Recent QBI publications

  • Proteostasis regulators restore function of epilepsy-associated GABAA receptors

    Proteostasis deficiency in mutated ion channels leads to a variety of ion channel diseases that are caused by excessive endoplasmic reticulum-associated degradation (ERAD) and inefficient membrane trafficking. We investigated proteostasis maintenance of γ-aminobutyric acid type A (GABAA) receptors, the primary mediators of neuronal inhibition in the mammalian central nervous system. We screened a structurally diverse, Food and Drug Administration-approved drug library and identified dinoprost (DNP) and dihydroergocristine (DHEC) as highly efficacious enhancers of surface expression of four epilepsy-causing trafficking-deficient mutant receptors. Furthermore, DNP and DHEC restore whole-cell and synaptic currents by incorporating mutated subunits into functional receptors. Mechanistic studies revealed that both drugs reduce subunit degradation by attenuating the Grp94/Hrd1/Sel1L/VCP-mediated ERAD pathway and enhance the subunit folding by promoting subunit interactions with major GABAA receptors-interacting chaperones, BiP and calnexin. In summary, we report that DNP and DHEC remodel the endoplasmic reticulum proteostasis network to restore the functional surface expression of mutant GABAA receptors.
  • A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank

    Depression is a leading cause of worldwide disability but there remains considerable uncertainty regarding its neural and behavioural associations. Here, using non-overlapping Psychiatric Genomics Consortium (PGC) datasets as a reference, we estimate polygenic risk scores for depression (depression-PRS) in a discovery (N = 10,674) and replication (N = 11,214) imaging sample from UK Biobank. We report 77 traits that are significantly associated with depression-PRS, in both discovery and replication analyses. Mendelian Randomisation analysis supports a potential causal effect of liability to depression on brain white matter microstructure (β: 0.125 to 0.868, p < 0.043). Several behavioural traits are also associated with depression-PRS (β: 0.014 to 0.180, p: 0.049 to 1.28 × 10) and we find a significant and positive interaction between depression-PRS and adverse environmental exposures on mental health outcomes. This study reveals replicable associations between depression-PRS and white matter microstructure. Our results indicate that white matter microstructure differences may be a causal consequence of liability to depression.
  • Alertness fluctuations when performing a task modulate cortical evoked responses to transcranial magnetic stimulation

    Transcranial magnetic stimulation (TMS) has been widely used in human cognitive neuroscience to examine the causal role of distinct cortical areas in perceptual, cognitive and motor functions. However, it is widely acknowledged that the effects of focal cortical stimulation can vary substantially between participants and even from trial to trial within individuals. Recent work from resting state functional magnetic resonance imaging (fMRI) studies has suggested that spontaneous fluctuations in alertness over a testing session can modulate the neural dynamics of cortical processing, even when participants remain awake and responsive to the task at hand. Here we investigated the extent to which spontaneous fluctuations in alertness during wake-to-sleep transition can account for the variability in neurophysiological responses to TMS. We combined single-pulse TMS with neural recording via electroencephalography (EEG) to quantify changes in motor and cortical reactivity with fluctuating levels of alertness defined objectively on the basis of ongoing brain activity. We observed rapid, non-linear changes in TMS-evoked responses with decreasing levels of alertness, even while participants remained responsive in the behavioural task. Specifically, we found that the amplitude of motor evoked potentials peaked during periods of EEG flattening, whereas TMS-evoked potentials increased and remained stable during EEG flattening and the subsequent occurrence of theta ripples that indicate the onset of NREM stage 1 sleep. Our findings suggest a rapid and complex reorganization of active neural networks in response to spontaneous fluctuations of alertness over relatively short periods of behavioural testing during wake-to-sleep transition.
  • Neurocognitive performance of repeated versus single intravenous subanesthetic ketamine in treatment resistant depression

    Background: Ketamine demonstrated rapid antidepressant effects in treatment-resistant depression (TRD). However, evaluation of ketamine's neurocognitive effect in TRD is unclear. We aim to (1) characterize baseline neurocognitive performance as a predictor of the change in severity of depressive symptoms over time, and (2) investigate the association of six versus single intravenous (IV) ketamine and neurocognitive changes from baseline to the end of treatment. Methods: Subjects with TRD were randomized to receive either five IV midazolam followed by a single IV ketamine or six IV ketamine during a 12-day period. Depression symptom assessments occurred prior and 24 h after infusion days using the Montgomery–Åsberg Depression Rating Scale. Neurocognitive tasks were designed to test attention, memory, speed of processing, and set shifting using the CogState battery at baseline and at the end of treatment. Results: Better complex working memory at baseline predicted improvement in MADRS scores of ketamine (vs midazolam) after 5 infusions. Most, but not all, neurocognitive functions remained stable or improved after repeated or single ketamine. There was a greater differential effect of treatment on speed of processing, set shifting, and spatial working memory that favors subjects in the six ketamine group. These cognitive improvements from baseline to the end of treatment were robust when controlling for age and changes in depression severity. Conclusion: The study suggests that six IV ketamine compared to single IV ketamine has a mood independent procognitive effect among TRD patients. Large scale studies are needed to confirm whether ketamine enhances cognitive function in TRD.
  • Manipulating the structure of natural scenes using wavelets to study the functional architecture of perceptual hierarchies in the brain

    Functional neuroimaging experiments that employ naturalistic stimuli (natural scenes, films, spoken narratives) provide insights into cognitive function “in the wild”. Natural stimuli typically possess crowded, spectrally dense, dynamic, and multimodal properties within a rich multiscale structure. However, when using natural stimuli, various challenges exist for creating parametric manipulations with tight experimental control. Here, we revisit the typical spectral composition and statistical dependences of natural scenes, which distinguish them from abstract stimuli. We then demonstrate how to selectively degrade subtle statistical dependences within specific spatial scales using the wavelet transform. Such manipulations leave basic features of the stimuli, such as luminance and contrast, intact. Using functional neuroimaging of human participants viewing degraded natural images, we demonstrate that cortical responses at different levels of the visual hierarchy are differentially sensitive to subtle statistical dependences in natural images. This demonstration supports the notion that perceptual systems in the brain are optimally tuned to the complex statistical properties of the natural world. The code to undertake these stimulus manipulations, and their natural extension to dynamic natural scenes (films), is freely available.
  • Drug repositioning in neurodegeneration: an overview of the use of ambroxol in neurodegenerative diseases

    Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults. While it is primarily characterized by the death of upper and lower motor neurons, there is a significant metabolic component involved in the progression of the disease. Two-thirds of ALS patients have metabolic alterations that are associated with the severity of symptoms. In ALS, as in other neurodegenerative diseases, the metabolism of glycosphingolipids, a class of complex lipids, is strongly dysregulated. We therefore assume that this pathway constitutes an interesting avenue for therapeutic approaches. We have shown that the glucosylceramide degrading enzyme, glucocerebrosidase (GBA) 2 is abnormally increased in the spinal cord of the SOD1 mouse model of ALS. Ambroxol, a chaperone molecule that inhibits GBA2, has been shown to have beneficial effects by slowing the development of the disease in SOD1 mice. Currently used in clinical trials for Parkinson's and Gaucher disease, ambroxol could be considered as a promising therapeutic treatment for ALS.
  • Genome-wide microRNA profiling in brain and blood samples in a mouse model of epileptogenesis

