Recent QBI publications

  • Dysfunction in nonsense-mediated decay, protein homeostasis, mitochondrial function, and brain connectivity in ALS-FUS mice with cognitive deficits

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of the same disease spectrum of adult-onset neurodegenerative diseases that affect the motor and cognitive functions, respectively. Multiple common genetic loci such as fused in sarcoma (FUS) have been identified to play a role in ALS and FTD etiology. Current studies indicate that FUS mutations incur gain-of-toxic functions to drive ALS pathogenesis. However, how the disease-linked mutations of FUS affect cognition remains elusive. Using a mouse model expressing an ALS-linked human FUS mutation (R514G-FUS) that mimics endogenous expression patterns, we found that FUS proteins showed an age-dependent accumulation of FUS proteins despite the downregulation of mouse FUS mRNA by the R514G-FUS protein during aging. Furthermore, these mice developed cognitive deficits accompanied by a reduction in spine density and long-term potentiation (LTP) within the hippocampus. At the physiological expression level, mutant FUS is distributed in the nucleus and cytosol without apparent FUS aggregates or nuclear envelope defects. Unbiased transcriptomic analysis revealed a deregulation of genes that cluster in pathways involved in nonsense-mediated decay, protein homeostasis, and mitochondrial functions. Furthermore, the use of in vivo functional imaging demonstrated widespread reduction in cortical volumes but enhanced functional connectivity between hippocampus, basal ganglia and neocortex in R514G-FUS mice. Hence, our findings suggest that disease-linked mutation in FUS may lead to changes in proteostasis and mitochondrial dysfunction that in turn affect brain structure and connectivity resulting in cognitive deficits.
  • Sofosbuvir plus Ribavirin is effective for HCV elimination in people living with HIV from rural area of China

    People living with HIV (PLWH) bear higher prevalence of HCV coinfection. An accessible directly acting antivirals regimen with less drug–drug interaction with antiretroviral therapy (ART) is urgently needed in source limited regions. We aimed to assess the efficacy and safety of SOF + RBV for 24 weeks regimen in HIV–HCV coinfected patients in Liangshan Prefecture, China. PLWH under ART from China’s national free antiretroviral treatment project (CNFATP) and diagnosed with treatment-naïve HCV infection were enrolled. SOF + RBV was administrated for 24 weeks and patients were followed for ≥ 12 weeks. The efficacy and safety were analyzed and related factors were explored. 58 patients completed 24 weeks of SOF + RBV and had all tests done. Genotype prevalence in this population was G3 44.8% (n = 26), G6 31.0% (n = 18) and G1 17.2% (n = 10) respectively. 52/58 (89.7%) patients achieved SVR12 while 10.3% experienced therapeutic failure. However, SVR12 was neither significantly different between groups of different gender, age, transmission routines, CD4 cell count, HIV infection duration, ART duration and HBsAg prevalence nor influenced by HCV viral load, genotypes and hepatic stiffness. The regimen was well-tolerated without any serious AEs or AEs leading to treatment adjustment or discontinuation reported. PLWH in Liangshan showed a high prevalence of HCV coinfection with GT3 and GT6 as the most frequent genotypes. SOF + RBV for 24 weeks could achieve good SVR12 in this population and was well-tolerated. It has great potential to be generalized in coinfected population in source-limited regions.
  • Task-related brain functional network reconfigurations relate to motor recovery in chronic subcortical stroke

    Stroke leads to both regional brain functional disruptions and network reorganization. However, how brain functional networks reconfigure as task demand increases in stroke patients and whether such reorganization at baseline would facilitate post-stroke motor recovery are largely unknown. To address this gap, brain functional connectivity (FC) were examined at rest and motor tasks in eighteen chronic subcortical stroke patients and eleven age-matched healthy controls. Stroke patients underwent a 2-week intervention using a motor imagery-assisted brain computer interface-based (MI-BCI) training with or without transcranial direct current stimulation (tDCS). Motor recovery was determined by calculating the changes of the upper extremity component of the Fugl–Meyer Assessment (FMA) score between pre- and post-intervention divided by the pre-intervention FMA score. The results suggested that as task demand increased (i.e., from resting to passive unaffected hand gripping and to active affected hand gripping), patients showed greater FC disruptions in cognitive networks including the default and dorsal attention networks. Compared to controls, patients had lower task-related spatial similarity in the somatomotor–subcortical, default–somatomotor, salience/ventral attention–subcortical and subcortical–subcortical connections, suggesting greater inefficiency in motor execution. Importantly, higher baseline network-specific FC strength (e.g., dorsal attention and somatomotor) and more efficient brain network reconfigurations (e.g., somatomotor and subcortical) from rest to active affected hand gripping at baseline were related to better future motor recovery. Our findings underscore the importance of studying functional network reorganization during task-free and task conditions for motor recovery prediction in stroke.
  • A binge high sucrose diet provokes systemic and cerebral inflammation in rats without inducing obesity

    While the dire cardiometabolic consequences of the hypercaloric modern ‘Western’ diet are well known, there is not much information on the health impact of a high sucrose diet not inducing weight gain. Here, we tested the hypothesis that rats reared with intermittent binge access to sucrose in addition to normal chow would develop an inflammatory response in brain. To test this hypothesis, we undertook serial PET/MRI scans with the TSPO ligand [F]DPA714 in a group of (n=9) rats at baseline and again after voluntarily consuming 5% sucrose solution three days a week for three months. Compared to a control group fed with normal chow (n=9), the sucrose rats indeed showed widespread increases in the availability of cerebral binding sites for the microglial marker, despite normal weight gain compared to the control diet group. Subsequent immunofluorescence staining of the brains confirmed the PET findings, showing a widespread 20% increase in the abundance of IBA-1-positive microglia with characteristic ‘semi-activated’ morphology in the binge sucrose rats, which had 23% lower density of microglial endpoints and 25% lower mean process length compared to microglia in the control rats with ordinary feeding. GFAP immunofluorescence showed no difference in astroglial coverage in the sucrose rats, except for a slight reduction in hypothalamus. The binge sucrose diet-induced neuroinflammation was associated with a significant elevation of white blood cell counts. Taking these results together, we find that long-term intake of sucrose in a binge paradigm, similar in sucrose content to the contemporary Western diet, triggered a low-grade systemic and central inflammation in non-obese rats. The molecular mechanism of this phenomenon remains to be established.
  • Modulatory effects of autophagy on app processing as a potential treatment target for Alzheimer’s disease

    Alzheimer’s disease (AD) is characterized by the formation of intracellular aggregate com-posed of heavily phosphorylated tau protein and extracellular deposit of amyloid-β (Aβ) plaques derived from proteolysis cleavage of amyloid precursor protein (APP). Autophagy refers to the lysosomal-mediated degradation of cytoplasmic constituents, which plays a critical role in maintaining cellular homeostasis. Importantly, recent studies reported that dysregulation of autophagy is associated in the pathogenesis of AD, and therefore, autophagy modulation has gained attention as a promising approach to treat AD pathogenesis. In AD, both the maturation of autolysosomes and its retrograde transports have been obstructed, which causes the accumulation of autophagic vacuoles and eventually leads to degenerating and dystrophic neurites function. However, the mechanism of autophagy modulation in APP processing and its pathogenesis have not yet been fully elucidated in AD. In the early stage of AD, APP processing and Aβ accumulation-mediated autophagy facilitate the removal of toxic protein aggregates via mTOR-dependent and-independent pathways. In addition, a number of autophagy-related genes (Atg) and APP are thought to influence the development of AD, providing a bidirectional link between autophagy and AD pathology. In this review, we summarized the current observations related to autophagy regulation and APP processing in AD, focusing on their modulation associated with the AD progression. Moreover, we emphasizes the application of small molecules and natural compounds to modulate autophagy for the removal and clearance of APP and Aβ deposits in the pathological condition of AD.
  • Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network

    Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism.
  • JM-20 treatment prevents neuronal damage and memory impairment induced by aluminum chloride in rats

