critically, older individuals with comparable MDN EC as younger individuals exhibited superior gF compared with their age-matched counterparts. Taken together, these data provide support for the maintenance of youth-like functional architecture of the MDN and its implication for superior intelligence in successful aging.
  • The interaction between contactin and amyloid precursor protein and its role in Alzheimer’s disease

    Alzheimer's disease (AD) is a debilitating disease and the most common cause of dementia. As the world population ages even modest advances in therapies and preventative strategies would be of benefit. The specific physiological function of the amyloid precursor protein (APP) remains unclear despite strong genetic and biochemical evidence of APP involvement in AD. The intricate molecular processes of the nervous system rely on interactions between cell surface receptors coupled to intracellular downstream signaling networks. APP is an integral membrane protein which interacts with members of the Contactin family of proteins. Here we review recent progresses in the field and discuss the physiological importance of APP-Contactin interaction, as well as their roles and contributions in the pathophysiology of AD.
  • Light detection in open-circuit voltage mode of organic photodetectors

    Organic photodetectors (OPDs) are promising candidates for next-generation light sensors as they combine unique material properties with high-level performance in converting photons into electrical signals. However, low-level light detection with OPD is often limited by device dark current. Here, the open-circuit voltage (V) regime of OPDs is shown to be efficient for detecting low light signals (<100 µW cm). It is established that the light-dependence of V exhibits two distinct regimes as function of irradiance: linear and logarithmic. Whereas the observed logarithmic regime is well understood in organic photovoltaic cells (OPVs), it is shown experimentally and theoretically that the linear regime is due to the non-infinite shunt resistance of the OPD device. Overall, OPDs composed of rubrene and fullerene show photovoltage light sensitivity across nine orders of magnitude with a detection limit as low as 400 pW cm. A photovoltage responsivity of 1.75 V m W demonstrates highly efficient performance without the necessity to supress high dark current. This approach opens up new possibilities for resolving low light signals and provides simplified design rules for OPDs.
  • Visual system development of the spotted unicornfish, Naso brevirostris (Acanthuridae)

    Ontogenetic changes of the visual system are often correlated to shifts in habitat and feeding behaviour of animals. Coral reef fishes begin their lives in the pelagic zone and then migrate to the reef. This habitat transition frequently involves a change in diet and light environment as well as major morphological modifications. The spotted unicornfish, , is known to shift diet from zooplankton to algae and back to mainly zooplankton when transitioning from larval to juvenile and then to adult stages. Concurrently, also moves from an open pelagic to a coral-associated habitat before migrating up in the water column when reaching adulthood. Using retinal mapping techniques, we discovered that the distribution and density of ganglion and photoreceptor cells in mostly changes during the transition from the larval to the juvenile stage, with only minor modifications thereafter. Similarly, visual gene (opsin) expression based on RNA sequencing, although qualitatively similar between stages (all fishes mainly expressed the same three cone opsins; ), also showed the biggest quantitative difference when transitioning from larvae to juveniles. The juvenile stage in particular seems mismatched with its reef-associated ecology, which may be due to this stage only lasting a fraction of the lifespan of these fishes. Hence, the visual ontogeny found in is very different from the progressive changes found in other reef fishes calling for a thorough analysis of visual system development of the reef fish community.
  • TwoLumps ascending neurons mediate touch-evoked reversal of walking direction in Drosophila

    External cues, including touch, enable walking animals to flexibly maneuver around obstacles and extricate themselves from dead-ends (for reviews, see [1-3]). In a screen for neurons that enable Drosophila melanogaster to retreat when it encounters a dead-end, we identified a pair of ascending neurons, the TwoLumps Ascending (TLA) neurons. Silencing TLA activity impairs backward locomotion, whereas optogenetic activation triggers backward walking. TLA-induced reversal is mediated in part by the Moonwalker Descending Neurons (MDNs) [4], which receive excitatory input from the TLAs. Silencing the TLAs decreases the extent to which freely walking flies back up upon encountering a physical barrier in the dark, and TLAs show calcium responses to optogenetic activation of neurons expressing the mechanosensory channel NOMPC. We infer that TLAs convey feedforward mechanosensory stimuli to transiently activate MDNs in response to anterior body touch.
  • Efficacy of folic acid as an adjunct to lithium therapy on manic-like behaviors, oxidative stress and inflammatory parameters in an animal model of mania

    Evaluate the efficacy of folic acid (FA) as a therapeutic adjunct to lithium (Li) on the manic-like behaviors as well as parameters of oxidative stress and inflammation in an animal model of mania induced by m-amphetamine (m-AMPH). Wistar rats first received m-AMPH or saline (NaCl 0.9%, Sal) for 14 days. Between the 8th and 14th day, rats were treated with water, Li, FA or a combination of thereof drugs (Li + FA). Manic-like behaviors were assessed in the open-field test. Oxidative stress and inflammation parameters were assessed in the frontal cortex, striatum, and hippocampus. Administration of m-AMPH in rats significantly enhanced the exploratory and locomotor behaviors, as well as the risk-taking and stereotypic behaviors. Li + FA reversed these behavioral alterations elicited by m-AMPH. Administration of this psychostimulant also increased oxidative damage to lipids and proteins, whereas Li + FA reversed these oxidative damages. m-AMPH also induced an increase in the glutathione peroxidase (GPx) activity and a decrease in the glutathione reductase (GR) activity. Li + FA reversed the alteration in GR activity, but not in GPx activity. In addition, m-AMPH increased the IL-1β and TNF-α levels in the rat brain; Li + FA combined therapy reversed the alterations on these inflammatory parameters. FA administration per se reduced the increased TNF-α content induced by m-AMPH. Present study provides evidence that FA is effective as an adjunct to Li standard therapy on manic-like behaviors, oxidative stress and inflammatory parameters in a model of mania induced by m-AMPH.
  • Common Regulatory Targets of NFIA, NFIX and NFIB during Postnatal Cerebellar Development