    Objectives: This study profiled circulating and hippocampal microRNAs (miRNAs) to identify alterations associated with the risk of epileptogenesis in a mouse temporal lobe epilepsy model. Methods: Next-generation sequencing was performed to examine the changes in miRNA expression 24 h after pilocarpine-induced status epilepticus (SE) in C57BL/6NCrl mice using both blood and hippocampus samples. Differentially expressed miRNAs were identified from SE animals and matched controls that failed to develop SE after receiving equal doses of pilocarpine (NS animals). Blood and brain miRNA profiles were then compared to identify circulating miRNA alterations reflecting the changes in the brain. Results: We identified 3 miRNAs that were significantly up-regulated and 4 miRNAs that were significantly down-regulated in the blood of SE animals compared with NS animals. When hippocampal miRNAs of SE animals and NS animals were compared, 5 miRNAs were up-regulated and 4 were down-regulated. Of these, miR-434-3p and miR-133a-3p were observed to have greatest changes in both blood and brain of SE animals. Significance: This study extends current knowledge of changes in miRNAs associated with epileptogenesis by profiling miRNAs in SE and NS animals in an experimental temporal lobe epilepsy model. The study was designed to allow non-specific changes due to the activation of muscarinic cholinergic receptors in peripheral organs by pilocarpine to be ruled out. Significantly altered circulating miRNAs that reflect changes in the brain during epileptogenesis after SE have the potential to be developed as prognostic biomarkers for epileptogenesis.
  • Mechanisms of mindfulness meditation, cognitive therapy, and mindfulness-based cognitive therapy for chronic low back pain

    OBJECTIVES: This study evaluated theoretically derived mechanisms and common therapeutic factors to test their role in accounting for pain-related outcome change during group-delivered cognitive therapy, mindfulness meditation, and mindfulness-based cognitive therapy for chronic low back pain. METHODS: A secondary analysis of a pilot randomized controlled trial was used to explore the primary mechanisms of pretreatment to posttreatment changes in pain control beliefs, mindful observing, and pain catastrophizing, and the secondary common factor mechanisms of therapeutic alliance, group cohesion, and amount of at-home skill practice during treatment. The primary outcome was pain interference; pain intensity was a secondary outcome. RESULTS: Large effect size changes in the 3 primary mechanisms and the outcome variables were found across the conditions. Across all 3 treatment conditions, change in pain control beliefs and pain catastrophizing were significantly associated with improved pain interference, but not pain intensity. Therapeutic alliance was significantly associated with pain intensity improvement and change in the therapy-specific mechanisms across the 3 conditions. Mindful observing, group cohesion, and amount of at-home practice were not significantly associated with changes in the outcomes. DISCUSSION: Cognitive therapy, mindfulness meditation, and mindfulness-based cognitive therapy for chronic low back pain were all associated with significant changes in the primary mechanisms to a similar degree. Change in perceived pain control and pain catastrophizing emerged as potential "meta-mechanisms" that might be a shared pathway that contributes to improved pain-related outcomes across treatments. Further, strong working alliance may represent a critical therapeutic process that both promotes and interacts with therapeutic techniques to influence outcome.
  • Altered brain-wide auditory networks in a zebrafish model of fragile X syndrome

    Loss or disrupted expression of the FMR1 gene causes fragile X syndrome (FXS), the most common monogenetic form of autism in humans. Although disruptions in sensory processing are core traits of FXS and autism, the neural underpinnings of these phenotypes are poorly understood. Using calcium imaging to record from the entire brain at cellular resolution, we investigated neuronal responses to visual and auditory stimuli in larval zebrafish, using fmr1 mutants to model FXS. The purpose of this study was to model the alterations of sensory networks, brain-wide and at cellular resolution, that underlie the sensory aspects of FXS and autism.

    Combining functional analyses with the neurons' anatomical positions, we found that fmr1 animals have normal responses to visual motion. However, there were several alterations in the auditory processing of fmr1 animals. Auditory responses were more plentiful in hindbrain structures and in the thalamus. The thalamus, torus semicircularis, and tegmentum had clusters of neurons that responded more strongly to auditory stimuli in fmr1 animals. Functional connectivity networks showed more inter-regional connectivity at lower sound intensities (a - 3 to - 6 dB shift) in fmr1 larvae compared to wild type. Finally, the decoding capacities of specific components of the ascending auditory pathway were altered: the octavolateralis nucleus within the hindbrain had significantly stronger decoding of auditory amplitude while the telencephalon had weaker decoding in fmr1 mutants.

    We demonstrated that fmr1 larvae are hypersensitive to sound, with a 3-6 dB shift in sensitivity, and identified four sub-cortical brain regions with more plentiful responses and/or greater response strengths to auditory stimuli. We also constructed an experimentally supported model of how auditory information may be processed brain-wide in fmr1 larvae. Our model suggests that the early ascending auditory pathway transmits more auditory information, with less filtering and modulation, in this model of FXS.
  • Families, health registers, and biobanks: making the unmeasurable measurable

  • The reliability and heritability of cortical folds and their genetic correlations across hemispheres

    Cortical folds help drive the parcellation of the human cortex into functionally specific regions. Variations in the length, depth, width, and surface area of these sulcal landmarks have been associated with disease, and may be genetically mediated. Before estimating the heritability of sulcal variation, the extent to which these metrics can be reliably extracted from in-vivo MRI must be established. Using four independent test-retest datasets, we found high reliability across the brain (intraclass correlation interquartile range: 0.65-0.85). Heritability estimates were derived for three family-based cohorts using variance components analysis and pooled (total N > 3000); the overall sulcal heritability pattern was correlated to that derived for a large population cohort (N > 9000) calculated using genomic complex trait analysis. Overall, sulcal width was the most heritable metric, and earlier forming sulci showed higher heritability. The inter-hemispheric genetic correlations were high, yet select sulci showed incomplete pleiotropy, suggesting hemisphere-specific genetic influences.
  • An inverted CAV1 (caveolin 1) topology defines novel autophagy-dependent exosome secretion from prostate cancer cells

    CAV1 (caveolin 1) expression and secretion is associated with prostate cancer (PCa) disease progression, but the mechanisms underpinning CAV1 release remain poorly understood. Numerous studies have shown CAV1 can be secreted within exosome-like vesicles, but antibody-mediated neutralization can mitigate PCa progression; this is suggestive of an inverted (non-exosomal) CAV1 topology. Here we show that CAV1 can be secreted from specific PCa types in an inverted vesicle-associated form consistent with the features of bioactive CAV1 secretion. Characterization of the isolated vesicles by electron microscopy, single-molecule fluorescence microscopy and proteomics reveals they represent a novel class of exosomes ~40 nm in diameter containing ~50-60 copies of CAV1 and, strikingly, are released via a non-canonical secretory macroautophagy/autophagy pathway. This study provides novel insights into a mechanism whereby CAV1 translocates from a normal plasma membrane distribution to an inverted secreted form implicated in PCa disease progression.
  • Correction: Behavioral signatures of a developing neural code

    Correction: Behavioral Signatures of a Developing Neural Code Lilach Avitan, Zac Pujic, Jan Mo ̈lter, Michael McCullough, Shuyu Zhu, Biao Sun, Ann-Elin Myhre, and Geoffrey J. Goodhill (Current Biology 30, 3352–3363.e1–e5; September 7, 2020)​​​​​​​In the original paper, panel I was inadvertently omitted from Figure 2. The original panel J was then labeled as panel I, original panel Kas panel J, and there was no panel K, so all these panels were then wrongly described in the figure caption and main text. This error has now been corrected online.
  • Differential patterns of internally generated responses in parkinsonian disorders