    The number of people with dementia worldwide is estimated at 50 million by 2018 and continues to rise mainly due to increasing aging and population growth. Clinical impact of current interventions remains modest and all efforts aimed at the identification of new therapeutic approaches are therefore critical. Previously, we showed that JM-20, a dihydropyridine-benzodiazepine hybrid molecule, protected memory processes against scopolamine-induced cholinergic dysfunction. In order to gain further insight into the therapeutic potential of JM-20 on cognitive decline and Alzheimer's disease (AD) pathology, here we evaluated its neuroprotective effects after chronic aluminum chloride (AlCl) administration to rats and assessed possible alterations in several types of episodic memory and associated pathological mechanisms. Oral administration of aluminum to rodents recapitulates several neuropathological alterations and cognitive impairment, being considered a convenient tool for testing the efficacy of new therapies for dementia. We used behavioral tasks to test spatial, emotional- associative and novel object recognition memory, as well as molecular, enzymatic and histological assays to evaluate selected biochemical parameters. Our study revealed that JM-20 prevented memory decline alongside the inhibition of AlCl -induced oxidative stress, increased AChE activity, TNF-α and pro-apoptotic proteins (like Bax, caspase-3, and 8) levels. JM-20 also protected against neuronal damage in the hippocampus and prefrontal cortex. Our findings expanded our understanding of the ability of JM-20 to preserve memory in rats under neurotoxic conditions and confirm its potential capacity to counteract cognitive impairment and etiological factors of AD by breaking the progression of key steps associated with neurodegeneration.
  • Identification of specific gene modules and candidate signatures in necrotizing enterocolitis disease: Networkbased gene co-expression approach

    Necrotizing enterocolitis (NEC) is a serious disease of the gastrointestinal systems that primarily affects premature newborns' intestine in neonatal intensive care units. The present study aimed to detect NEC molecular signatures and pathways from comprehensive bioinformatics analysis of NEC's RNA-seq transcriptomics. We performed systems biology analysis of RNA-seq transcriptomics data (with accession GSE64801) of NEC from nine NEC and five healthy controls. Differential expression of gene expression was performed using a combination of three R packages "DESeq2", "edgeR", “edger robust”. Gene co-expression analysis was performed using a weighted WGCNA package to identify gene modules, Gene Ontology (GO), pathway analysis, protein-protein interaction, gene-transcription factor, and gene-microRNA interaction analysis was performed. The differential expression analysis identified 966 differentially expressed genes (DEGs) in NEC from the RNA-seq dataset related to corresponding controls. The WGCNA showed the presence of three key gene modules. The GO analysis showed genes are enriched in metabolic processes, regulation of immune response and immune systems, cell communication, and cellular process. The immune and complement pathways are related to co-expressed key modules that were detected. The protein-protein interactions analysis showed the presence of key hub genes related to the modules. Integration of these co-expressed gene modules with regulatory networks showed the presence of significant key transcription factors and microRNAs as hub molecules. The present study's findings suggested the immune systems and complement cascade are key mechanisms of NEC pathogenesis. The comprehensive network analysis showed several key hub molecules that might be potential biomarkers and drug targets in NEC.
  • The transcription factor BCL11A defines distinct subsets of midbrain dopaminergic neurons

    Midbrain dopaminergic (mDA) neurons are diverse in their projection targets, effect on behavior, and susceptibility to neurodegeneration. Little is known about the molecular mechanisms establishing this diversity during development. We show that the transcription factor BCL11A is expressed in a subset of mDA neurons in the developing and adult murine brain and in a subpopulation of pluripotent-stem-cell-derived human mDA neurons. By combining intersectional labeling and viral-mediated tracing, we demonstrate that Bcl11a-expressing mDA neurons form a highly specific subcircuit within the murine dopaminergic system. In the substantia nigra, the Bcl11a-expressing mDA subset is particularly vulnerable to neurodegeneration upon α-synuclein overexpression or oxidative stress. Inactivation of Bcl11a in murine mDA neurons increases this susceptibility further, alters the distribution of mDA neurons, and results in deficits in skilled motor behavior. In summary, BCL11A defines mDA subpopulations with highly distinctive characteristics and is required for establishing and maintaining their normal physiology.
  • Effects of slow oscillatory transcranial alternating current stimulation on motor cortical excitability assessed by transcranial magnetic stimulation

    Converging evidence suggests that transcranial alternating current stimulation (tACS) may entrain endogenous neural oscillations to match the frequency and phase of the exogenously applied current and this entrainment may outlast the stimulation (although only for a few oscillatory cycles following the cessation of stimulation). However, observing entrainment in the electroencephalograph (EEG) during stimulation is extremely difficult due to the presence of complex tACS artifacts. The present study assessed entrainment to slow oscillatory (SO) tACS by measuring motor cortical excitability across different oscillatory phases during (i.e., online) and outlasting (i.e., offline) stimulation. 30 healthy participants received 60 trials of intermittent SO tACS (0.75 Hz; 16 s on/off interleaved) at an intensity of 2 mA peak-to-peak. Motor cortical excitability was assessed using transcranial magnetic stimulation (TMS) of the hand region of the primary motor cortex (M1HAND) to induce motor evoked potentials (MEPs) in the contralateral thumb. MEPs were acquired at four time-points within each trial – early online, late online, early offline, and late offline – as well as at the start and end of the overall stimulation period (to probe longer-lasting aftereffects of tACS). A significant increase in MEP amplitude was observed from pre- to post-tACS (paired-sample t-test; t29 = 2.64, P = 0.013, d = 0.48) and from the first to the last tACS block (t29 = −2.93, P = 0.02, d = 0.54). However, no phase-dependent modulation of excitability was observed. Therefore, although SO tACS had a facilitatory effect on motor cortical excitability that outlasted stimulation, there was no evidence supporting entrainment of endogenous oscillations as the underlying mechanism.
  • Limited memory for ensemble statistics in visual change detection

    Accounts of working memory based on independent item representations may overlook a possible contribution of ensemble statistics, higher-order regularities of a scene such as the mean or variance of a visual attribute. Here we used change detection tasks to investigate the hypothesis that observers store ensemble statistics in working memory and use them to detect changes in the visual environment. We controlled changes to the ensemble mean or variance between memory and test displays across six experiments. We made specific predictions of observers' sensitivity using an optimal summation model that integrates evidence across separate items but does not detect changes in ensemble statistics. We found strong evidence that observers outperformed this model, but only when task difficulty was high, and only for changes in stimulus variance. Under these conditions, we estimated that the variance of items contributed to change detection sensitivity more strongly than any individual item in this case. In contrast, however, we found strong evidence against the hypothesis that the average feature value is stored in working memory: when the mean of memoranda changed, sensitivity did not differ from the optimal summation model, which was blind to the ensemble mean, in five out of six experiments. Our results reveal that change detection is primarily limited by uncertainty in the memory of individual features, but that memory for the variance of items can facilitate detection under a limited set of conditions that involve relatively high working memory demands.
  • Protocols for electrophysiological recordings and electron microscopy at C. elegans neuromuscular junction

    Release of neurotransmitters by synaptic vesicle exocytosis at presynaptic terminals is critical for neuronal communication within the nervous system. Electrophysiology and electron microscopy are powerful and complementary approaches used to evaluate the function of synaptic proteins in synaptic transmission. Here, we provide a protocol detailing the use of these two approaches at C. elegans neuromuscular junctions, including steps for worm picking and dissection, in vivo electrophysiological recording, and sample preparation for electron microscopy, followed by imaging and analysis.
  • Investigating shared genetic basis across tourette syndrome and comorbid neurodevelopmental disorders along the impulsivity-compulsivity spectrum

    Background: Tourette syndrome (TS) is often found comorbid with other neurodevelopmental disorders across the impulsivity-compulsivity spectrum, with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) as most prevalent. This points to the possibility of a common etiological thread along an impulsivity-compulsivity continuum. Methods: Investigating the shared genetic basis across TS, ADHD, ASD, and OCD, we undertook an evaluation of cross-disorder genetic architecture and systematic meta-analysis, integrating summary statistics from the latest genome-wide association studies (93,294 individuals, 6,788,510 markers). Results: As previously identified, a common unifying factor connects TS, ADHD, and ASD, while TS and OCD show the highest genetic correlation in pairwise testing among these disorders. Thanks to a more homogeneous set of disorders and a targeted approach that is guided by genetic correlations, we were able to identify multiple novel hits and regions that seem to play a pleiotropic role for the specific disorders analyzed here and could not be identified through previous studies. In the TS-ADHD-ASD genome-wide association study single nucleotide polymorphism–based and gene-based meta-analysis, we uncovered 13 genome-wide significant regions that host single nucleotide polymorphisms with a high posterior probability for association with all three studied disorders (m-value > 0.9), 11 of which were not identified in previous cross-disorder analysis. In contrast, we also identified two additional pleiotropic regions in the TS-OCD meta-analysis. Through conditional analysis, we highlighted genes and genetic regions that play a specific role in a TS-ADHD-ASD genetic factor versus TS-OCD. Cross-disorder tissue specificity analysis implicated the hypothalamus-pituitary-adrenal gland axis in TS-ADHD-ASD. Conclusions: Our work underlines the value of redefining the framework for research across traditional diagnostic categories.
  • Cholinergic modulation of sensory processing in awake mouse cortex