    Transcriptional regulation plays a central role in controlling neural stem and progenitor cell proliferation and differentiation during neurogenesis. For instance, transcription factors from the nuclear factor I (NFI) family have been shown to co-ordinate neural stem and progenitor cell differentiation within multiple regions of the embryonic nervous system, including the neocortex, hippocampus, spinal cord and cerebellum. Knockout of individual Nfi genes culminates in similar phenotypes, suggestive of common target genes for these transcription factors. However, whether or not the NFI family regulates common suites of genes remains poorly defined. Here, we use granule neuron precursors (GNPs) of the postnatal murine cerebellum as a model system to analyse regulatory targets of three members of the NFI family: NFIA, NFIB and NFIX. By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development.
  • Genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders

    Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Genome-wide analyses of eight different psychiatric disorders reveals common loci and shared genetic structures underlying many of them.
  • Optimising non-invasive brain-computer interface systems for free communication between naïve human participants

    Free communication is one of the cornerstones of modern civilisation. While manual keyboards currently allow us to interface with computers and manifest our thoughts, a next frontier is communication without manual input. Brain-computer interface (BCI) spellers often achieve this by decoding patterns of neural activity as users attend to flickering keyboard displays. To date, the highest performing spellers report typing rates of ~10.00 words/minute. While impressive, these rates are typically calculated for experienced users repetitively typing single phrases. It is therefore not clear whether naïve users are able to achieve such high rates with the added cognitive load of genuine free communication, which involves continuously generating and spelling novel words and phrases. In two experiments, we developed an open-source, high-performance, non-invasive BCI speller and examined its feasibility for free communication. The BCI speller required users to focus their visual attention on a flickering keyboard display, thereby producing unique cortical activity patterns for each key, which were decoded using filter-bank canonical correlation analysis. In Experiment 1, we tested whether seventeen naïve users could maintain rapid typing during prompted free word association. We found that information transfer rates were indeed slower during this free communication task than during typing of a cued character sequence. In Experiment 2, we further evaluated the speller's efficacy for free communication by developing a messaging interface, allowing users to engage in free conversation. The results showed that free communication was possible, but that information transfer was reduced by voluntary textual corrections and turn-taking during conversation. We evaluated a number of factors affecting the suitability of BCI spellers for free communication, and make specific recommendations for improving classification accuracy and usability. Overall, we found that developing a BCI speller for free communication requires a focus on usability over reduced character selection time, and as such, future performance appraisals should be based on genuine free communication scenarios.
  • The global burden of disease methodology has been good for mental disorders: But not good enough

  • The low-dimensional neural architecture of cognitive complexity is related to activity in medial thalamic nuclei

    Cognitive activity emerges from large-scale neuronal dynamics that are constrained to a low-dimensional manifold. How this low-dimensional manifold scales with cognitive complexity, and which brain regions regulate this process, are not well understood. We addressed this issue by analyzing sub-second high-field fMRI data acquired during performance of a task that systematically varied the complexity of cognitive reasoning. We show that task performance reconfigures the low-dimensional manifold and that deviations from these patterns relate to performance errors. We further demonstrate that individual differences in thalamic activity relate to reconfigurations of the low-dimensional architecture during task engagement. Shine et al. demonstrate that cognitive complexity reconfigures the low-dimensional state space of the human brain. The low-dimensional trajectories of whole-brain activity dissociate correct and error trials and relate to activity within the medial and posterior thalamic nuclei.
  • Parallel processing of two mechanosensory modalities by a single neuron in C.elegans

    Sensory neurons process multiple sensory modalities to generate diverse behaviors. Tao et al. show that the C. elegans PVD neuron detects both proprioceptive and nociceptive stimuli but with distinct sensors. In response, PVD generates two types of depolarization patterns via either dendrite or axon, ultimately leading to distinct behaviors.Neurons convert synaptic or sensory inputs into cellular outputs. It is not well understood how a single neuron senses, processes multiple stimuli, and generates distinct neuronal outcomes. Here, we describe the mechanism by which the C. elegans PVD neurons sense two mechanical stimuli: external touch and proprioceptive body movement. These two stimuli are detected by distinct mechanosensitive DEG/ENaC/ASIC channels, which trigger distinct cellular outputs linked to mechanonociception and proprioception. Mechanonociception depends on DEGT-1 and activates PVD's downstream command interneurons through its axon, while proprioception depends on DEL-1, UNC-8, and MEC-10 to induce local dendritic Ca increase and dendritic release of a neuropeptide NLP-12. NLP-12 directly modulates neuromuscular junction activity through the cholecystokinin receptor homolog on motor axons, setting muscle tone and movement vigor. Thus, the same neuron simultaneously uses both its axon and dendrites as output apparatus to drive distinct sensorimotor outcomes.
  • Quantitative Colour Pattern Analysis (QCPA): A comprehensive framework for the analysis of colour patterns in nature