    Internally generated responses are centrally affected in parkinsonian disorders. This study investigated the cognitive components crucial for response generation as reflected in performance on verbal and non-verbal fluency tasks, which require voluntary internal generation of multiple responses. Participants with parkinsonian disorders (N = 58: 29 Parkinson's disease [PD], 22 corticobasal syndrome [CBS], 8 progressive supranuclear palsy [PSP]) and 89 age-matched controls completed baseline cognitive assessments and eight fluency tasks of four types: word, design, gesture, and ideational. We analysed the total number of correct responses generated and error rates (including repetitions and rule breaks) for PD, CBS and Control groups. The small PSP patient group's performance is reported for comparative purposes only. CBS patients were significantly reduced in the number of correct responses generated across all fluency tasks, without incurring significant errors. The only exception was that CBS patients produced a significantly higher number of repetitions on one nonverbal task (design fluency). By contrast, PD patients' generation was reduced on only three fluency tasks (phonemic word, meaningless gesture, conventional idea). However, they also produced a high error rate on four fluency tasks (rule-break errors: phonemic/semantic word; repetitions: semantic word, meaningless gestures). Overall, the pattern of fluency task performance differs between patient groups. Specifically, the quantity of responses generated is differentially and primarily affected in CBS patients, whereas the quality of responses generated is primarily affected in PD patients. This suggests potentially different patterns of performance for parkinsonian disorders and has implications for the cognitive processes crucial for internally-guided response generation.
  • Longitudinal Automatic Segmentation of Hippocampal Subfields (LASHiS) using multi-contrast MRI

    The volumetric and morphometric examination of hippocampus formation subfields in a longitudinal manner using in vivo MRI could lead to more sensitive biomarkers for neuropsychiatric disorders and diseases including Alzheimer's disease, as the anatomical subregions are functionally specialised. Longitudinal processing allows for increased sensitivity due to reduced confounds of inter-subject variability and higher effect-sensitivity than cross-sectional designs. We examined the performance of a new longitudinal pipeline (Longitudinal Automatic Segmentation of Hippocampus Subfields [LASHiS]) against three freely available, published approaches. LASHiS automatically segments hippocampus formation subfields by propagating labels from cross-sectionally labelled time point scans using joint-label fusion to a non-linearly realigned 'single subject template', where image segmentation occurs free of bias to any individual time point. Our pipeline measures tissue characteristics available in in vivo high-resolution MRI scans, at both clinical (3 Tesla) and ultra-high field strength (7 Tesla) and differs from previous longitudinal segmentation pipelines in that it leverages multi-contrast information in the segmentation process. LASHiS produces robust and reliable automatic multi-contrast segmentations of hippocampus formation subfields, as measured by higher volume similarity coefficients and Dice coefficients for test-retest reliability and robust longitudinal Bayesian Linear Mixed Effects results at 7 T, while showing sound results at 3 T. All code for this project including the automatic pipeline is available at
  • Role for caveolin-mediated transcytosis in facilitating transport of large cargoes into the brain via ultrasound

    The blood-brain barrier (BBB) is a dynamic diffusional barrier regulating the molecular and chemical flux between the blood and brain, thereby preserving cerebral homeostasis. Endothelial cells form the core anatomical component of the BBB based on properties such as specialized junctional complexes between cells, which restricts paracellular transport, and extremely low levels of vesicular transport, restricting transcytosis. In performing its protective function, the BBB also constrains the entry of therapeutics into the brain, hampering the treatment of various neurological disorders. Focused ultrasound is a novel therapeutic modality that has shown efficacy in transiently and non-invasively opening the BBB for the targeted delivery of therapeutics to the brain. Although the ability of ultrasound to disrupt the junctional assembly of endothelial cells has been partially investigated, its effect on the transcellular mode of transport has been largely neglected. In this study, we found that ultrasound induces a pronounced increase in the levels of the vesicle-forming protein caveolin-1. In order to investigate the role of vesicle-mediated transcytoplasmic transport, we compared the leakage of various cargo sizes between a mouse model that lacks caveolin-1 and wild-type mice following sonication of the hippocampus. The absence of caveolin-1 did not lead to overt abnormalities in the cerebral vasculature in the mice. We found that caveolin-1 has a critical role specifically in the transport of large (500 kDa), but not smaller (3 and 70 kDa) cargoes. Our findings indicate differential effects of therapeutic ultrasound on cellular transport mechanisms, with implications for therapeutic interventions.
  • Subthalamic deep brain stimulation identifies frontal networks supporting initiation, inhibition and strategy use in Parkinson's disease

    Initiation and inhibition are executive functions whose disruption in Parkinson's disease impacts substantially on everyday activities. Management of Parkinson's disease with subthalamic deep brain stimulation (DBS) modifies initiation and inhibition, with prior work suggesting that these effects may be mediated via the connectivity of the subthalamic nucleus (STN) with the frontal cortex. Here, we employed high-resolution structural neuroimaging to investigate the variability in initiation, inhibition and strategy use in a cohort of twenty-five (ten females, mean age 62.5, mean Hoehn and Yahr stage 2.5) participants undertaking subthalamic DBS for Parkinson's disease. Neuropsychological assessment of initiation and inhibition was performed preoperatively and at six months postoperatively. We first reconstructed the preoperative connectivity of the STN with a frontal network of anterior and superior medial cortical regions. We then modelled the postoperative site of subthalamic stimulation and reconstructed the connectivity of the stimulation field within this same network. We found that, at both pre- and postoperative intervals, inter-individual variability in inhibition and initiation were strongly associated with structural network connectivity. Measures of subcortical atrophy and local stimulation effects did not play a significant role. Preoperatively, we replicated prior work, including a role for the right inferior frontal gyrus in inhibition and strategy use, as well as the left inferior frontal gyrus in tasks requiring selection under conditions of maintained inhibition. Postoperatively, greater connectivity of the stimulation field with right anterior cortical regions was associated with greater rule violations and suppression errors, supporting prior work implicating right-hemispheric STN stimulation in disinhibition. Our findings suggest that, in Parkinson's disease, connectivity of the frontal cortex with the STN is an important mediator of individual variability in initiation and inhibition,. Personalised information on brain network architecture could guide individualised brain circuit manipulation to minimise neuropsychological disruption after STN-DBS.
  • An epilepsy-associated GRIN2A rare variant disrupts CaMKIIα phosphorylation of GluN2A and NMDA receptor trafficking

    Rare variants in GRIN genes, which encode NMDAR subunits, are strongly associated with neurodevelopmental disorders. Among these, GRIN2A, which encodes the GluN2A subunit of NMDARs, is widely accepted as an epilepsy-causative gene. Here, we functionally characterize the de novo GluN2A-S1459G mutation identified in an epilepsy patient. We show that S1459 is a CaMKIIα phosphorylation site, and that endogenous phosphorylation is regulated during development and in response to synaptic activity in a dark rearing model. GluN2A-S1459 phosphorylation results in preferential binding of NMDARs to SNX27 and a corresponding decrease in PSD-95 binding, which consequently regulates NMDAR trafficking. Furthermore, the epilepsy-associated GluN2A-S1459G variant displays defects in interactions with both SNX27 and PSD-95, resulting in trafficking deficits, reduced spine density, and decreased excitatory synaptic transmission. These data demonstrate a role for CaMKIIα phosphorylation of GluN2A in receptor targeting and implicate NMDAR trafficking defects as a link to epilepsy.Mota Vieira et al. identify CaMKII phosphorylation of the GluN2A subunit on S1459 as a mechanism regulating NMDAR trafficking. An epilepsy-associated rare variant at this same residue, GluN2A-S1459G, results in altered protein interactions, decreased NMDAR surface expression, and reduced synaptic function, providing potential insight into an epilepsy phenotype.
  • Availability of substances for use in personal vaporisers on three online cryptomarkets

  • Availability of substances for use in personal vaporisers on three online cryptomarkets