    Cholinergic modulation of brain activity is fundamental for awareness and conscious sensorimotor behaviours, but deciphering the timing and significance of acetylcholine actions for these behaviours is challenging. The widespread nature of cholinergic projections to the cortex means that new insights require access to specific neuronal populations, and on a time-scale that matches behaviourally relevant cholinergic actions. Here, we use fast, voltage imaging of L2/3 cortical pyramidal neurons exclusively expressing the genetically-encoded voltage indicator Butterfly 1.2, in awake, head-fixed mice, receiving sensory stimulation, whilst manipulating the cholinergic system. Altering muscarinic acetylcholine function re-shaped sensory-evoked fast depolarisation and subsequent slow hyperpolarisation of L2/3 pyramidal neurons. A consequence of this re-shaping was disrupted adaptation of the sensory-evoked responses, suggesting a critical role for acetylcholine during sensory discrimination behaviour. Our findings provide new insights into how the cortex processes sensory information and how loss of acetylcholine, for example in Alzheimer’s Disease, disrupts sensory behaviours.
  • An early proinflammatory transcriptional response to tau pathology is age‐specific and foreshadows reduced tau burden

    Age is one of the strongest risk factors for the development of neurodegenerative diseases, the majority of which involve misfolded protein aggregates in the brain. These protein aggregates are thought to drive pathology and are attractive targets for the development of new therapies. However, it is unclear how age influences the onset of pathology and the accompanying molecular response. To address this knowledge gap, we used a model of seeded tau pathology to profile the transcriptomic changes in 3 and 12 month old mice in response to developing tau hyperphosphorylation and aggregation. First, we found the burden of hyperphosphorylated tau pathology in mice injected at 12 months of age was moderately reduced compared to animals injected at 3 months. On a molecular level, we found an inflammation-related subset of genes, including C3 and the disease-associated microglia genes Ctsd, Cst7, and Clec7a, were more expressed early in disease in 12 but not 3 month old mice. These findings provide evidence of an early, age-specific response to tau pathology, which could serve as a marker for the severity of downstream pathology.
  • RNA-induced inflammation and migration of precursor neurons initiates neuronal circuit regeneration in zebrafish

    Tissue regeneration and functional restoration after injury are considered as stem- and progenitor-cell-driven processes. In the central nervous system, stem cell-driven repair is slow and problematic because function needs to be restored rapidly for vital tasks. In highly regenerative vertebrates, such as zebrafish, functional recovery is rapid, suggesting a capability for fast cell production and functional integration. Surprisingly, we found that migration of dormant “precursor neurons” to the injury site pioneers functional circuit regeneration after spinal cord injury and controls the subsequent stem-cell-driven repair response. Thus, the precursor neurons make do before the stem cells make new. Furthermore, RNA released from the dying or damaged cells at the site of injury acts as a signal to attract precursor neurons for repair. Taken together, our data demonstrate an unanticipated role of neuronal migration and RNA as drivers of neural repair.
  • In vitro anthelmintic activity of Dennettia tripetala G. Baker (Annonaceae) Fruits against Haemonchus contortus

    Helminthosis is one of the greatest causes of parasitic disease and loss in animal productivity. As such, the control of helminth parasites is of critical importance. This study was aimed to investigate the in vitro anthelmintic activity of Dennettia tripetala G. Baker (Annonaceae) fruits against Haemonchus contortus. Using in vitro techniques, the anthelmintic activity of extracts and fractions of D. tripetala G. Baker (Annonaceae) was evaluated for ovicidal (Egg hatch inhibition test) and larvicidal (larval mortality test) activity. Besides, the maximum tolerated dose was determined in adult albino rats administered, 300, 400, and 500 mg/kg body weight of the CME fraction, and observed over a period of 48 h for signs of toxicity and mortality. Phytochemical screening uncovered the occurrence of flavonoids, steroids/triterpenes, cardiac glycosides, saponins, tannins, carbohydrates, and alkaloids in the crude methanol extract (CME), the ethyl acetate fraction (EAF), and butanol fraction. The maximum tolerated dose of the CME of D. tripetala did not produce observable signs of toxicity or death in all the rats given up to 500 mg/kg. The CME and EAF of D. tripetala fruits produced a significant (p<0.05p<0.05) reduction in the hatchability of H. contortus eggs in a concentration-dependent manner, while the CME at concentrations between 12.5 and 100 mg/ml completely inhibited the hatching of H. contortus eggs. Similarly, EAF at doses of 25, 50, and 100 mg/ml completely inhibited the hatching of H. contortus eggs. The CME and EAF of D. tripetala fruits produced significant (p<0.05p<0.05) larvicidal activity against L3 of H. contortus in a concentration-dependent manner while the CME at concentrations between 6.25 and 100 mg/ml caused larval mortality of H. contortus L3 larvae completely. This study suggests that methanol extract and fractions of D. tripetala fruits possess beneficial anthelmintic (ovicidal and larvicidal) activity against H. contortus, and may be a suitable alternative anthelmintic candidate for the control of nematodes.
  • No evidence of human genome integration of SARS-CoV-2 found by long-read DNA sequencing

    A recent study proposed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hijacks the LINE-1 (L1) retrotransposition machinery to integrate into the DNA of infected cells. If confirmed, this finding could have significant clinical implications. Here, we apply deep (>50×) long-read Oxford Nanopore Technologies (ONT) sequencing to HEK293T cells infected with SARS-CoV-2, and do not find the virus integrated into the genome. By examining ONT data from separate HEK293T cultivars, we completely resolve 78 L1 insertions arising in vitro in the absence of L1 overexpression systems. ONT sequencing applied to hepatitis B virus (HBV) positive liver cancer tissues located a single HBV insertion. These experiments demonstrate reliable resolution of retrotransposon and exogenous virus insertions via ONT sequencing. That we find no evidence of SARS-CoV-2 integration suggests such events are, at most, extremely rare in vivo, and therefore are unlikely to drive oncogenesis or explain post-recovery detection of the virus.
  • Monocyte CD14 and HLA-DR expression increases with disease duration and severity in amyotrophic lateral sclerosis

    To investigate changes in immune markers and frequencies throughout disease progression in patients with amyotrophic lateral sclerosis (ALS). : In this longitudinal study, serial blood samples were collected from 21 patients with ALS over a time period of up to 16 months. Flow cytometry was used to quantitate CD14, HLA-DR, and CD16 marker expression on monocyte subpopulations and neutrophils, as well as their cell population frequencies. A Generalized Estimating Equation model was used to assess the association between changes in these immune parameters and disease duration and the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). : CD14 expression on monocyte subpopulations increased with both disease duration and a decrease in ALSFRS-R score in patients with ALS. HLA-DR expression on monocyte subpopulations also increased with disease severity and/or duration. The expression of CD16 did not change relative to disease duration or ALSFRS-R. Finally, patients had a reduction in non-classical monocytes and an increase in the classical to non-classical monocyte ratio throughout disease duration. : The progressive immunological changes observed in this study provide further support that monocytes are implicated in ALS pathology. Monocytic CD14 and HLA-DR surface proteins may serve as a therapeutic target or criteria for the recruitment of patients with ALS into clinical trials for immunomodulatory therapies.
  • Polygenic risk scores derived from varying definitions of depression and risk of depression