    1. To understand the function of colour signals in nature, we require robust quantitative analytical frameworks to enable us to estimate how animal and plant colour patterns appear against their natural background as viewed by ecologically relevant species. Due to the quantitative limitations of existing methods, colour and pattern are rarely analysed in conjunction with one another, despite a large body of literature and decades of research on the importance of spatio‐chromatic colour pattern analyses. Furthermore, key physiological limitations of animal visual systems such as spatial acuity, spectral sensitivities, photoreceptor abundances and receptor noise levels are rarely considered together in colour pattern analyses. 2. Here, we present a novel analytical framework, called the Quantitative Colour Pattern Analysis (QCPA). We have overcome many quantitative and qualitative limitations of existing colour pattern analyses by combining calibrated digital photography and visual modelling. We have integrated and updated existing spatio‐chromatic colour pattern analyses, including adjacency, visual contrast and boundary strength analysis, to be implemented using calibrated digital photography through the Multispectral Image Analysis and Calibration (MICA) Toolbox. 3. This combination of calibrated photography and spatio‐chromatic colour pattern analyses is enabled by the inclusion of psychophysical colour and luminance discrimination thresholds for image segmentation, which we call ‘Receptor Noise Limited Clustering’, used here for the first time. Furthermore, QCPA provides a novel psycho‐physiological approach to the modelling of spatial acuity using convolution in the spatial or frequency domains, followed by ‘Receptor Noise Limited Ranked Filtering’ to eliminate intermediate edge artefacts and recover sharp boundaries following smoothing. We also present a new type of colour pattern analysis, the ‘local edge intensity analysis’ as well as a range of novel psycho‐physiological approaches to the visualization of spatio‐chromatic data. 4. QCPA combines novel and existing pattern analysis frameworks into what we hope is a unified, free and open source toolbox and introduces a range of novel analytical and data‐visualization approaches. These analyses and tools have been seamlessly integrated into the MICA toolbox providing a dynamic and user‐friendly workflow.
  • Enhanced dopamine in prodromal schizophrenia (EDiPS): a new animal model of relevance to schizophrenia

    One of the most robust neurochemical abnormalities reported in patients living with schizophrenia is an increase in dopamine (DA) synthesis and release in the dorsal striatum (DS). Importantly, it appears that this increase progresses as a patient transitions from a prodromal stage to the clinical diagnosis of schizophrenia. Here we have recreated this pathophysiology in an animal model by increasing the capacity for DA synthesis preferentially within the DS. To achieve this we administer a genetic construct containing the rate-limiting enzymes in DA synthesis—tyrosine hydroxylase (TH), and GTP cyclohydrolase 1 (GCH1) (packaged within an adeno-associated virus)—into the substantia nigra pars compacta (SNpc) of adolescent animals. We refer to this model as “Enhanced Dopamine in Prodromal Schizophrenia” (EDiPS). We first confirmed that the TH enzyme is preferentially increased in the DS. As adults, EDiPS animals release significantly more DA in the DS following a low dose of amphetamine (AMPH), have increased AMPH-induced hyperlocomotion and show deficits in pre-pulse inhibition (PPI). The glutamatergic response to AMPH is also altered, again in the DS. EDiPS represents an ideal experimental platform to (a) understand how a preferential increase in DA synthesis capacity in the DS relates to “positive” symptoms in schizophrenia; (b) understand how manipulation of DS DA may influence other neurotransmitter systems shown to be altered in patients with schizophrenia; (c) allow researchers to follow an “at risk”-like disease course from adolescence to adulthood; and (d) ultimately allow trials of putative prophylactic agents to prevent disease onset in vulnerable populations.
  • Intra- and extracellular β-amyloid overexpression via adeno-associated virus-mediated gene transfer impairs memory and synaptic plasticity in the hippocampus

    Alzheimer’s disease (AD), the most common age-related neurodegenerative disorder, is currently conceptualized as a disease of synaptic failure. Synaptic impairments are robust within the AD brain and better correlate with dementia severity when compared with other pathological features of the disease. Nevertheless, the series of events that promote synaptic failure still remain under debate, as potential triggers such as β-amyloid (Aβ) can vary in size, configuration and cellular location, challenging data interpretation in causation studies. Here we present data obtained using adeno-associated viral (AAV) constructs that drive the expression of oligomeric Aβ either intra or extracellularly. We observed that expression of Aβ in both cellular compartments affect learning and memory, reduce the number of synapses and the expression of synaptic-related proteins, and disrupt chemical long-term potentiation (cLTP). Together, these findings indicate that during the progression AD the early accumulation of Aβ inside neurons is sufficient to promote morphological and functional cellular toxicity, a phenomenon that can be exacerbated by the buildup of Aβ in the brain parenchyma. Moreover, our AAV constructs represent a valuable tool in the investigation of the pathological properties of Aβ oligomers both in vivo and in vitro.
  • Comparative genetic architectures of schizophrenia in East Asian and European populations

    Schizophrenia is a debilitating psychiatric disorder with approximately 1% lifetime risk globally. Large-scale schizophrenia genetic studies have reported primarily on European ancestry samples, potentially missing important biological insights. Here, we report the largest study to date of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide-significant associations in 19 genetic loci. Common genetic variants that confer risk for schizophrenia have highly similar effects between East Asian and European ancestries (genetic correlation = 0.98 ± 0.03), indicating that the genetic basis of schizophrenia and its biology are broadly shared across populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries identified 208 significant associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping reduced the sets of candidate causal variants in 44 loci. Polygenic risk scores had reduced performance when transferred across ancestries, highlighting the importance of including sufficient samples of major ancestral groups to ensure their generalizability across populations.
  • Usp9X Controls Ankyrin-Repeat Domain Protein Homeostasis during Dendritic Spine Development

    Variants in the ANK3 gene encoding ankyrin-G are associated with neurodevelopmental disorders, including intellectual disability, autism, schizophrenia, and bipolar disorder. However, no upstream regulators of ankyrin-G at synapses are known. Here, we show that ankyrin-G interacts with Usp9X, a neurodevelopmental-disorder-associated deubiquitinase (DUB). Usp9X phosphorylation enhances their interaction, decreases ankyrin-G polyubiquitination, and stabilizes ankyrin-G to maintain dendritic spine development. In forebrain-specific Usp9X knockout mice (Usp9X), ankyrin-G as well as multiple ankyrin-repeat domain (ANKRD)-containing proteins are transiently reduced at 2 but recovered at 12 weeks postnatally. However, reduced cortical spine density in knockouts persists into adulthood. Usp9X mice display increase of ankyrin-G ubiquitination and aggregation and hyperactivity. USP9X mutations in patients with intellectual disability and autism ablate its catalytic activity or ankyrin-G interaction. Our data reveal a DUB-dependent mechanism of ANKRD protein homeostasis, the impairment of which only transiently affects ANKRD protein levels but leads to persistent neuronal, behavioral, and clinical abnormalities.
  • Impaired adult hippocampal neurogenesis in a mouse model of familial hypercholesterolemia: a role for the LDL receptor and cholesterol metabolism in adult neural precursor cells