    Background Personal vaporisers are gaining popularity as an alternative route of administration for a range of substances. Online cryptomarkets are becoming increasingly popular among people who use substances due to their perceived anonymity, ease of use, and reduced risk of violence compared to traditional face-to-face dealers. We examined the diversity of substances marketed for use in a personal vaporiser on these marketplaces. Methods Vaping related listings were extracted from three online cryptomarkets (‘Agartha’, ‘Cryptonia’, and ‘Tochka’) using The Onion Router browser. Data collection occurred between October and November 2019. Results We identified 1929 listings from 201 unique sellers. The top product on Agartha, Cryptonia, and Tochka were vape cartridges prefilled with the e-liquid (70.4 %, 39.4 %, 52.3 % respectively). The most common substance in these products was cannabis oil (96.1 %, 82.1 %, 87.8 %), followed by synthetic cannabinoids (3.7 %, 9.7 %, 9.8 %) and psychedelic substances (0.2 %, 6.4 %, 1.2 %). Vendors were primarily from the USA. Many products offered worldwide shipping (96.3 %, 42.4 %, 51.2 %). Conclusion Vaping products listed on online cryptomarkets in 2019 primarily contained cannabis oils. Future studies should continue to examine cryptomarkets to identify emerging trends of substances that can be used in personal vaporisers.
  • Fusogen-mediated neuron−neuron fusion disrupts neural circuit connectivity and alters animal behavior

    The 100-y-old neuron doctrine from Ramón y Cajal states that neurons are individual cells, rejecting the process of cell-cell fusion in the normal development and function of the nervous system. However, fusogens-specialized molecules essential and sufficient for the fusion of cells-are expressed in the nervous system of different species under conditions of viral infection, stress, or disease. Despite these findings, whether the expression of fusogens in neurons leads to cell-cell fusion, and, if so, whether this affects neuronal fate, function, and animal behavior, has not been explored. Here, using chemosensory neurons as a model system, we provide proof-of-principle that aberrant expression of fusogens in neurons results in neuron-neuron fusion and behavioral impairments. We demonstrate that fusion between chemoattractive neurons does not affect the response to odorants, whereas fusion between chemoattractive and chemorepulsive neurons compromises chemosensation. Moreover, we provide evidence that fused neurons are viable and retain their original specific neuronal fate markers. Finally, analysis of calcium transients reveals that fused neurons become electrically coupled, thereby compromising neural circuit connectivity. Thus, we propose that aberrant expression of fusogens in the nervous system disrupts neuronal individuality, which, in turn, leads to a change in neural circuit connectivity and disruption of normal behavior. Our results expose a previously uncharacterized basis of circuit malfunction, and a possible underlying cause of neurological diseases.
  • Altered Expression of the m6A Methyltransferase METTL3 in Alzheimer’s Disease

    Cognitive impairment in Alzheimer's disease (AD) is associated with dysregulation of the RNA and protein expression profiles in the brain. Recent studies have highlighted the importance of RNA post-transcriptional regulation (epitranscriptomics) in higher order brain functions. Specifically, 6-methyladenosine (m6A), which controls RNA stability, splicing, translation and trafficking, plays an important role in learning and memory. This raises the question of whether m6A signaling is perturbed in AD. To address this, we investigated the expression profile of known m6A-regulatory genes using a public RNA-seq dataset and identified a subset of genes which were significantly dysregulated in the human AD brain. Among these, genes encoding the m6A methyltransferase, , and a member of the m6A methyltransferase complex (MACOM), , were downregulated and upregulated in the hippocampus, respectively. These findings were validated at the protein level using an independent cohort of postmortem human brain samples. Unexpectedly, we observed an accumulation of methyltransferase-like 3 (METTL3), but not RBM15B, in the insoluble fractions, which positively correlated with the levels of insoluble Tau protein in the postmortem human AD samples. Aberrant expression and distribution of METTL3 in the hippocampus of the AD brain may therefore represent an epitranscriptomic mechanism underlying the altered gene expression patterns associated with disease pathogenesis.
  • Genetic control of temperament traits across species: association of autism spectrum disorder risk genes with cattle temperament

    BACKGROUND: Temperament traits are of high importance across species. In humans, temperament or personality traits correlate with psychological traits and psychiatric disorders. In cattle, they impact animal welfare, product quality and human safety, and are therefore of direct commercial importance. We hypothesized that genetic factors that contribute to variation in temperament among individuals within a species will be shared between humans and cattle. Using imputed whole-genome sequence data from 9223 beef cattle from three cohorts, a series of genome-wide association studies was undertaken on cattle flight time, a temperament phenotype measured as the time taken for an animal to cover a short-fixed distance after release from an enclosure. We also investigated the association of cattle temperament with polymorphisms in bovine orthologs of risk genes for neuroticism, schizophrenia, autism spectrum disorders (ASD), and developmental delay disorders in humans. RESULTS: Variants with the strongest associations were located in the bovine orthologous region that is involved in several behavioural and cognitive disorders in humans. These variants were also partially validated in independent cattle cohorts. Genes in these regions (BARHL2, NDN, SNRPN, MAGEL2, ABCA12, KIFAP3, TOPAZ1, FZD3, UBE3A, and GABRA5) were enriched for the GO term neuron migration and were differentially expressed in brain and pituitary tissues in humans. Moreover, variants within 100 kb of ASD susceptibility genes were associated with cattle temperament and explained 6.5% of the total additive genetic variance in the largest cattle cohort. The ASD genes with the most significant associations were GABRB3 and CUL3. Using the same 100 kb window, a weak association was found with polymorphisms in schizophrenia risk genes and no association with polymorphisms in neuroticism and developmental delay disorders risk genes. CONCLUSIONS: Our analysis showed that genes identified in a meta-analysis of cattle temperament contribute to neuron development functions and are differentially expressed in human brain tissues. Furthermore, some ASD susceptibility genes are associated with cattle temperament. These findings provide evidence that genetic control of temperament might be shared between humans and cattle and highlight the potential for future analyses to leverage results between species.
  • Optimizing diffusion MRI acquisition efficiency of rodent brain using simultaneous multislice EPI

    Diffusion tensor imaging (DTI) of the brain provides essential information on the white matter integrity and structural connectivity. However, it suffers from a low signal‐to‐noise ratio (SNR) and requires a long scan time to achieve high spatial and/or diffusion resolution and wide brain coverage. With recent advances in parallel and simultaneous multislice (multiband) imaging, the SNR efficiency has been improved by reducing the repetition time (TR). However, due to the limited number of RF coil channels available on preclinical MRI scanners, simultaneous multislice acquisition has not been practical. In this study, we demonstrate the ability of multiband DTI to acquire high‐resolution data of the mouse brain with 84 slices covering the whole brain in 0.2 mm isotropic resolution without a coil array at 9.4 T. Hadamard‐encoding four‐band pulses were used to acquire four slices simultaneously, with the reduction in the TR maximizing the SNR efficiency. To overcome shot‐to‐shot phase variations, Hadamard decoding with a self‐calibrated phase was developed. Compared with single‐band DTI acquired with the same scan time, the multiband DTI leads to significantly increased SNR by 40% in the white matter. This SNR gain resulted in reduced variations in fractional anisotropy, mean diffusivity, and eigenvector orientation. Furthermore, the cerebrospinal fluid signal was attenuated, leading to reduced free‐water contamination. Without the need for a high‐density coil array or parallel imaging, this technique enables highly efficient preclinical DTI that will facilitate connectome studies.
  • Increased lipid metabolism impairs NK cell function and mediates adaptation to the lymphoma environment

    NK cells play critical roles in protection against haematological malignancies but can acquire a dysfunctional state, which limits anti-tumour immunity. However, the underlying reasons for this impaired NK cell function remain to be uncovered. We found that NK cells in aggressive B cell lymphoma underwent substantial transcriptional reprogramming associated with increased lipid metabolism, including elevated expression of the transcriptional regulator PPAR-g. Exposure to fatty acids in the lymphoma environment potently suppressed NK cell effector response and cellular metabolism. NK cells from both diffuse large B cell lymphoma patients and Eµ-myc B cell lymphoma-bearing mice displayed reduced IFN-g production. Activation of PPAR-g partially restored mitochondrial membrane potential and IFN-g production. Overall our data indicate that increased lipid metabolism, while impairing their function, is a functional adaptation of NK cells to the fatty-acid rich lymphoma environment.
  • Gray matter-based age prediction characterizes different regional patterns