    Importance: Genetic studies with broad definitions of depression may not capture genetic risk specific to major depressive disorder (MDD), raising questions about how depression should be operationalized in future genetic studies. Objective: To use a large, well-phenotyped single study of MDD to investigate how different definitions of depression used in genetic studies are associated with estimation of MDD and phenotypes of MDD, using polygenic risk scores (PRSs). Design, Setting, and Participants: In this case-control polygenic risk score analysis, patients meeting diagnostic criteria for a diagnosis of MDD were drawn from the Australian Genetics of Depression Study, a cross-sectional, population-based study of depression, and controls and patients with self-reported depression were drawn from QSkin, a population-based cohort study. Data analyzed herein were collected before September 2018, and data analysis was conducted from September 10, 2020, to January 27, 2021. Main Outcome and Measures: Polygenic risk scores generated from genome-wide association studies using different definitions of depression were evaluated for estimation of MDD in and within individuals with MDD for an association with age at onset, adverse childhood experiences, comorbid psychiatric and somatic disorders, and current physical and mental health. Results: Participants included 12106 (71% female; mean age, 42.3 years; range, 18-88 years) patients meeting criteria for MDD and 12621 (55% female; mean age, 60.9 years; range, 43-87 years) control participants with no history of psychiatric disorders. The effect size of the PRS was proportional to the discovery sample size, with the largest study having the largest effect size with the odds ratio for MDD (1.75; 95% CI, 1.73-1.77) per SD of PRS and the PRS derived from ICD-10 codes documented in hospitalization records in a population health cohort having the lowest odds ratio (1.14; 95% CI, 1.12-1.16). When accounting for differences in sample size, the PRS from a genome-wide association study of patients meeting diagnostic criteria for MDD and control participants was the best estimator of MDD, but not in those with self-reported depression, and associations with higher odds ratios with childhood adverse experiences and measures of somatic distress. Conclusions and Relevance: These findings suggest that increasing sample sizes, regardless of the depth of phenotyping, may be most informative for estimating risk of depression. The next generation of genome-wide association studies should, like the Australian Genetics of Depression Study, have both large sample sizes and extensive phenotyping to capture genetic risk factors for MDD not identified by other definitions of depression.
  • Multi-modal magnetic resonance imaging in a mouse model of concussion

    This data collection contains Magnetic Resonance Imaging (MRI) data, including structural, diffusion, stimulus-evoked, and resting-state functional MRI and behavioural assessment results, including acute post-impact Loss-of-Righting Reflex time and acute, subacute, and longer-term Neural Severity Score, and Open Field Behaviour obtained from a mouse model of concussion. Four cohorts with 43 3-4 months old male mice in total were used: Sham (n = 14, n = 6 day 2, n = 3 day 7, n = 5 day 14), concussion day 2 (CON 2; n = 9), concussion day 7 (CON 7; n = 10), concussion day 14 (CON 14; n = 10). The data collection contains the aforementioned MRI data in compressed NIFTI format, data sheets on animal's backgrounds and behavioural outcomes and is made publicly available from a data repository. The available data are intended to facility cross-study comparisons, meta-analysis, and science reproducibility.
  • Interleukin-8 and lower severity of depression in females, but not males, with treatment-resistant depression

    Introduction: In cross-sectional studies of depressed patients, relationships between depression and levels of IL-8 are inconsistent, and have not been examined in relation to sex. Given identified sex differences in longitudinal data, it is important to evaluate sex-specific cross-sectional relationships between IL-8 and depressive symptoms, which may explain some inconsistency in the extant literature. It is further unknown whether IL-8 levels may relate to specific symptom profiles among depressed patients, with or without regard to sex. Methods: Among 108 patients with treatment resistant depression (50 females), we evaluated cross-sectional relationships between IL-8 and depression severity, as measured by the Hamilton Depression Rating Scale [HAM-D] Score, and examined sex-specific relationships, as well as relationships with depressive symptom profiles. Other inflammatory markers (IL-6, IL-10, TNF-α, CRP) were also explored in relation to HAM-D. Results: Higher IL-8 was associated with lower total HAM-D score (standardized β = −0.19, p = 0.049). Sex-specific effects were identified (IL-8 x sex interaction: p = 0.03), in which higher IL-8 related to lower HAM-D score in females (standardized β = −0.41, p = 0.004, effect size (sr) = 0.17), but not males (standardized β = 0.02, p = 0.91). Among a subset of 94 patients (41 females) who had individual HAM-D items available, we evaluated relationships between IL-8 and HAM-D factor subscores. Across sexes, higher IL-8 was associated with lower anxiety/hypochondriasis subscores (standardized β = −0.31, p = 0.002; sex interaction: p = 0.99). Sex differences were identified for relationships between IL-8 and two other HAM-D factor subscores. Conclusions: IL-8 may be related to anxiety symptoms across sexes, but may have a sex-specific relationship with other depressive symptoms. Further evaluation of sex-specific relationships between IL-8, depression symptom profiles, treatment response, and potential neurobiological correlates, may inform mechanisms of depression pathophysiology and aid in development of precision medicine strategies.
  • The detection of mild traumatic brain injury in paediatrics using artificial neural networks

    Head computed tomography (CT) is the gold standard in emergency departments (EDs) to evaluate mild traumatic brain injury (mTBI) patients, especially for paediatrics. Data-driven models for successfully classifying head CT scans that have mTBI will be valuable in terms of timeliness and cost-effectiveness for TBI diagnosis. This study applied two different machine learning (ML) models to diagnose mTBI in a paediatric population collected as part of the paediatric emergency care applied research network (PECARN) study between 2004 and 2006. The models were conducted using 15,271 patients under the age of 18 years with mTBI and had a head CT report. In the conventional model, random forest (RF) ranked the features to reduce data dimensionality and the top ranked features were used to train a shallow artificial neural network (ANN) model. In the second model, a deep ANN applied to classify positive and negative mTBI patients using the entirety of the features available. The dataset was divided into two subsets: 80% for training and 20% for testing using five-fold cross-validation. Accuracy, sensitivity, precision, and specificity were calculated by comparing the model's prediction outcome to the actual diagnosis for each patient. RF ranked ten clinical demographic features and twelve CT-findings; the hybrid RF-ANN model achieved an average specificity of 99.96%, sensitivity of 95.98%, precision of 99.25%, and accuracy of 99.74% in identifying positive mTBI from negative mTBI subjects. The deep ANN proved its ability to carry out the task efficiently with an average specificity of 99.9%, sensitivity of 99.2%, precision of 99.9%, and accuracy of 99.9%. The performance of the two proposed models demonstrated the feasibility of using ANN to diagnose mTBI in a paediatric population. This is the first study to investigate deep ANN in a paediatric cohort with mTBI using clinical and non-imaging data and diagnose mTBI with balanced sensitivity and specificity using shallow and deep ML models. This method, if validated, would have the potential to reduce the burden of TBI evaluation in EDs and aide clinicians in the decision-making process.
  • Vision, perception, navigation and ‘cognition’ in honeybees and applications to aerial robotics

    This review summarizes research carried out in the author's laboratory investigating the ways in which honeybees use vision to guide their flight and navigate in their environment, and describes how these principles have been used to design, build and test biologically-inspired systems for the guidance and navigation of unmanned aerial vehicles. It also outlines studies investigating the capacities of honeybees in the areas of visual perception, pattern recognition, and ‘cognition’.
  • Genetic association study of childhood aggression across raters, instruments, and age

    Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGG) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGG. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (r) among rater-specific assessment of AGG ranged from r = 0.46 between self- and teacher-assessment to r = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
  • Are Sex Differences in Human Brain Structure Associated With Sex Differences in Behavior?