    Objective: In familial hypercholesterolemia (FH), mutations in the low-density lipoprotein (LDL) receptor (LDLr) gene result in increased plasma LDL cholesterol. Clinical and preclinical studies have revealed an association between FH and hippocampus-related memory and mood impairment. We here asked whether hippocampal pathology in FH might be a consequence of compromised adult hippocampal neurogenesis.Methods: We evaluated hippocampus-dependent behavior and neurogenesis in adult C57BU6JRj and LDLr (-/-) mice. We investigated the effects of elevated cholesterol and the function of LDLr in neural precursor cells (NPC) isolated from adult C57BU6JRj mice in vitro.Results: Behavioral tests revealed that adult LDLr -/- mice showed reduced performance in a dentate gyrus (DG)-dependent metric change task. This phenotype was accompanied by a reduction in cell proliferation and adult neurogenesis in the DG of LDLr (-/-) mice, suggesting a potential direct impact of LDLr mutation on NPC. Exposure of NPC to LDL as well as LDLr gene knockdown reduced proliferation and disrupted transcriptional activity of genes involved in endogenous cholesterol synthesis and metabolism. The LDL treatment also induced an increase in intracellular lipid storage. Functional analysis of differentially expressed genes revealed parallel modulation of distinct regulatory networks upon LDL treatment and LDLr knockdown.Conclusions: Together, these results suggest that high LDL levels and a loss of LDLr function, which are characteristic to individuals with FH, might contribute to a disease-related impairment in adult hippocampal neurogenesis and, consequently, cognitive functions. (C) 2019 The Authors. Published by Elsevier GmbH.
  • Non-linear realignment improves hippocampus subfield segmentation reliability

    Participant movement can deleteriously affect MR image quality. Further, for the visualization and segmentation of small anatomical structures, there is a need to improve image quality, specifically signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR), by acquiring multiple anatomical scans consecutively. We aimed to ameliorate movement artefacts and increase SNR in a high-resolution turbo spin-echo (TSE) sequence acquired thrice using non-linear realignment in order to improve segmentation consistency of the hippocampus subfields. We assessed the method in 29 young healthy participants, 11 Motor Neuron Disease patients, and 11 age matched controls at 7T, and 24 healthy adolescents at 3T. Results show improved image segmentation of the hippocampus subfields when comparing template-based segmentations with individual segmentations with Dice overlaps N = 75; ps < 0.001 (Friedman's test) and higher sharpness ps < 0.001 in non-linearly realigned scans as compared to linearly, and arithmetically averaged scans.
  • Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

    Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.
  • Longitudinal trajectories of amyloid deposition, cortical thickness, and tau in Down syndrome: A deep-phenotyping case report

    Introduction: Comorbid Alzheimer disease pathologies are frequently found in people with Down syndrome (DS). We report a deep phenotyping study undertaken over 7 years in a participant with DS who was nondemented at baseline but developed dementia after 5 years. Methods: Throughout the course of the study, the participant was seen 4 times (2010, 2013, 2015, and 2017). Multimodal neuroimaging, including three serial scans of [C]-PiB-PET, four structural magnetic resonance imagings, as well as a [F]-AV1451 scan, was interpreted alongside detailed neuropsychological assessments over the study period. Results: Amyloid beta accumulation preceded the onset of dementia and cognitive decline, which in turn corresponded to the predominant deposition of tau in temporoparietal cortices. Discussion: Until now, data on the longitudinal trajectories of amyloid accumulation, tau pathology, and brain atrophy over multiple time points remain scarce in DS. This case report highlights the potential for deep phenotyping imaging to elucidate the substrates of cognitive decline in DS, although further longitudinal studies are necessary to clarify the relative contributions of both amyloid and tau.
  • A new visual illusion of aspect-ratio context

    Perception of local properties of the visual field is influenced by aftereffects of adaptation. The tilt aftereffect describes repulsion of the perceived orientation of a line from the orientation of an adapting line. Analogous effects of spatial context are often called illusions. Repulsion of the perceived orientation of a grating from the orientation of a surrounding grating is referred to as the tilt illusion. In the same manner, the size aftereffect and Ebbinghaus illusion form a complementary pair of temporal and spatial context effects of size. Here we report psychophysical evidence for a previously unknown aspect-ratio illusion which causes the perceived aspect-ratio of a rectangle to be repelled from the aspect-ratio of rectangles surrounding it. This illusion provides a spatial analogue to the aspect-ratio aftereffect.
  • Neuroimaging biomarkers for clinical trials in atypical parkinsonian disorders: Proposal for a Neuroimaging Biomarker Utility System