  • The cost of mental disorders: a systematic review

    Aims. To identify and synthesise the literature on the cost of mental disorders. Methods. Systematic literature searches were conducted in the databases PubMed, EMBASE, Web of Science, EconLit, NHS York Database and PsychInfo using key terms for cost and mental disorders. Searches were restricted to January 1980–May 2019. The inclusion criteria were: (1) cost-of-illness studies or cost-analyses; (2) diagnosis of at least one mental disorder; (3) study population based on the general population; (4) outcome in monetary units. The systematic review was preregistered on PROSPERO (ID: CRD42019127783). Results. In total, 13 579 potential titles and abstracts were screened and 439 full-text articles were evaluated by two independent reviewers. Of these, 112 articles were included from the systematic searches and 31 additional articles from snowball searching, resulting in 143 included articles. Data were available from 48 countries and categorised according to nine mental disorder groups. The quality of the studies varied widely and there was a lack of studies from low- and middle-income countries and for certain types of mental disorders (e.g. intellectual disabilities and eating disorders). Our study showed that certain groups of mental disorders are more costly than others and that these rankings are relatively stable between countries. An interactive data visualisation site can be found here: Conclusions. This is the first study to provide a comprehensive overview of the cost of mental disorders worldwide.
  • Fyn kinase controls tau aggregation in vivo

    Alzheimer’s disease (AD) is a proteinopathy exhibiting aggregation of β-amyloid (Aβ) as amyloid plaques and tau as neurofibrillary tangles (NFTs), whereas primary tauopathies display only a tau pathology. Aβ toxicity is mediated by Fyn kinase in a tau-dependent process; however, whether Fyn controls tau pathology in diseases that lack Aβ pathology remains unexplored. To address this, we generate the Tg/Fyn−/− mouse, which couples mutant tau overexpression with Fyn knockout. Surprisingly, Tg/Fyn−/− mice exhibit a near-complete ablation of NFTs, alongside reduced tau hyperphosphorylation, altered tau solubility, and diminished synaptic tau accumulation. Furthermore, Tg/Fyn−/− brain lysates elicit less tau seeding in tau biosensor cells. Lastly, the fibrillization of tau is boosted by its pseudophosphorylation at the Fyn epitope Y18. Together, this identifies Fyn as a key regulator of tau pathology independently of Aβ-induced toxicity and thereby represents a potentially valuable therapeutic target for not only AD but also tauopathies more generally.
  • Cognitive capacity limits are remediated by practice-induced plasticity between the Putamen and Pre-Supplementary Motor Area

    Humans show striking limitations in information processing when multitasking, yet can modify these limits with practice. Such limitations have been linked to a frontal-parietal network, but recent models of decision-making implicate a striatal-cortical network. We adjudicated these accounts by investigating the circuitry underpinning multitasking in 100 human individuals and the plasticity caused by practice. We observed that multitasking costs, and their practice induced remediation, are best explained by modulations in information transfer between the striatum and the cortical areas that represent stimulus-response mappings. Specifically, our results support the view that multitasking stems at least in part from taxation in information sharing between the putamen and pre-supplementary motor area (pre-SMA). Moreover, we propose that modulations to information transfer between these two regions leads to practice-induced improvements in multitasking. Significance statement Humans show striking limitations in information processing when multitasking, yet can modify these limits with practice. Such limitations have been linked to a frontal-parietal network, but recent models of decision-making implicate a striatal-cortical network. We adjudicated these accounts by investigating the circuitry underpinning multitasking in 100 individuals and the plasticity caused by practice. Our results support the view that multitasking stems at least in part from taxation in information sharing between the putamen and pre-supplementary motor area (pre-SMA). We therefore show that models of cognitive capacity limits must consider how subcortical and cortical structures interface to produce cognitive behaviours, and we propose a novel neurophysiological substrate of multitasking limitations.
  • Multiscale neurobiological correlates of human neuroticism

    Neuroticism is a heritable personality trait associated with negative emotionality; however, we know little regarding the association between the microscale and macroscale neurobiological substrates of human neuroticism. Cross-scale correlation analysis may provide such information. In this study, voxel-wise neuroimaging-neuroticism correlation analyses consistently showed a positive correlation between neuroticism and functional connectivity density (FCD) in the ventral striatum in 274 young Chinese adults. Partial least squares regression analysis showed that the FCD-neuroticism correlation map was significantly spatially correlated with gene expression profiles in each of six donated human brains. Neuroticism-related genes derived from the six donors consistently showed significant enrichment in the chemical synaptic transmission, circadian entrainment, long-term potentiation, inflammatory mediator regulation of transient receptor potential channels, and amphetamine addiction pathways. The protein-protein interaction analysis revealed four hub genes involved in the above pathways, including G protein subunit gamma 10, 5-hydroxytryptamine receptor 2C, prodynorphin, and calcium/calmodulin-dependent protein kinase II alpha. By combining multiscale correlation analyses and functional annotations, this study advances our understanding of the genetic and neural substrates of human neuroticism and emphasizes the importance of striatal functional properties in human neuroticism.
  • Altered structural connectivity networks in a mouse model of complete and partial dysgenesis of the corpus callosum

    Corpus callosum dysgenesis (CCD) describes a collection of brain malformations in which the main fiber tract connecting the two hemispheres is either absent (complete CCD, or 'agenesis of the corpus callosum') or reduced in size (partial CCD). Humans with these neurodevelopmental disorders have a wide range of cognitive outcomes, including seemingly preserved features of interhemispheric communication in some cases. However, the structural substrates that could underlie this variability in outcome remain to be fully elucidated. Here, for the first time, we characterize the global brain connectivity of a mouse model of complete and partial CCD. We demonstrate features of structural brain connectivity that model those predicted in humans with CCD, including Probst bundles in complete CCD and heterotopic sigmoidal connections in partial CCD. Crucially, we also histologically validate the recently predicted ectopic sigmoid bundle present in humans with partial CCD, validating the utility of this mouse model for fine anatomical studies of this disorder. Taken together, this work describes a mouse model of altered structural connectivity in variable severity CCD and forms a foundation for future studies investigating the function and mechanisms of development of plastic tracts in developmental disorders of brain connectivity.
  • Long-distance aberrant heterotopic connectivity in a mouse strain with a high incidence of callosal anomalies

    Corpus callosum dysgenesis (CCD) is a developmental brain condition in which some white matter fibers fail to find their natural course across the midplane, reorganizing instead to form new aberrant pathways. This type of white matter reorganization is known as long-distance plasticity (LDP). The present work aimed to characterize the Balb/c mouse strain as a model of CCD. We employed high-resolution anatomical MRI in 81 Balb/c and 27 C57bl6 mice to show that the Balb/c mouse strain presents a variance in the size of the CC that is 3.9 times higher than the variance of normotypical C57bl6. We also performed high-resolution diffusion-weighted imaging (DWI) in 8 Balb/c and found that the Balb/c strain shows aberrant white matter bundles, such as the Probst (5/8 animals) and the Sigmoid bundles (7/8 animals), which are similar to those found in humans with CCD. Using a histological tracer technique, we confirmed the existence of these aberrant bundles in the Balb/c strain. Interestingly, we also identified sigmoid-like fibers in the C57bl6 strain, thought to a lesser degree. Next, we used a connectome approach and found widespread brain connectivity differences between Balb/c and C57bl6 strains. The Balb/c strain also exhibited increased variability of global connectivity. These findings suggest that the Balb/c strain presents local and global changes in brain structural connectivity. This strain often presents with callosal abnormalities, along with the Probst and the Sigmoid bundles, making it is an attractive animal model for CCD and LDP in general. Our results also show that even the C57bl6 strain, which typically serves as a normotypical control animal in a myriad of studies, presents sigmoid-fashion pattern fibers laid out in the brain. These results suggest that these aberrant fiber pathways may not necessarily be a pathological hallmark, but instead an alternative roadmap for misguided axons. Such findings offer new insights for interpreting the significance of CCD-associated LDP in humans.
  • Comorbidity within mental disorders: a comprehensive analysis based on 145 990 survey respondents from 27 countries