    On average, men and women differ in brain structure and behavior, raising the possibility of a link between sex differences in brain and behavior. But women and men are also subject to different societal and cultural norms. We navigated this challenge by investigating variability of sex-differentiated brain structure within each sex. Using data from the Queensland Twin IMaging study ( = 1,040) and Human Connectome Project ( = 1,113), we obtained data-driven measures of individual differences along a male-female dimension for brain and behavior based on average sex differences in brain structure and behavior, respectively. We found a weak association between these brain and behavioral differences, driven by brain size. These brain and behavioral differences were moderately heritable. Our findings suggest that behavioral sex differences are, to some extent, related to sex differences in brain structure but that this is mainly driven by differences in brain size, and causality should be interpreted cautiously.
  • Driving Oscillatory Dynamics: Neuromodulation for Recovery After Stroke

    Stroke is a leading cause of death and disability worldwide, with limited treatments being available. However, advances in optic methods in neuroscience are providing new insights into the damaged brain and potential avenues for recovery. Direct brain stimulation has revealed close associations between mental states and neuroprotective processes in health and disease, and activity-dependent calcium indicators are being used to decode brain dynamics to understand the mechanisms underlying these associations. Evoked neural oscillations have recently shown the ability to restore and maintain intrinsic homeostatic processes in the brain and could be rapidly deployed during emergency care or shortly after admission into the clinic, making them a promising, non-invasive therapeutic option. We present an overview of the most relevant descriptions of brain injury after stroke, with a focus on disruptions to neural oscillations. We discuss the optical technologies that are currently used and lay out a roadmap for future studies needed to inform the next generation of strategies to promote functional recovery after stroke.
  • Stimulation of the social brain improves perspective selection in older adults: a HD-tDCS study

    There is evidence for dissociable, causal roles for two key social brain regions in young adults. Specifically, the right temporoparietal junction (rTPJ) is associated with embodied perspective taking, whereas the dorsomedial prefrontal cortex (dmPFC) is associated with the integration of social information. However, it is unknown whether these causal brain-behaviour associations are evident in older adults. Fifty-two healthy older adults were stratified to receive either rTPJ or dmPFC anodal high-definition transcranial direct current stimulation in a sham-controlled, double-blinded, repeated-measures design. Self-other processing was assessed across implicit and explicit level one (line-of-sight) and level two (embodied rotation) visual perspective taking (VPT) tasks, and self-other encoding effects on episodic memory. Both rTPJ and dmPFC stimulation reduced the influence of the alternate perspective during level one VPT, indexed by a reduced congruency effect (difference between congruent and incongruent perspectives). There were no stimulation effects on level two perspective taking nor self-other encoding effects on episodic memory. Stimulation to the rTPJ and dmPFC improved perspective selection during level one perspective taking. However, dissociable effects on self-other processing, previously observed in young adults, were not identified in older adults. The results provide causal evidence for age-related changes in social brain function that requires further scrutinization.
  • Mood regulatory actions of active and sham nucleus accumbens deep brain stimulation in antidepressant resistant rats

    The antidepressant actions of deep brain stimulation (DBS) are associated with progressive neuroadaptations within the mood network, modulated in part, by neurotrophic mechanisms. We investigated the antidepressant-like effects of chronic nucleus accumbens (NAc) DBS and its association with change in glycogen synthase kinase 3 (GSK3) and mammalian target of rapamycin (mTOR) expression in the infralimbic cortex (IL), and the dorsal (dHIP) and ventral (vHIP) subregions of the hippocampus of antidepressant resistant rats. Antidepressant resistance was induced via daily injection of adrenocorticotropic hormone (ACTH; 100 μg/day; 15 days) and confirmed by non-response to tricyclic antidepressant treatment (imipramine, 10 mg/kg). Portable microdevices provided continuous bilateral NAc DBS (130 Hz, 200 μA, 90 μs) for 7 days. A control sham electrode group was included, together with ACTH- and saline-treated control groups. Home cage monitoring, open field, sucrose preference, and, forced swim behavioral tests were performed. Post-mortem levels of GSK3 and mTOR, total and phosphorylated, were determined with Western blot. As previously reported, ACTH treatment blocked the immobility-reducing effects of imipramine in the forced swim test. In contrast, treatment with either active DBS or sham electrode placement in the NAc significantly reduced forced swim immobility time in ACTH-treated animals. This was associated with increased homecage activity in the DBS and sham groups relative to ACTH and saline groups, however, no differences in locomotor activity were observed in the open field test, nor were any group differences seen for sucrose consumption across groups. The antidepressant-like actions of NAc DBS and sham electrode placements were associated with an increase in levels of IL and vHIP phospho-GSK3β and phospho-mTOR, however, no differences in these protein levels were observed in the dHIP region. These data suggest that early response to electrode placement in the NAc, irrespective of whether active DBS or sham, has antidepressant-like effects in the ACTH-model of antidepressant resistance associated with distal upregulation of phospho-GSK3β and phospho-mTOR in the IL and vHIP regions of the mood network.
  • Discovering common pathogenetic processes between COVID-19 and diabetes mellitus by differential gene expression pattern analysis

    Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the newly discovered coronavirus, SARS-CoV-2. Increased severity of COVID-19 has been observed in patients with diabetes mellitus (DM). This study aimed to identify common transcriptional signatures, regulators and pathways between COVID-19 and DM. We have integrated human whole-genome transcriptomic datasets from COVID-19 and DM, followed by functional assessment with gene ontology (GO) and pathway analyses. In peripheral blood mononuclear cells (PBMCs), among the upregulated differentially expressed genes (DEGs), 32 were found to be commonly modulated in COVID-19 and type 2 diabetes (T2D), while 10 DEGs were commonly downregulated. As regards type 1 diabetes (T1D), 21 DEGs were commonly upregulated, and 29 DEGs were commonly downregulated in COVID-19 and T1D. Moreover, 35 DEGs were commonly upregulated in SARS-CoV-2 infected pancreas organoids and T2D islets, while 14 were commonly downregulated. Several GO terms were found in common between COVID-19 and DM. Prediction of the putative transcription factors involved in the upregulation of genes in COVID-19 and DM identified RELA to be implicated in both PBMCs and pancreas. Here, for the first time, we have characterized the biological processes and pathways commonly dysregulated in COVID-19 and DM, which could be in the next future used for the design of personalized treatment of COVID-19 patients suffering from DM as comorbidity.
  • Pkd1 and Wnt5a genetically interact to control lymphatic vascular morphogenesis in mice

    Lymphatic vascular development is regulated by well-characterised signalling and transcriptional pathways. These pathways regulate lymphatic endothelial cell (LEC) migration, motility, polarity and morphogenesis. Canonical and non-canonical WNT signalling pathways are known to control LEC polarity and development of lymphatic vessels and valves. PKD1, encoding Polycystin-1, is the most commonly mutated gene in polycystic kidney disease but has also been shown to be essential in lymphatic vascular morphogenesis. The mechanism by which Pkd1 acts during lymphangiogenesis remains unclear.

    Here we find that loss of non-canonical WNT signalling components Wnt5a and Ryk phenocopy lymphatic defects seen in Pkd1 knockout mice. To investigate genetic interaction, we generated Pkd1;Wnt5a double knockout mice. Loss of Wnt5a suppressed phenotypes seen in the lymphatic vasculature of Pkd1 mice and Pkd1 deletion suppressed phenotypes observed in Wnt5a mice. Thus, we report mutually suppressive roles for Pkd1 and Wnt5a, with developing lymphatic networks restored to a more wild type state in double mutant mice. This genetic interaction between Pkd1 and the non-canonical WNT signalling pathway ultimately controls LEC polarity and the morphogenesis of developing vessel networks.

    Our work suggests that Pkd1 acts at least in part by regulating non-canonical WNT signalling during the formation of lymphatic vascular networks. This article is protected by copyright. All rights reserved.
  • Genetic risk for chronic pain is associated with lower antidepressant effectiveness: converging evidence for a depression subtype

    Chronic pain and depression are highly comorbid and difficult-to-treat disorders. We previously showed this comorbidity is associated with higher depression severity, lower antidepressant treatment effectiveness and poorer prognosis in the Australian Genetics of Depression Study.

    The current study aimed to assess whether a genetic liability to chronic pain is associated with antidepressant effectiveness over and above the effect of genetic factors for depression in a sample of 12,863 Australian Genetics of Depression Study participants.

    Polygenic risk scores were calculated using summary statistics from genome-wide association studies of multisite chronic pain and major depression. Cumulative linked regressions were employed to assess the association between polygenic risk scores and antidepressant treatment effectiveness across 10 different medications.