    Introduction: Therapeutic strategies targeting protein aggregations are ready for clinical trials in atypical parkinsonian disorders. Therefore, there is an urgent need for neuroimaging biomarkers to help with the early detection of neurodegenerative processes, the early differentiation of the underlying pathology, and the objective assessment of disease progression. However, there currently is not yet a consensus in the field on how to describe utility of biomarkers for clinical trials in atypical parkinsonian disorders. Methods: To promote standardized use of neuroimaging biomarkers for clinical trials, we aimed to develop a conceptual framework to characterize in more detail the kind of neuroimaging biomarkers needed in atypical parkinsonian disorders, identify the current challenges in ascribing utility of these biomarkers, and propose criteria for a system that may guide future studies. Results: As a consensus outcome, we describe the main challenges in ascribing utility of neuroimaging biomarkers in atypical parkinsonian disorders, and we propose a conceptual framework that includes a graded system for the description of utility of a specific neuroimaging measure. We included separate categories for the ability to accurately identify an intention-to-treat patient population early in the disease (Early), to accurately detect a specific underlying pathology (Specific), and the ability to monitor disease progression (Progression). Discussion: We suggest that the advancement of standardized neuroimaging in the field of atypical parkinsonian disorders will be furthered by a well-defined reference frame for the utility of biomarkers. The proposed utility system allows a detailed and graded description of the respective strengths of neuroimaging biomarkers in the currently most relevant areas of application in clinical trials.
  • The blood-brain barrier: physiology and strategies for drug delivery

    The blood-brain barrier (BBB) is a dynamic structure that functions as a gatekeeper, reflecting the unique requirements of the brain. In this review, following a brief historical overview of how the concepts of the BBB and the neurovascular unit (NVU) developed, we describe its physiology and architecture, which pose a particular challenge to therapeutic intervention. We then discuss how the restrictive nature of this barrier can be overcome for the delivery of therapeutic agents. Alterations to drug formulation offer one option, in part by utilizing distinct transport modes; another is invasive or non-invasive strategies to bypass the BBB. An emerging non-invasive technology for targeted drug delivery is focused ultrasound that allows for the safe and reversible disruption of the BBB. We discuss the underlying mechanisms and provide an outlook, emphasizing the need for more research into the NVU and investment in innovative technologies to overcome the BBB for drug delivery.
  • The α1-adrenoceptor inhibitor ρ-TIA facilitates net hunting in piscivorous Conus tulipa

    Cone snails use separately evolved venoms for prey capture and defence. While most use a harpoon for prey capture, the Gastridium clade that includes the well-studied Conus geographus and Conus tulipa, have developed a net hunting strategy to catch fish. This unique feeding behaviour requires secretion of "nirvana cabal" peptides to dampen the escape response of targeted fish allowing for their capture directly by mouth. However, the active components of the nirvana cabal remain poorly defined. In this study, we evaluated the behavioural effects of likely nirvana cabal peptides on the teleost model, Danio rerio (zebrafish). Surprisingly, the conantokins (NMDA receptor antagonists) and/or conopressins (vasopressin receptor agonists and antagonists) found in C. geographus and C. tulipa venom failed to produce a nirvana cabal-like effect in zebrafish. In contrast, low concentrations of the non-competitive adrenoceptor antagonist ρ-TIA found in C. tulipa venom (EC = 190 nM) dramatically reduced the escape response of zebrafish larvae when added directly to aquarium water. ρ-TIA inhibited the zebrafish α-adrenoceptor, confirming ρ-TIA has the potential to reverse the known stimulating effects of norepinephrine on fish behaviour. ρ-TIA may act alone and not as part of a cabal, since it did not synergise with conopressins and/or conantokins. This study highlights the importance of using ecologically relevant animal behaviour models to decipher the complex neurobiology underlying the prey capture and defensive strategies of cone snails.
  • Accurate, scalable and integrative haplotype estimation

    The number of human genomes being genotyped or sequenced increases exponentially and efficient haplotype estimation methods able to handle this amount of data are now required. Here we present a method, SHAPEIT4, which substantially improves upon other methods to process large genotype and high coverage sequencing datasets. It notably exhibits sub-linear running times with sample size, provides highly accurate haplotypes and allows integrating external phasing information such as large reference panels of haplotypes, collections of pre-phased variants and long sequencing reads. We provide SHAPEIT4 in an open source format and demonstrate its performance in terms of accuracy and running times on two gold standard datasets: the UK Biobank data and the Genome In A Bottle.
  • A resource-efficient tool for mixed model association analysis of large-scale data

    The genome-wide association study (GWAS) has been widely used as an experimental design to detect associations between genetic variants and a phenotype. Two major confounding factors, population stratification and relatedness, could potentially lead to inflated GWAS test statistics and hence to spurious associations. Mixed linear model (MLM)-based approaches can be used to account for sample structure. However, genome-wide association (GWA) analyses in biobank samples such as the UK Biobank (UKB) often exceed the capability of most existing MLM-based tools especially if the number of traits is large. Here, we develop an MLM-based tool (fastGWA) that controls for population stratification by principal components and for relatedness by a sparse genetic relationship matrix for GWA analyses of biobank-scale data. We demonstrate by extensive simulations that fastGWA is reliable, robust and highly resource-efficient. We then apply fastGWA to 2,173 traits on array-genotyped and imputed samples from 456,422 individuals and to 2,048 traits on whole-exome-sequenced samples from 46,191 individuals in the UKB.
  • Transcription factors NFIA and NFIB induce cellular differentiation in high-grade astrocytoma

    Malignant astrocytomas are composed of heterogeneous cell populations. Compared to grade IV glioblastoma, low-grade astrocytomas have more differentiated cells and are associated with a better prognosis. Therefore, inducing cellular differentiation to alter the behaviour of high-grade astrocytomas may serve as a therapeutic strategy. The nuclear factor one (NFI) transcription factors are essential for normal astrocytic differentiation. Here, we investigate whether family members NFIA and NFIB act as effectors of cellular differentiation in glioblastoma.

    We analysed expression of NFIA and NFIB in mRNA expression data of high-grade astrocytoma and with immunofluorescence co-staining. Furthermore, we induced NFI expression in patient-derived subcutaneous glioblastoma xenografts via in vivo electroporation.