    AIMS: Epidemiological studies indicate that individuals with one type of mental disorder have an increased risk of subsequently developing other types of mental disorders. This study aimed to undertake a comprehensive analysis of pair-wise lifetime comorbidity across a range of common mental disorders based on a diverse range of population-based surveys. METHODS: The WHO World Mental Health (WMH) surveys assessed 145 990 adult respondents from 27 countries. Based on retrospectively-reported age-of-onset for 24 DSM-IV mental disorders, associations were examined between all 548 logically possible temporally-ordered disorder pairs. Overall and time-dependent hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. Absolute risks were estimated using the product-limit method. Estimates were generated separately for men and women. RESULTS: Each prior lifetime mental disorder was associated with an increased risk of subsequent first onset of each other disorder. The median HR was 12.1 (mean = 14.4; range 5.2-110.8, interquartile range = 6.0-19.4). The HRs were most prominent between closely-related mental disorder types and in the first 1-2 years after the onset of the prior disorder. Although HRs declined with time since prior disorder, significantly elevated risk of subsequent comorbidity persisted for at least 15 years. Appreciable absolute risks of secondary disorders were found over time for many pairs. CONCLUSIONS: Survey data from a range of sites confirms that comorbidity between mental disorders is common. Understanding the risks of temporally secondary disorders may help design practical programs for primary prevention of secondary disorders.
  • Late guidance resolves the search slope paradox in contextual cueing

    Visual search is facilitated by statistical learning of repeated search contexts, termed ‘contextual cueing’. Repeated displays are thought to enhance attentional guidance, but this has been challenged by the absence of search-slope differences between repeated and novel displays. Here we use eye-tracking to resolve this paradox by calculating a measure of when during search the contextual cueing benefit emerges. In 24 human participants we observe typical reaction time and fixation count benefits for repeated contexts, but no slope differences between repeated and novel search contexts. Eye-tracking showed that the attentional guidance benefit emerged over time, occurring later for larger set sizes, and producing similar response time benefits for small and large set sizes. We argue that repeated and novel contexts have similar slopes because learning benefits are confined to target-adjacent regions of roughly equivalent area across set sizes. This finding rules out one of the strongest pieces of evidence against an attentional account of contextual cueing.
  • Adult neurogenesis in the olfactory system: improving performance for difficult discrimination tasks?

    What is the function of new neurons entering the olfactory bulb? Many insights regarding the molecular control of adult neurogenesis have been uncovered, but the purpose of new neurons entering the olfactory bulb has been difficult to ascertain. Here, studies investigating the role of adult neurogenesis in olfactory discrimination in mice are reviewed. Studies in which adult neurogenesis is affected are highlighted, with a focus on the role of environment enrichment and what happens during ageing. There is evidence for a role of adult neurogenesis in fine discrimination tasks, as underscored by studies that enhance adult neurogenesis. This is also observed in ageing studies, where older mice with reduced levels of adult neurogenesis perform poorly in olfactory discrimination. Differences in methodology that could account for alternative conclusions, and the importance of specificity in methods being used to investigate the effect of adult neurogenesis in olfactory performance are emphasized.
  • Dynamic courtship signals and mate preferences in Sepia plangon

    Communication in cuttlefish includes rapid changes in skin coloration and texture, body posture and movements, and potentially polarized signals. The dynamic displays are fundamental for mate choice and agonistic behavior. We analyzed the reproductive behavior of the mourning cuttlefish Sepia plangon in the laboratory. Mate preference was analyzed via choice assays (n = 33) under three sex ratios, 1 male (M): 1 female (F), 2M:1F, and 1M:2F. We evaluated the effect of modifying polarized light from the arms stripes and ambient light with polarized and unpolarized barriers between the cuttlefish. Additionally, to assess whether a particular trait was a determinant for mating, we used 3D printed cuttlefish dummies. The dummies had different sets of visual signals: two sizes (60 or 90 mm mantle length), raised or dropped arms, high or low contrast body coloration, and polarized or unpolarized filters to simulate the arms stripes. Frequency and duration (s) of courtship displays, mating, and agonistic behaviors were analyzed with GLM and ANOVAs. The behaviors, body patterns, and their components were integrated into an ethogram to describe the reproductive behavior of S. plangon. We identified 18 body patterns, 57 body patterns components, and three reproductive behaviors (mating, courtship, and mate guarding). Only sex ratio had a significant effect on courtship frequency, and the male courtship success rate was 80%. Five small (ML < 80 mm) males showed the dual-lateral display to access mates while avoiding fights with large males; this behavior is characteristic of male “sneaker” cuttlefish. Winner males showed up to 17 body patterns and 33 components, whereas loser males only showed 12 patterns and 24 components. We identified 32 combinations of body patterns and components that tended to occur in a specific order and were relevant for mating success in males. Cuttlefish were visually aware of the 3D-printed dummies; however, they did not start mating or agonistic behavior toward the dummies. Our findings suggest that in S. plangon, the dynamic courtship displays with specific sequences of visual signals, and the sex ratio are critical for mate choice and mating success.
  • Randomized controlled trial of social cognition and interaction training compared to befriending group

    Background: Deficits in social cognition are common in people with schizophrenia and are associated with impaired functioning. Finding effective interventions to address these deficits is a priority. Social Cognition Interaction Training (SCIT) is a psychosocial intervention that has demonstrated acceptability and feasibility in various health care settings. Larger, well-designed randomized controlled trials are needed to examine the effectiveness of this intervention. Design: A randomized controlled trial. Methods: One hundred and twenty adults diagnosed with schizophrenia spectrum disorder were randomized to receive SCIT (n = 61) or Befriending Therapy (BT) (n = 59). Both intervention groups were delivered weekly for 2 hr over 12 weeks. Neurocognitive assessment was completed at baseline. Participants completed assessments of social cognition, social functioning, and meta-cognition at baseline, post-intervention, and 3-month follow-up. Results: There were no clinically significant differences between group outcomes on any measure of social cognition or social functioning. There was a trend for both groups to improve over time but not at a level of statistical significance. Conclusions: SCIT did not show any additional benefits on measures of social cognition compared to Befriending Therapy for people with schizophrenia spectrum disorder. The findings are discussed in terms of potential improvements to the programme. Practitioner points: Effective interventions for the social cognitive deficits of schizophrenia spectrum disorders are still being refined. Social Cognition Interaction Training is a promising therapy but requires further modifications to improve its effectiveness.
  • Down-regulation of a cytokine secreted from peripheral fat bodies improves visual attention while reducing sleep in Drosophila

    Sleep is vital for survival. Yet under environmentally challenging conditions, such as starvation, animals suppress their need for sleep. Interestingly, starvation-induced sleep loss does not evoke a subsequent sleep rebound. Little is known about how starvation-induced sleep deprivation differs from other types of sleep loss, or why some sleep functions become dispensable during starvation. Here, we demonstrate that down-regulation of the secreted cytokine unpaired 2 (upd2) in Drosophila flies may mimic a starved-like state. We used a genetic knockdown strategy to investigate the consequences of upd2 on visual attention and sleep in otherwise well-fed flies, thereby sidestepping the negative side effects of undernourishment. We find that knockdown of upd2 in the fat body (FB) is sufficient to suppress sleep and promote feeding-related behaviors while also improving selective visual attention. Furthermore, we show that this peripheral signal is integrated in the fly brain via insulin-expressing cells. Together, these findings identify a role for peripheral tissue-to-brain interactions in the simultaneous regulation of sleep quality and attention, to potentially promote adaptive behaviors necessary for survival in hungry animals.
  • Diversity of interneurons in the lateral and basal amygdala