    Mixed-effects logistic regressions showed that individual genetic propensity for chronic pain, but not major depression, was significantly associated with patient-reported chronic pain (Pain OR = 1.17 [1.12, 1.22]; MD OR = 1.01 [0.98, 1.06]). Significant associations were also found between lower antidepressant effectiveness and genetic risk for chronic pain or for major depression. However, a fully adjusted model showed the effect of Pain (adjOR = 0.93 [0.90, 0.96]) was independent of MD (adjOR = 0.96 [0.93, 0.99]). Sensitivity analyses were performed to assess the robustness of these results. After adjusting for depression severity measures (i.e. age of onset; number of depressive episodes; interval between age at study participation and at depression onset), the associations between Pain and patient-reported chronic pain with lower antidepressant effectiveness remained significant (0.95 [0.92, 0.98] and 0.84 [0.78, 0.90], respectively).

    These results suggest genetic risk for chronic pain accounted for poorer antidepressant effectiveness, independent of the genetic risk for major depression. Our results, along with independent converging evidence from other studies, point towards a difficult-to-treat depression subtype characterised by comorbid chronic pain. This finding warrants further investigation into the implications for biologically based nosology frameworks in pain medicine and psychiatry.
  • Deep brain stimulation for treatment-refractory obsessive-compulsive disorder should be an accepted therapy in Australia

    Deep brain stimulation has shown promise for the treatment of severe, treatment-refractory obsessive-compulsive disorder. With the recent publication of the first Australian, randomised, sham-controlled trial of deep brain stimulation for obsessive-compulsive disorder, there are now four placebo-controlled trials demonstrating the efficacy of this therapy. Together with recent data identifying a biological substrate of effective stimulation that can predict response and that has been successfully reproduced, studies comparing and finding equivalent efficacy among different targets, as well as recent, large, open trials supporting the long-term effectiveness of deep brain stimulation, we argue that this should now be considered an accepted therapy for a select group of patients in the Australasian setting. We call on the Royal Australian and New Zealand College of Psychiatrists to revise their memorandum describing deep brain stimulation for obsessive-compulsive disorder as an ‘experimental’ treatment and recognise that it has proven efficacy. We stress that this should remain a therapy offered only to those with high treatment-refractory illnesses and only at specialised centres where there is an experienced multidisciplinary team involved in work-up, implantation and follow-up and also where frameworks are in place to provide careful clinical governance and ensure appropriate fully informed consent.
  • Treating cognitive impairment in schizophrenia with GLP-1RAs: an overview of their therapeutic potential

    Schizophrenia is a neuropsychiatric disorder that affects approximately 1% of individuals worldwide. There are no available medications to treat cognitive impairment in this patient population currently. Preclinical evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve cognitive function. There is a need to evaluate how GLP-1RAs alter specific domains of cognition and whether they will be of therapeutic benefit in individuals with schizophrenia.

    This paper summarises the effects of GLP-1RAs on metabolic processes in the brain and how these mechanisms relate to improved cognitive function. We provide an overview of preclinical studies that demonstrate GLP-1RAs improve cognition and comment on their potential therapeutic benefit in individuals with schizophrenia.

    To understand the benefits of GLP-1RAs in individuals with schizophrenia, further preclinical research with rodent models relevant to schizophrenia symptomology are needed. Moreover, preclinical studies must focus on using a wider range of behavioral assays to understand whether important aspects of cognition such as executive function, attention, and goal-directed behavior are improved using GLP-1RAs. Further research into the specific mechanisms of how GLP-1RAs affect cognitive function and their interactions with antipsychotic medication commonly prescribed is necessary.
  • Developmental inhibition of long intergenic non-coding RNA, HOTAIRM1, impairs dopamine neuron differentiation and maturation

    The dopaminergic (DA) system is important for a range of brain functions and subcortical DA development precedes many cortical maturational processes. The dysfunction of DA systems has been associated with neuropsychiatric disorders such as schizophrenia, depression, and addiction. DA neuron cell fate is controlled by a complex web of transcriptional factors that dictate DA neuron specification, differentiation, and maturation. A growing body of evidence suggests that these transcriptional factors are under the regulation of newly discovered non-coding RNAs. However, with regard to DA neuron development, little is known of the roles of non-coding RNAs. The long non-coding RNA (lncRNA) HOX-antisense intergenic RNA myeloid 1 (HOTAIRM1) is present in adult DA neurons, suggesting it may have a modulatory role in DA systems. Moreover, HOTAIRM1 is involved in the neuronal differentiation in human stem cells suggesting it may also play a role in early DA neuron development. To determine its role in early DA neuron development, we knocked down HOTAIRM1 using RNAi in vitro in a human neuroblastoma cell line, and in vivo in mouse DA progenitors using a novel in utero electroporation technique. HOTAIRM1 inhibition decreased the expression of a range of key DA neuron specification factors and impaired DA neuron differentiation and maturation. These results provide evidence of a functional role for HOTAIRM1 in DA neuron development and differentiation. Understanding of the role of lncRNAs in the development of DA systems may have broader implications for brain development and neurodevelopmental disorders such as schizophrenia.
  • Cocaine-induced changes in tonic dopamine concentrations measured using multiple-cyclic square wave voltammetry in vivo

    For over 40 years, in vivo microdialysis techniques have been at the forefront in measuring the effects of illicit substances on brain tonic extracellular levels of dopamine that underlie many aspects of drug addiction. However, the size of microdialysis probes and sampling rate may limit this technique’s ability to provide an accurate assessment of drug effects in microneural environments. A novel electrochemical method known as multiple-cyclic square wave voltammetry (M-CSWV), was recently developed to measure second-to-second changes in tonic dopamine levels at microelectrodes, providing spatiotemporal resolution superior to microdialysis. Here, we utilized M-CSWV and fast-scan cyclic voltammetry (FSCV) to measure changes in tonic or phasic dopamine release in the nucleus accumbens core (NAcc) after acute cocaine administration. Carbon-fiber microelectrodes (CFM) and stimulating electrodes were implanted into the NAcc and medial forebrain bundle (MFB) of urethane anesthetized (1.5 g/kg i.p.) Sprague-Dawley rats, respectively. Using FSCV, depths of each electrode were optimized by determining maximal MFB electrical stimulation-evoked phasic dopamine release. Changes in phasic responses were measured after a single dose of intravenous saline or cocaine hydrochloride (3 mg/kg; n = 4). In a separate group, changes in tonic dopamine levels were measured using M-CSWV after intravenous saline and after cocaine hydrochloride (3 mg/kg; n = 5). Both the phasic and tonic dopamine responses in the NAcc were augmented by the injection of cocaine compared to saline control. The phasic and tonic levels changed by approximately x2.4 and x1.9, respectively. These increases were largely consistent with previous studies using FSCV and microdialysis. However, the minimal disruption/disturbance of neuronal tissue by the CFM may explain why the baseline tonic dopamine values (134 ± 32 nM) measured by M-CSWV were found to be 10-fold higher when compared to conventional microdialysis. In this study, we demonstrated phasic dopamine dynamics in the NAcc with acute cocaine administration. M-CSWV was able to record rapid changes in tonic levels of dopamine, which cannot be achieved with other current voltammetric techniques. Taken together, M-CSWV has the potential to provide an unprecedented level of physiologic insight into dopamine signaling, both in vitro and in vivo, which will significantly enhance our understanding of neurochemical mechanisms underlying psychiatric conditions.
  • Regulation of NMDA receptor trafficking and gating by activity-dependent CaMKIIα phosphorylation of the GluN2A subunit

    NMDA receptor (NMDAR)-dependent Ca influx underpins multiple forms of synaptic plasticity. Most synaptic NMDAR currents in the adult forebrain are mediated by GluN2A-containing receptors, which are rapidly inserted into synapses during long-term potentiation (LTP); however, the underlying molecular mechanisms remain poorly understood. In this study, we show that GluN2A is phosphorylated at Ser-1459 by Ca/calmodulin-dependent kinase IIα (CaMKIIα) in response to glycine stimulation that mimics LTP in primary neurons. Phosphorylation of Ser-1459 promotes GluN2A interaction with the sorting nexin 27 (SNX27)-retromer complex, thereby enhancing the endosomal recycling of NMDARs. Loss of SNX27 or CaMKIIα function blocks the glycine-induced increase in GluN2A-NMDARs on the neuronal membrane. Interestingly, mutations of Ser-1459, including the rare S1459G human epilepsy variant, prolong the decay times of NMDAR-mediated synaptic currents in heterosynapses by increasing the duration of channel opening. These findings not only identify a critical role of Ser-1459 phosphorylation in regulating the function of NMDARs, but they also explain how the S1459G variant dysregulates NMDAR function.
  • Welcome to the Breakfast Club: Building academic psychiatry capacity in Queensland