    The expression of NFIA and NFIB is reduced in glioblastoma as compared to lower grade astrocytomas. At a cellular level, their expression is associated with differentiated and mature astrocyte-like tumour cells. In vivo analyses consistently demonstrate that expression of either NFIA or NFIB is sufficient to promote tumour cell differentiation in glioblastoma xenografts.

    Our findings indicate that both NFIA and NFIB may have an endogenous pro-differentiative function in astrocytomas, similar to their role in normal astrocyte differentiation. Overall, our study establishes a basis for further investigation of targeting NFI-mediated differentiation as a potential differentiation therapy.
  • Construction and reconstruction of brain circuits: normal and pathological axon guidance

    Perception of our environment entirely depends on the close interaction between the central and peripheral nervous system. In order to communicate each other, both systems must develop in parallel and in coordination. During development, axonal projections from the CNS as well as the PNS must extend over large distances to reach their appropriate target cells. To do so, they read and follow a series of axon guidance molecules. Interestingly, while these molecules play critical roles in guiding developing axons, they have also been shown to be critical in other major neurodevelopmental processes, such as the migration of cortical progenitors. Currently, a major hurdle for brain repair after injury or neurodegeneration is the absence of axonal regeneration in the mammalian CNS. By contrasts, PNS axons can regenerate. Many hypotheses have been put forward to explain this paradox but recent studies suggest that hacking neurodevelopmental mechanisms may be the key to promote CNS regeneration. Here we provide a seminar report written by trainees attending the second Flagship school held in Alpbach, Austria in September 2018 organized by the International Society for Neurochemistry (ISN) together with the Journal of Neurochemistry (JCN). This advanced school has brought together leaders in the fields of neurodevelopment and regeneration in order to discuss major keystones and future challenges in these respective fields.
  • Population densities predict forebrain size variation in the cleaner fish Labroides dimidiatus

    The 'social brain hypothesis' proposes a causal link between social complexity and either brain size or the size of key brain parts known to be involved in cognitive processing and decision-making. While previous work has focused on comparisons between species, how social complexity affects plasticity in brain morphology at the intraspecific level remains mostly unexplored. A suitable study model is the mutualist 'cleaner' fish , a species that removes ectoparasites from a variety of 'client' fishes in iterative social interactions. Here, we report a positive relationship between the local density of cleaners, as a proxy of both intra- and interspecific sociality, and the size of the cleaner's brain parts suggested to be associated with cognitive functions, such as the diencephalon and telencephalon (that together form the forebrain). In contrast, the size of the mesencephalon, rhombencephalon, and brain stem, assumed more basal in function, were independent of local fish densities. Selective enlargement of brain parts, that is mosaic brain adjustment, appears to be driven by population density in cleaner fish.
  • Wnt receptor gene FZD1 was associated with schizophrenia in genome-wide SNP analysis of the Australian Schizophrenia Research Bank cohort

    Objectives: Large-scale genetic analysis of common variation in schizophrenia has been a powerful approach to understanding this complex but highly heritable psychotic disorder. To further investigate loci, genes and pathways associated more specifically in the well-characterized Australian Schizophrenia Research Bank cohort, we applied genome-wide single-nucleotide polymorphism analysis in these three annotation categories. Methods: We performed a case-control genome-wide association study in 429 schizophrenia samples and 255 controls. Post-genome-wide association study analyses were then integrated with genomic annotations to explore the enrichment of variation at the gene and pathway level. We also examine candidate single-nucleotide polymorphisms with potential function within expression quantitative trait loci and investigate overall enrichment of variation within tissue-specific functional regulatory domains of the genome. Results: The strongest finding (p = 2.01 x 10(-6), odds ratio = 1.82, 95% confidence interval = [1.42, 2.33]) in genome-wide association study was with rs10252923 at 7q21.13, downstream of FZD1 (frizzled class receptor 1). While this did not stand alone after correction, the involvement of FZD1 was supported by gene-based analysis, which exceeded the threshold for genome-wide significance (p = 2.78 x 10(-6)). Conclusion: The identification of FZD1, as an independent association signal at the gene level, supports the hypothesis that the Wnt signalling pathway is altered in the pathogenesis of schizophrenia and may be an important target for therapeutic development.
  • Functional connectivity of brain associated with passive range of motion exercise: proprioceptive input promoting motor activation?

    Soft robotics have come to the forefront of devices available for rehabilitation following stroke; however, objective evaluation of the specific brain changes following rehabilitation with these devices is lacking. In this study, we utilized functional Magnetic Resonance Imaging (fMRI) and dynamic causal modeling (DCM) to characterize the activation of brain areas with a MRI compatible glove actuator compared to the conventional manual therapy. Thirteen healthy volunteers engaged in a motor-visual fMRI task under four different conditions namely active movement, manual passive movement, passive movement using a glove actuator, and crude tactile stimulation. Brain activity following each task clearly identified the somatosensory motor area (SMA) as a major hub orchestrating activity between the primary motor (M1) and sensory (S1) cortex. During the glove-induced passive movement, activity in the motor-somatosensory areas was reduced, but there were significant increases in motor cortical activity compared to manual passive movement. We estimated the modulatory signaling from within a defined sensorimotor network (SMA, M1, and S1), through DCM and highlighted a dual-gating of sensorimotor inputs to the SMA. Proprioceptive signaling from S1 to the SMA reflected positive coupling for the manually assisted condition, while M1 activity was positively coupled to the SMA during the glove condition. Importantly, both the S1 and M1 were shown to influence each other's connections with the SMA, with inhibitory nonlinear modulation by the M1 on the S1-SMA connection, and similarly S1 gated the M1-SMA connection. The work is one of the first to have applied effective connectivity to examine sensorimotor activity ensued by manual or robotic passive range of motion exercise, crude tactile stimulation, and voluntary movements to provide a basis for the mechanism by which soft actuators can alter brain activity.
  • 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.
  • Variants in nuclear factor I genes influence growth and development