    The basolateral amygdala (BLA) is a temporal lobe structure that contributes to a host of behaviors. In particular, it is a central player in learning about aversive events and thus assigning emotional valence to sensory events. It is a cortical-like structure and contains glutamatergic pyramidal neurons and GABAergic interneurons. It is divided into the lateral (LA) and basal (BA) nuclei that have distinct cell types and connections. Interneurons in the BLA are a heterogenous population, some of which have been implicated in specific functional roles. Here we use optogenetics and slice electrophysiology to investigate the innervation, postsynaptic receptor stoichiometry, and plasticity of excitatory inputs onto interneurons within the BLA. Interneurons were divided into six groups based on their discharge properties, each of which received input from the auditory thalamus (AT) and auditory cortex (AC). Auditory innervation was concentrated in the LA, and optogenetic stimulation evoked robust synaptic responses in nearly all interneurons, drove many cells to threshold, and evoked disynaptic inhibition in most interneurons. Auditory input to the BA was sparse, innervated fewer interneurons, and evoked smaller synaptic responses. Biophysically, the subunit composition and distribution of AMPAR and NMDAR also differed between the two nuclei, with fewer BA IN expressing calcium permeable AMPAR, and a higher proportion expressing GluN2B-containing NMDAR. Finally, unlike LA interneurons, LTP could not be induced in the BA. These findings show that interneurons in the LA and BA are physiologically distinct populations and suggest they may have differing roles during associative learning.
  • Behavioral and electrophysiological evidence for a dissociation between working memory capacity and feature-based attention

    When attending to visual objects with particular features, neural processing is typically biased toward those features. Previous work has suggested that maintaining such feature-based attentional sets may involve the same neural resources as visual working memory. If so, the extent to which feature-based attention influences stimulus processing should be related to individuals’ working memory capacity. Here we used electroencephalography (EEG) to record brain activity in 60 human observers while they monitored stimulus streams for targets of a specific color. Distractors presented at irrelevant locations evoked strong electrophysiological markers of attentional signal enhancement (the N2pc and PD components) despite producing little or no behavioral interference. Critically, there was no relationship between individual differences in the magnitude of these feature-based biases on distractor processing and individual differences in working memory capacity as measured using three separate working memory tasks. Bayes factor analyses indicated substantial evidence in support of the null hypothesis of no relationship between working memory capacity and the effects of feature-based attention on distractor processing. We consider three potential explanations for these findings. One is that working memory and feature-based attention draw upon distinct neural resources, contrary to previous claims. A second is that working memory is only related to feature-based attention when the attentional template has recently changed. A third is that feature-based attention tasks of the kind employed in the current study recruit just one of several subcomponents of working memory, and so are not invariably correlated with an individual’s overall working memory capacity.
  • The role of lipids in ependymal development and the modulation of adult neural stem cell function during aging and disease

    Within the adult mammalian central nervous system, the ventricular-subventricular zone (V-SVZ) lining the lateral ventricles houses neural stem cells (NSCs) that continue to produce neurons throughout life. Developmentally, the V-SVZ neurogenic niche arises during corticogenesis following the terminal differentiation of telencephalic radial glial cells (RGCs) into either adult neural stem cells (aNSCs) or ependymal cells. In mice, these two cellular populations form rosettes during the late embryonic and early postnatal period, with ependymal cells surrounding aNSCs. These aNSCs and ependymal cells serve a number of key purposes, including the generation of neurons throughout life (aNSCs), and acting as a barrier between the CSF and the parenchyma and promoting CSF bulk flow (ependymal cells). Interestingly, the development of this neurogenic niche, as well as its ongoing function, has been shown to be reliant on different aspects of lipid biology. In this review we discuss the developmental origins of the rodent V-SVZ neurogenic niche, and highlight research which has implicated a role for lipids in the physiology of this part of the brain. We also discuss the role of lipids in the maintenance of the V-SVZ niche, and discuss new research which has suggested that alterations to lipid biology could contribute to ependymal cell dysfunction in aging and disease.
  • The Trypanosoma brucei KIFC1 kinesin ensures the fast antibody clearance required for parasite infectivity

  • Role of epigenetic regulatory enzymes in animal models of mania induced by amphetamine and paradoxical sleep deprivation

    It is known that bipolar disorder has a multifactorial aetiology where the interaction between genetic and environmental factors is responsible for its development. Because of this, epigenetics has been largely studied in psychiatric disorders. The present study aims to evaluate the effects of histone deacetylase inhibitors on epigenetic enzyme alterations in rats or mice submitted to animal models of mania induced by dextro-amphetamine or sleep deprivation, respectively. Adult male Wistar rats were subjected to 14 days of dextro-amphetamine administration, and from the eighth to the fourteenth day, the animals were treated with valproate and sodium butyrate in addition to dextro-amphetamine injections. Adult C57BL/6 mice received 7 days of valproate or sodium butyrate administration, being sleep deprived at the last 36 hr of the protocol. Locomotor and exploratory activities of rats and mice were evaluated in the open-field test, and histone deacetylase, DNA methyltransferase, and histone acetyltransferase activities were assessed in the frontal cortex, hippocampus, and striatum. Dextro-amphetamine and sleep deprivation induced hyperactivity and increased histone deacetylase and DNA methyltransferase activities in the animal's brain. Valproate and sodium butyrate were able to reverse hyperlocomotion induced by both animal models, as well as the alterations on histone deacetylase and DNA methyltransferase activities. There was a positive correlation between enzyme activities and number of crossings for both models. Histone deacetylase and DNA methyltransferase activities also presented a positive correlation between theirselves. These results suggest that epigenetics can play an important role in BD pathophysiology as well as in its treatment.
  • A dedicated eight‐channel receive RF coil array for monkey brain MRI at 9.4 T

    The neuroimaging of nonhuman primates (NHPs) realised with magnetic resonance imaging (MRI) plays an important role in understanding brain structures and functions, as well as neurodegenerative diseases and pathological disorders. Theoretically, an ultrahigh field MRI (≥7 T) is capable of providing a higher signal‐to‐noise ratio (SNR) for better resolution; however, the lack of appropriate radiofrequency (RF) coils for 9.4 T monkey MRI undermines the benefits provided by a higher field strength. In particular, the standard volume birdcage coil at 9.4 T generates typical destructive interferences in the periphery of the brain, which reduces the SNR in the neuroscience‐focused cortex region. Also, the standard birdcage coil is not capable of performing parallel imaging. Consequently, extended scan durations may cause unnecessary damage due to overlong anaesthesia. In this work, assisted by numerical simulations, an eight‐channel receive RF coil array was specially designed and manufactured for imaging NHPs at 9.4 T. The structure and geometry of the proposed receive array was optimised with numerical simulations, so that the SNR enhancement region was particularly focused on monkey brain. Validated with rhesus monkey and cynomolgus monkey brain images acquired from a 9.4 T MRI scanner, the proposed receive array outperformed standard birdcage coil with higher SNR, mean diffusivity and fractional anisotropy values, as well as providing better capability for parallel imaging.
  • Reduced effective connectivity between right parietal and inferior frontal cortex during audiospatial perception in neglect patients with a right-hemisphere lesion: Reduced effective connectivity in neglect syndrome