  • Age-related differences in negative cognitive empathy but similarities in positive affective empathy

    Empathy, among other social-cognitive processes, changes across adulthood. More specifically, cognitive components of empathy (understanding another’s perspective) appear to decline with age, while findings for affective empathy (sharing another’s emotional state) are rather mixed. Structural and functional correlates underlying cognitive and affective empathy in aging and the extent to which valence affects empathic response in brain and behavior are not well understood yet. To fill these research gaps, younger and older adults completed a modified version of the Multifaceted Empathy Test, which measures both cognitive and affective empathy as well as empathic responding to both positive and negative stimuli (i.e., positive vs. negative empathy). Adopting a multimodal imaging approach and applying multivariate analysis, the study found that for cognitive empathy to negative emotions, regions of the salience network including the anterior insula and anterior cingulate were more involved in older than younger adults. For affective empathy to positive emotions, in contrast, younger and older adults recruited a similar brain network including main nodes of the default mode network. Additionally, increased structural microstructure (fractional anisotropy values) of the posterior cingulum bundle (right henisphere) was related to activation of default mode regions during affective empathy for positive emotions in both age groups. These findings provide novel insights into the functional networks subserving cognitive and affective empathy in younger and older adults and highlight the importance of considering valence in empathic response in aging research. Further this study, for the first time, underscores the role of the posterior cingulum bundle in higher-order social-cognitive processes such as empathy, specifically for positive emotions, in aging.
  • Therapeutic ultrasound as a treatment modality for physiological and pathological ageing including Alzheimer’s disease

    Physiological and pathological ageing (as exemplified by Alzheimer’s disease, AD) are characterized by a progressive decline that also includes cognition. How this decline can be slowed or even reversed is a critical question. Here, we discuss therapeutic ultrasound as a novel modality to achieve this goal. In our studies, we explored three fundamental strategies, (i) scanning ultrasound on its own (SUSonly), (ii) therapeutic ultrasound in concert with intravenously injected microbubbles (which transiently opens the blood–brain barrier, SUS+MB), and (iii) SUS+MB in combination with therapeutic antibodies (SUS+MB+mAb). These studies show SUS+MB effectively clears amyloid and restores memory in amyloid-depositing mice and partially clears Tau and ameliorates memory impairments in Tau transgenic mice, with additional improvements found in combination trials (SUS+MB+mAb). Interestingly, both SUSonly and SUS+MB restored the induction of long-term potentiation (LTP, electrophysiological correlate of memory) in senescent wild-type mice. Both lead to increased neurogenesis, and SUSonly, in particular, resulted in improved spatial memory. We discuss these findings side-by-side with our findings obtained in AD mouse models. We conclude that therapeutic ultrasound is a non-invasive, pleiotropic modality that may present a treatment option not only for AD but also for enhancing cognition in physiological ageing.
  • Comparison of diurnal rectal and body surface temperatures in large white piglets during the hot-dry season in a tropical Guinea savannah

    The aim of the study was to determine the differences in rectal and body surface temperatures and their extent of conformity using digital and infrared thermometers, respectively, in piglets during the hot-dry season in a tropical guinea savannah of Nigeria. Thirty Large White piglets of both sexes, aged 10–14 days, served as the experimental subjects. The rectal and surface body temperatures were recorded concurrently with those of the ambient dry- and wet-bulbs, during the day at 06:00, 09:00, 12:00, 15:00 and 18:00 h (GMT +1). There were significant (P < 0.05) diurnal variations in all body and ambient temperature readings, with the highest values obtained in the afternoon (at 15:00 h GMT + 1). The mean diurnal rectal and body surface temperatures in the piglets at 09:00–18:00 h were significantly higher (P < 0.001) than the corresponding values at 06:00 h. The overall mean rectal temperature (39.00 ± 0.04 °C) was higher (P < 0.01) than body surface temperature recorded for the eye (38.05 ± 0.04 °C), ear (38.10 ± 0.07 °C), head (37.97 ± 0.05 °C), nose (35.68 ± 0.13 °C), scapula (38.16 ± 0.06 °C), thigh (38.00 ± 0.06 °C), back (38.02 ± 0.06 °C) and hoof (36.83 ± 0.07 °C). The largest and smallest mean difference between rectal and body surface temperatures was -3.32 ± 0.12 °C and -0.84 ± 0.06 °C for the temperature of the nose and scapula, respectively. The positive correlation (P < 0.05) between body temperatures (rectal and surface) of the piglets with ambient temperature implied that the later had a tremendous effect on the former. Body surface temperatures at the region of eye, ear, head, nose, scapula, thigh, back and hoof had significantly (P < 0.0001) linear and positive relationships with rectal temperature. In conclusion, the similar diurnal trends, highly significant correlation coefficients and linear relationships between the rectal and body surface temperatures suggest that the later may serve as valid and reliable estimates of the former in piglets.
  • Genomic partitioning of inbreeding depression in humans

    Across species, offspring of related individuals often exhibit significant reduction in fitness-related traits, known as inbreeding depression (ID), yet the genetic and molecular basis for ID remains elusive. Here, we develop a method to quantify enrichment of ID within specific genomic annotations and apply it to human data. We analyzed the phenomes and genomes of ∼350,000 unrelated participants of the UK Biobank and found, on average of over 11 traits, significant enrichment of ID within genomic regions with high recombination rates (>21-fold; p < 10), with conserved function across species (>19-fold; p < 10), and within regulatory elements such as DNase I hypersensitive sites (∼5-fold; p = 8.9 × 10). We also quantified enrichment of ID within trait-associated regions and found suggestive evidence that genomic regions contributing to additive genetic variance in the population are enriched for ID signal. We find strong correlations between functional enrichment of SNP-based heritability and that of ID (r = 0.8, standard error: 0.1). These findings provide empirical evidence that ID is most likely due to many partially recessive deleterious alleles in low linkage disequilibrium regions of the genome. Our study suggests that functional characterization of ID may further elucidate the genetic architectures and biological mechanisms underlying complex traits and diseases.
  • Hippocampal neurogenesis mediates sex-specific effects of social isolation and exercise on fear extinction in adolescence

    Impaired extinction of conditioned fear is associated with anxiety disorders. Common lifestyle factors, like isolation stress and exercise, may alter the ability to extinguish fear. However, the effect of and interplay between these factors on adolescent fear extinction, and the relevant underlying neural mechanisms are unknown. Here we examined the effects of periadolescent social isolation and physical activity on adolescent fear extinction in rats and explored neurogenesis as a potential mechanism. Isolation stress impaired extinction recall in male adolescents, an effect prevented by exercise. Extinction recall in female adolescents was unaffected by isolation stress. However, exercise disrupted extinction recall in isolated females. Extinction recall in isolated females was positively correlated to the number of immature neurons in the ventral hippocampus, suggesting that exercise affected extinction recall via neurogenesis in females. Pharmacologically suppressing cellular proliferation in isolated adolescents using temozolomide blocked the effect of exercise on extinction recall in both sexes. Together, these findings highlight sex-specific outcomes of isolation stress and exercise on adolescent brain and behavior, and highlights neurogenesis as a potential mechanism underlying lifestyle effects on adolescent fear extinction.
  • Connectomic deep brain stimulation for obsessive-compulsive disorder

    Obsessive-compulsive disorder is among the most disabling psychiatric disorders. Although deep brain stimulation is considered an effective treatment, its use in clinical practice is not fully established. This is, at least in part, due to ambiguity about the best suited target and insufficient knowledge about underlying mechanisms. Recent advances suggest that changes in broader brain networks are responsible for improvement of obsessions and compulsions, rather than local impact at the stimulation site. These findings were fueled by innovative methodological approaches using brain connectivity analyses in combination with neuromodulatory interventions. Such a connectomic approach for neuromodulation constitutes an integrative account that aims to characterize optimal target networks. In this critical review, we integrate findings from connectomic studies and deep brain stimulation interventions to characterize a neural network presumably effective in reducing obsessions and compulsions. To this end, we scrutinize methodologies and seemingly conflicting findings with the aim to merge observations to identify common and diverse pathways for treating obsessive-compulsive disorder. Ultimately, we propose a unified network that—when modulated by means of cortical or subcortical interventions—alleviates obsessive-compulsive symptoms.
  • Size-dependent dendritic maladaptations of hypoglossal motor neurons in SOD1G93A mice