    The nuclear factor one (NFI) site-specific DNA-binding proteins represent a family of transcription factors that are important for the development of multiple organ systems, including the brain. During brain development in mice, the expression patterns of Nfia, Nfib, and Nfix overlap, and knockout mice for each of these exhibit overlapping brain defects, including megalencephaly, dysgenesis of the corpus callosum, and enlarged ventricles, which implies a common but not redundant function in brain development. In line with these models, human phenotypes caused by haploinsufficiency of NFIA, NFIB, and NFIX display significant overlap, sharing neurodevelopmental deficits, macrocephaly, brain anomalies, and variable somatic overgrowth. Other anomalies may be present depending on the NFI gene involved. The possibility of variants in NFI genes should therefore be considered in individuals with intellectual disability and brain overgrowth, with individual NFI-related conditions being differentiated from one another by additional signs and symptoms. The exception is provided by specific NFIX variants that act in a dominant negative manner, as these cause a recognizable entity with more severe cognitive impairment and marked bone dysplasia, Marshall-Smith syndrome. NFIX duplications are associated with a phenotype opposite to that of haploinsufficiency, characterized by short stature, small head circumference, and delayed bone age. The spectrum of NFI-related disorders will likely be further expanded, as larger cohorts are assessed.
  • Genetic risk scores for major psychiatric disorders and the risk of postpartum psychiatric disorders

    Postpartum psychiatric disorders are heritable, but how genetic liability varies by other significant risk factors is unknown. We aimed to (1) estimate associations of genetic risk scores (GRS) for major depression (MD), bipolar disorder (BD), and schizophrenia (SCZ) with postpartum psychiatric disorders, (2) examine differences by prior psychiatric history, and (3) compare genetic and familial risk of postpartum psychiatric disorders. We conducted a nested case-control study based on Danish population-based registers of all women in the iPSYCH2012 cohort who had given birth before December 31, 2015 (n = 8850). Cases were women with a diagnosed psychiatric disorder or a filled psychotropic prescription within one year after delivery (n = 5829 cases, 3021 controls). Association analyses were conducted between GRS calculated from Psychiatric Genomics Consortium discovery meta-analyses for MD, BD, and SCZ and case-control status of a postpartum psychiatric disorder. Parental psychiatric history was associated with postpartum psychiatric disorders among women with previous psychiatric history (OR, 1.14; 95% CI 1.02-1.28) but not without psychiatric history (OR, 1.08; 95% CI: 0.81-1.43). GRS for MD was associated with an increased risk of postpartum psychiatric disorders in both women with (OR, 1.44; 95% CI: 1.19-1.74) and without (OR, 1.88; 95% CI: 1.26-2.81) personal psychiatric history. SCZ GRS was only minimally associated with postpartum disorders and BD GRS was not. Results suggest GRS of lifetime psychiatric illness can be applied to the postpartum period, which may provide clues about distinct environmental or genetic elements of postpartum psychiatric disorders and ultimately help identify vulnerable groups.
  • 1,25-Dihydroxyvitamin D modulates L-type voltage-gated calcium channels in a subset of neurons in the developing mouse prefrontal cortex

    Schizophrenia has been associated with a range of genetic and environmental risk factors. Here we explored a link between two risk factors that converge on a shared neurobiological pathway. Recent genome-wide association studies (GWAS) have identified risk variants in genes that code for L-type voltage-gated calcium channels (L-VGCCs), while epidemiological studies have found an increased risk of schizophrenia in those with neonatal vitamin D deficiency. The active form of vitamin D (1,25(OH)D) is a secosteroid that rapidly modulates L-VGCCs via non-genomic mechanisms in a range of peripheral tissues, though its non-genomic effects within the brain remain largely unexplored. Here we used calcium imaging, electrophysiology and molecular biology to determine whether 1,25(OH)D non-genomically modulated L-VGCCs in the developing prefrontal cortex, a region widely implicated in schizophrenia pathophysiology. Wide-field Ca imaging revealed that physiological concentrations of 1,25(OH)D rapidly enhanced activity-dependent somatic Ca levels in a small subset of neurons in the developing PFC, termed vitamin D-responsive neurons (VDRNs). Somatic nucleated patch recordings revealed a rapid, 1,25(OH)D-evoked increase in high-voltage-activated (HVA) Ca currents. Enhanced activity-dependent Ca levels were mediated by L-VGCC but not associated with any changes to Cacna1c (L-VGCC pore-forming subunit) mRNA expression. Since L-VGCC activity is critical to healthy neurodevelopment, these data suggest that suboptimal concentrations of 1,25(OH)D could alter brain maturation through modulation of L-VGCC signalling and as such may provide a parsimonious link between epidemiologic and genetic risk factors for schizophrenia.
  • A detailed investigation of the visual system and visual ecology of the Barrier Reef anemonefish, Amphiprion akindynos

    Vision plays a major role in the life of most teleosts, and is assumingly well adapted to each species ecology and behaviour. Using a multidisciplinary approach, we scrutinised several aspects of the visual system and ecology of the Great Barrier Reef anemonefish, Amphiprion akindynos, including its orange with white patterning, retinal anatomy and molecular biology, its symbiosis with anemones and sequential hermaphroditism. Amphiprion akindynos possesses spectrally distinct visual pigments and opsins: one rod opsin, RH1 (498 nm), and five cone opsins, SWS1 (370 nm), SWS2B (408 nm), RH2B (498 nm), RH2A (520 nm), and LWS (554 nm). Cones were arranged in a regular mosaic with each single cone surrounded by four double cones. Double cones mainly expressed RH2B (53%) in one member and RH2A (46%) in the other, matching the prevailing light. Single cones expressed SWS1 (89%), which may serve to detect zooplankton, conspecifics and the host anemone. Moreover, a segregated small fraction of single cones coexpressed SWS1 with SWS2B (11%). This novel visual specialisation falls within the region of highest acuity and is suggested to increase the chromatic contrast of Amphiprion akindynos colour patterns, which might improve detection of conspecifics.
  • Improved polygenic prediction by Bayesian multiple regression on summary statistics