    A lesion to the right hemisphere of the brain in humans commonly leads to perceptual neglect of the left side of the sensorium. The clinical observation that lesions to disparate cortical and subcortical areas converge upon similar behavioural symptoms points to neglect as a dysconnection syndrome that may result from the disruption of a distributed network, rather than aberrant computations in any particular brain region. To test this hypothesis, we used Bayesian analysis of effective connectivity based on electroencephalographic recordings in ten patients (6 male, 4 female; age range 41–68) with left-sided neglect following a right-hemisphere lesion. In line with previous research, age-matched healthy controls showed a contralateral increase in connection strength between parietal and frontal cortex with respect to the laterality of audiospatial oddball stimuli. Neglect patients, however, showed a dysconnection between parietal and frontal cortex in the right hemisphere when oddballs appeared on their left side, but preserved connectivity in the left hemisphere when stimuli appeared on their right. This preserved fronto-parietal connectivity was associated with lower neglect severity. Moreover, we saw ipsilateral fronto-temporal connectivity increases for oddballs appearing on the neglected side, which might be a compensatory mechanism for residual left side awareness. No group differences were found in intrinsic (within-region) connectivity. While further validation is required in a bigger sample, our findings are in keeping with the idea that neglect results from the disruption of a distributed network, rather than a lesion to any single brain region. Significance statement: Lesions to the right hemisphere of the brain commonly lead to neglect syndrome, characterized by perceptual deficits where patients are unaware of the left side of their body and environment. Using analysis of non-invasive electrophysiological recordings, we provide evidence that patients with left-sided neglect have reduced connectivity between the right parietal and frontal cortex during audiospatial stimuli, but preserved connectivity between regions in the non-lesioned left hemisphere. Moreover, for these intact connections we observed an ipsilateral fronto-temporal increase in connectivity during oddballs appearing on the neglected side, which might be a compensatory mechanism for residual perception. Crucially, we found that patients with more severe neglect symptoms had reduced connectivity between parietal and frontal cortex in the left hemisphere. This suggests that neglect may be caused by the disruption of a distributed network in the brain, rather than a lesion to any particular brain region.
  • Changes of Effective Connectivity in the Alpha Band Characterize Differential Processing of Audiovisual Information in Cross-Modal Selective Attention

    Cross-modal selective attention enhances the processing of sensory inputs that are most relevant to the task at hand. Such differential processing could be mediated by a swift network reconfiguration on the macroscopic level, but this remains a poorly understood process. To tackle this issue, we used a behavioral paradigm to introduce a shift of selective attention between the visual and auditory domains, and recorded scalp electroencephalographic signals from eight healthy participants. The changes in effective connectivity caused by the cross-modal attentional shift were delineated by analyzing spectral Granger Causality (GC), a metric of frequency-specific effective connectivity. Using data-driven methods of pattern-classification and feature-analysis, we found that a change in the α band (12 Hz–15 Hz) of GC is a stable feature across different individuals that can be used to decode the attentional shift. Specifically, auditory attention induces more pronounced information flow in the α band, especially from the parietal–occipital areas to the temporal–parietal areas, compared to the case of visual attention, reflecting a reconfiguration of interaction in the macroscopic brain network accompanying different processing. Our results support the role of α oscillation in organizing the information flow across spatially-separated brain areas and, thereby, mediating cross-modal selective attention.
  • Behavioral signatures of a developing neural code

    During early life, neural codes must develop to appropriately transform sensory inputs into behavioral outputs. Here, we demonstrate a link between the maturity of neural coding in the visual brain and developmental changes in visually guided behavior. In zebrafish larvae, we show that visually driven hunting behavior improves from 4 to 15 days post-fertilization, becoming faster and more accurate. During the same period, population activity in parts of the optic tectum refines, improving decoding and information transmission for particular spatial positions. Remarkably, individual differences in decoding can predict each fish's hunting success. Together, these results help reveal how the neural codes required for a natural behavior emerge during development.How do neural codes critical for behavior emerge during development? Avitan et al. show that during early life, visually driven hunting in larval zebrafish improves, and this is accompanied by increasing mutual information and improved decoding of visual stimuli in the optic tectum. Moreover, decoding can predict individual differences in hunting.
  • Genetic and environmental determinants of variation in the plasma lipidome of older Australian twins

    The critical role of blood lipids in a broad range of health and disease states is well recognised but less explored is the interplay of genetics and environment within the broader blood lipidome. We examined heritability of the plasma lipidome among healthy older-aged twins (75 monozygotic/55 dizygotic pairs) enrolled in the Older Australian Twins Study (OATS) and explored corresponding gene expression and DNA methylation associations. 27/209 lipids (13.3%) detected by liquid chromatography-coupled mass spectrometry (LC-MS) were significantly heritable under the classical ACE twin model (h2 = 0.28–0.59), which included ceramides (Cer) and triglycerides (TG). Relative to non-significantly heritable TGs, heritable TGs had a greater number of associations with gene transcripts, not directly associated with lipid metabolism, but with immune function, signalling and transcriptional regulation. Genome-wide average DNA methylation (GWAM) levels accounted for variability in some non-heritable lipids. We reveal a complex interplay of genetic and environmental influences on the ageing plasma lipidome.
  • Kaempferol and zinc gluconate mitigate neurobehavioral deficits and oxidative stress induced by noise exposure in Wistar rats

    This study investigated the effects of kaempferol and zinc gluconate on neurobehavioural and oxidative stress changes in Wistar rats exposed to noise. Thirty (30) rats were randomly divided into five groups: Groups I and II were administered with deionized water (DW); Group III, kaempferol (K); Group IV, zinc gluconate (Zn); Group V, kaempferol + zinc gluconate. Groups II, III, IV, and V were subjected to noise stress (N) induced by exposing rats to 100 dB (4 h/day) for 15 days, from day 33 to day 48 after starting the drug treatments. Neuromuscular coordination, motor coordination, motor strength, sensorimotor reflex, and learning and memory, were evaluated using standard laboratory methods. Levels of nitric oxide (NO), malondialdehyde (MDA) and activities of glutathione peroxidase (GPx), catalase and superoxide dismutase (SOD) were evaluated in the hippocampus. Exposure of rats to noise, induced significant neurobehavioural deficits and oxidative stress while the combined administration of kaempferol and zinc gluconate significantly (P < 0.05) improved open-field performance, motor coordination, motor strength, sensorimotor reflex, and learning and memory. Co-administration of kaempferol and zinc gluconate ameliorated noise-induced oxidative stress as demonstrated by the significantly increased activities of GPx, catalase, and SOD, and decreased levels of NO and MDA (P < 0.05 and P < 0.01 respectively), compared to the DW + N group. Our results suggest that oxidative stress, evidenced by increased NO and MDA concentration and decreased activities of GPx, catalase and SOD, were involved in the molecular mechanism underlying neurobehavioural impairment in Wistar rats, exposed to noise stress. Single treatment of kaempferol exerted a more potent mitigative effect than zinc gluconate, while their combination produced an improved outcome.
  • Enhanced Sensory Coding in Mouse Vibrissal and Visual Cortex through TRPA1

    Transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel, broadly expressed throughout the body. Despite its expression in the mammalian brain, little is known about the contribution of TRPA1 to cortical function. Here, we characterize how TRPA1 affects sensory information processing in two cortical areas in mice: the primary vibrissal (whisker) somatosensory cortex (vS1) and the primary visual cortex (V1). In vS1, local activation of TRPA1 by allyl isothiocyanate (AITC) increases the ongoing activity of neurons and their evoked response to vibrissal stimulation, producing a positive gain modulation. The gain modulation is reversed by TRPA1 inhibitor HC-030031 and is absent in TRPA1 knockout mice. Similarly, in V1, TRPA1 activation increases the gain of direction and orientation selectivity. Linear decoding of V1 population activity confirms faster and more reliable encoding of visual signals under TRPA1 activation. Overall, our findings reveal a physiological role for TRPA1 in enhancing sensory signals in the mammalian cortex. Kheradpezhouh et al. investigate the role of TRPA1 in two cortical areas in mice: the primary somatosensory and visual cortices. They demonstrate that TRPA1 enhances sensory information processing in both areas, consistent with a positive gain modulation.