    The total motor neuron (MN) somato-dendritic surface area is correlated with motor unit type. MNs with smaller surface areas innervate slow (S) and fast fatigue-resistant (FR) motor units, while MNs with larger surface areas innervate fast fatigue-intermediate (FInt) and fast fatigable (FF) motor units. Differences in MN surface area (equivalent to membrane capacitance) underpin the intrinsic excitability of MNs and are consistent with the orderly recruitment of motor units (S > FR > FInt > FF) via the Size Principle. In amyotrophic lateral sclerosis (ALS), large MNs controlling FInt and FF motor units exhibit earlier denervation and death, compared to smaller and more resilient MNs of type S and FR motor units that are spared until late in ALS. Abnormal dendritic morphologies in MNs precede neuronal death in human ALS and in rodent models. We employed Golgi-Cox methods to investigate somal size-dependent changes in the dendritic morphology of hypoglossal MNs in wildtype and SOD1 mice (a model of ALS), at postnatal (P) day ~30 (pre-symptomatic), ~P60 (onset), and ~P120 (mid-disease) stages. In wildtype hypoglossal MNs, increased MN somal size correlated with increased dendritic length and spines in a linear fashion. By contrast, in SOD1 mice, significant deviations from this linear correlation were restricted to the larger vulnerable MNs at pre-symptomatic (maladaptive) and mid-disease (degenerative) stages. These findings are consistent with excitability changes observed in ALS patients and in rodent models. Our results suggest that intrinsic or synaptic increases in MN excitability are likely to contribute to ALS pathogenesis, not compensate for it.
  • Traumatic brain injury fast-forwards Alzheimer’s pathology: evidence from amyloid positron emission tomorgraphy imaging

    Traumatic brain injury (TBI) has been proposed as a risk factor for Alzheimer's disease (AD), although the mechanisms underlying the putative association are poorly understood. We investigated elderly individuals with a remote history of TBI, aiming to understand how this may have influenced amyloidosis, neurodegeneration, and clinical expression along the AD continuum.

    Total of 241 individual datasets including amyloid beta (Aβ) positron emission tomography ([F]-AV45), structural MRI, and neuropsychological measures, were obtained from the Alzheimer's Disease Neuroimaging Initiative. The data were stratified into groups with (TBI +) or without (TBI -) history of head injury, and by clinical dementia rating (CDR) scores, into subgroups with normal cognition (CDR = 0) and those with symptomatic cognitive decline (CDR ≥ 0.5). We contrasted the TBI + and TBI - subgroups with respect to the onset age and extent of cognitive decline, cortical thickness changes, and Aβ standard uptake value (SUVr).

    Compared to the TBI -/CDR ≥ 0.5 subgroup, the TBI + /CDR ≥ 0.5 subgroup showed a 3-4 year earlier age of cognitive impairment onset (ACIO, p = 0.005). Among those participants on the AD continuum (Aβ + , as defined by a cortical SUVr ≥ 1.23), irrespective of current CDR, a TBI + history was associated with greater Aβ deposition and more pronounced cortical thinning. When matched for severity of cognitive status, the TBI + /CDR ≥ 0.5 group showed greater Aβ burden, but earlier ACIO as compared to the TBI -/CDR ≥ 0.5, suggesting a more indolent clinical AD progression in those with TBI history.

    Remote TBI history may alter the AD onset trajectory, with approximately 4 years earlier ACIO, greater amyloid deposition, and cortical thinning.
  • Location Matters: Navigating Regional Heterogeneity of the Neurovascular Unit

    The neurovascular unit (NVU) of the brain is composed of multiple cell types that act synergistically to modify blood flow to locally match the energy demand of neural activity, as well as to maintain the integrity of the blood-brain barrier (BBB). It is becoming increasingly recognized that the functional specialization, as well as the cellular composition of the NVU varies spatially. This heterogeneity is encountered as variations in vascular and perivascular cells along the arteriole-capillary-venule axis, as well as through differences in NVU composition throughout anatomical regions of the brain. Given the wide variations in metabolic demands between brain regions, especially those of gray vs. white matter, the spatial heterogeneity of the NVU is critical to brain function. Here we review recent evidence demonstrating regional specialization of the NVU between brain regions, by focusing on the heterogeneity of its individual cellular components and briefly discussing novel approaches to investigate NVU diversity.
  • Joint control of visually guided actions involves concordant increases in behavioural and neural coupling

    It is often necessary for individuals to coordinate their actions with others. In the real world, joint actions rely on the direct observation of co-actors and rhythmic cues. But how are joint actions coordinated when such cues are unavailable? To address this question, we recorded brain activity while pairs of participants guided a cursor to a target either individually (solo control) or together with a partner (joint control) from whom they were physically and visibly separated. Behavioural patterns revealed that joint action involved real-time coordination between co-actors and improved accuracy for the lower performing co-actor. Concurrent neural recordings and eye tracking revealed that joint control affected cognitive processing across multiple stages. Joint control involved increases in both behavioural and neural coupling - both quantified as interpersonal correlations - peaking at action completion. Correspondingly, a neural offset response acted as a mechanism for and marker of interpersonal neural coupling, underpinning successful joint actions.
  • Reduced C9orf72 function leads to defective synaptic vesicle release and neuromuscular dysfunction in zebrafish

    The most common genetic cause of amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) is a hexanucleotide repeat expansion within the C9orf72 gene. Reduced levels of C9orf72 mRNA and protein have been found in ALS/FTD patients, but the role of this protein in disease pathogenesis is still poorly understood. Here, we report the generation and characterization of a stable C9orf72 loss-of-function (LOF) model in the zebrafish. We show that reduced C9orf72 function leads to motor defects, muscle atrophy, motor neuron loss and mortality in early larval and adult stages. Analysis of the structure and function of the neuromuscular junctions (NMJs) of the larvae, reveal a marked reduction in the number of presynaptic and postsynaptic structures and an impaired release of quantal synaptic vesicles at the NMJ. Strikingly, we demonstrate a downregulation of SV2a upon C9orf72-LOF and a reduced rate of synaptic vesicle cycling. Furthermore, we show a reduced number and size of Rab3a-postive synaptic puncta at NMJs. Altogether, these results reveal a key function for C9orf72 in the control of presynaptic vesicle trafficking and release at the zebrafish larval NMJ. Our study demonstrates an important role for C9orf72 in ALS/FTD pathogenesis, where it regulates synaptic vesicle release and neuromuscular functions.
  • Using monozygotic twins to dissect common genes in posttraumatic stress disorder and migraine

    Epigenetic mechanisms have been associated with genes involved in Posttraumatic stress disorder (PTSD). PTSD often co-occurs with other health conditions such as depression, cardiovascular disorder and respiratory illnesses. PTSD and migraine have previously been reported to be symptomatically positively correlated with each other, but little is known about the genes involved. The aim of this study was to understand the comorbidity between PTSD and migraine using a monozygotic twin disease discordant study design in six pairs of monozygotic twins discordant for PTSD and 15 pairs of monozygotic twins discordant for migraine. DNA from peripheral blood was run on Illumina EPIC arrays and analyzed. Multiple testing correction was performed using the Bonferroni method and 10% false discovery rate (FDR). We validated 11 candidate genes previously associated with PTSD including DOCK2, DICER1, and ADCYAP1. In the epigenome-wide scan, seven novel CpGs were significantly associated with PTSD within/near IL37, WNT3, ADNP2, HTT, SLFN11, and NQO2, with all CpGs except the IL37 CpG hypermethylated in PTSD. These results were significantly enriched for genes whose DNA methylation was previously associated with migraine (p-value = 0.036). At 10% FDR, 132 CpGs in 99 genes associated with PTSD were also associated with migraine in the migraine twin samples. Genes associated with PTSD were overrepresented in vascular smooth muscle, axon guidance and oxytocin signaling pathways, while genes associated with both PTSD and migraine were enriched for AMPK signaling and longevity regulating pathways. In conclusion, these results suggest that common genes and pathways are likely involved in PTSD and migraine, explaining at least in part the co-morbidity between the two disorders.