    Accurate prediction of an individual's phenotype from their DNA sequence is one of the great promises of genomics and precision medicine. We extend a powerful individual-level data Bayesian multiple regression model (BayesR) to one that utilises summary statistics from genome-wide association studies (GWAS), SBayesR. In simulation and cross-validation using 12 real traits and 1.1 million variants on 350,000 individuals from the UK Biobank, SBayesR improves prediction accuracy relative to commonly used state-of-the-art summary statistics methods at a fraction of the computational resources. Furthermore, using summary statistics for variants from the largest GWAS meta-analysis (n ≈ 700, 000) on height and BMI, we show that on average across traits and two independent data sets that SBayesR improves prediction R by 5.2% relative to LDpred and by 26.5% relative to clumping and p value thresholding.
  • Developmental vitamin D deficiency in the rat impairs recognition memory, but has no effect on social approach or hedonia

    Developmental vitamin D (DVD) deficiency is a risk factor for schizophrenia. In rodents we show that DVD-deficiency alters brain development and produces behavioral phenotypes in the offspring of relevance to the positive symptoms of schizophrenia. The aims of this study are to examine behavioral phenotypes specific to the cognitive and negative symptoms of schizophrenia in this model, and to vary the duration of vitamin D deficiency during gestation and beyond birth. We hypothesize that a longer duration of DVD-deficiency would result in greater behavioral impairments. Female vitamin D-deficient Sprague Dawley dams were mated at 10 weeks of age. Dietary vitamin D was reintroduced to dams and/or pups at different developmental time-points: Conception, Birth, Post-natal day (PND) 6 and PND21. Adult male and female offspring were assessed on a battery of behavioral tests, including sucrose preference, open field, novel object recognition (NOR), social approach and social novelty. We find that all windows of DVD-deficiency impaired NOR a cognitive measure that requires intact recognition memory. Sucrose consumption, social approach and social memory negative symptom-like phenotypes were unaffected by any maternal dietary manipulation. In addition, contrary to our hypothesis, we find that rats in the Conception group, that is the shortest duration of vitamin D deficiency, demonstrate increased locomotor activity, and decreased interaction time with novel objects. These findings have implications for the increasing number of studies examining the preclinical consequences of maternal vitamin D deficiency, and continue to suggest that adequate levels of maternal vitamin D are required for normal brain development.
  • Interneurons in the prefrontal cortex: a role in the genesis of anxiety in adolescence?

  • Scanning ultrasound in the absence of blood-brain barrier opening is not sufficient to clear β-amyloid plaques in the APP23 mouse model of Alzheimer's disease

    A major challenge in treating brain diseases is presented by the blood-brain barrier (BBB) that constitutes an efficient barrier not only for toxins but also a wide range of therapeutic agents. In overcoming this impediment, ultrasound in combination with intravenously injected microbubbles has emerged as a powerful technology that allows for the selective brain uptake of blood-borne factors and therapeutic agents by transient opening of the blood-brain barrier. We have previously shown that ultrasound in combination with microbubbles, but in the absence of a therapeutic agent, can effectively clear protein aggregates such as the hallmark lesions of Alzheimer's disease, amyloid-β (Aβ) plaques and Tau-containing neurofibrillary tangles. We have also demonstrated that the associated memory and motor impairments can be ameliorated or even restored. These studies included a negative sham control that received microbubbles in the absence of ultrasound. However, considering that ultrasound on its own is a pressure wave which has bioeffects, the possibility remained that ultrasound, without microbubbles, would also clear amyloid. We addressed this by performing repeated ultrasound only treatments of one brain hemisphere of Aβ-depositing APP23 mice, using the contralateral hemisphere as the unsonicated control. This was followed by an extensive histological analysis of fibrillar and non-fibrillar amyloid. We found that ultrasound on its own was not sufficient to clear amyloid. This implies that although ultrasound on its own has neuromodulatory effects, exogenously supplied microbubbles are required for the clearance of Aβ deposits.
  • Co-expression of synaptic genes in the sponge Amphimedon queenslandica uncovers ancient neural submodules

    The synapse is a complex cellular module crucial to the functioning of neurons. It evolved largely through the exaptation of pre-existing smaller submodules, each of which are comprised of ancient sets of proteins that are conserved in modern animals and other eukaryotes. Although these ancient submodules themselves have non-neural roles, it has been hypothesized that they may mediate environmental sensing behaviors in aneural animals, such as sponges. Here we identify orthologues in the sponge Amphimedon queenslandica of genes encoding synaptic submodules in neural animals, and analyse their cell-type specific and developmental expression to determine their potential to be co-regulated. We find that genes comprising certain synaptic submodules, including those involved in vesicle trafficking, calcium-regulation and scaffolding of postsynaptic receptor clusters, are co-expressed in adult choanocytes and during metamorphosis. Although these submodules may contribute to sensory roles in this cell type and this life cycle stage, total synaptic gene co-expression profiles do not support the existence of a functional synapse in A. queenslandica. The lack of evidence for the co-regulation of genes necessary for pre- and post-synaptic functioning in A. queenslandica suggests that sponges, and perhaps the last common ancestor of sponges and other extant animals, had the ability to promulgate sensory inputs without complete synapse-like functionalities. The differential co-expression of multiple synaptic submodule genes in sponge choanocytes, which have sensory and feeding roles, however, is consistent with the metazoan ancestor minimally being able to undergo exo- and endocytosis in a controlled and localized manner.