Search

Background. Only some individuals using drugs recreationally eventually develop a substance use disorder, characterised in part by the rigid engagement in drug foraging behaviour (drug seeking), often maintained in the face of adverse consequences (e.g., is compulsive). The neurobehavioral determinants of this individual vulnerability have not been fully elucidated. Methods. Using a prospective longitudinal study involving 40 male rats we combined a multidimensional characterisation of behavioral traits of vulnerability to stimulant use disorder (impulsivity and stickiness) and resilience (sign tracking and sensation seeking/locomotor reactivity to novelty) with magnetic resonance imaging (MRI) to identify in drug-naïve subjects the structural and functional brain correlates of the later emergence of compulsive drug seeking. We developed a novel behavioral procedure to investigate in subjects with a prolonged history of cocaine seeking under the control of the conditioned reinforcing properties of a drug-paired Pavlovian conditioned stimulus, the individual tendency to persist in drug seeking behavior in the face of punishment in a drug free state. Results. We report that in drug-naïve rats the future tendency to develop compulsive cocaine seeking is characterised by behavioral stickiness-related functional hypoconnectivity between the prefrontal cortex and posterior dorsomedial striatum in combination with impulsivity-related structural alterations in the infralimbic cortex, anterior insula and nucleus accumbens. Conclusions. These findings show that the vulnerability to develop compulsive cocaine seeking behavior stems from pre-existing structural or functional changes in two distinct cortico-striatal systems that underlie deficits in impulse control and goal-directed behavior.

KPTN-related disorder (KRD) is an autosomal recessive disorder associated with germline variants in KPTN (kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KRD, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn−/− mice display many of the key KRD phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. Assessment of affected individuals has identified concordant selectivity of cognitive deficits, postnatal onset of brain overgrowth, and a previously unrecognised KPTN dosage-sensitivity, resulting in increased head circumference in their heterozygous parents. Molecular and structural analysis of Kptn−/− mice revealed pathological changes, including differences in brain size, shape, and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated iPSC models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. Increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KRD in the broader group of mTORC1 related disorders affecting brain structure, cognitive function, and network integrity.

Task-free functional connectivity in animal models provides an experimental framework to examine connectivity phenomena under controlled conditions and allows comparison with invasive or terminal procedures. To date, animal acquisitions are performed with varying protocols and analyses that hamper result comparison and integration. We introduce StandardRat, a consensus rat functional MRI acquisition protocol tested across 20 centers. To develop this protocol with optimized acquisition and processing parameters, we initially aggregated 65 functional imaging datasets acquired in rats from 46 centers. We developed a reproducible pipeline for the analysis of rat data acquired with diverse protocols and determined experimental and processing parameters associated with a more robust functional connectivity detection. We show that the standardized protocol enhances biologically plausible functional connectivity patterns, relative to pre-existing acquisitions. The protocol and processing pipeline described here are openly shared with the neuroimaging community to promote interoperability and cooperation towards tackling the most important challenges in neuroscience.

Contains fulltext : 239574.pdf (Publisher’s version ) (Closed access) Open science initiatives are creating opportunities to increase research coordination and impact in nonhuman primate (NHP) imaging. The PRIMatE Data and Resource Exchange community recently developed a collaboration-based strategic plan to advance NHP imaging as an integrative approach for multiscale neuroscience. 5 p.

© 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. Background and Purpose: Apelin is an endogenous vasodilatory and inotropic peptide that is down-regulated in human pulmonary arterial hypertension, although the density of the apelin receptor is not significantly attenuated. We hypothesised that a G protein-biased apelin analogue MM07, which is more stable than the endogenous apelin peptide, may be beneficial in this condition with the advantage of reduced β-arrestin-mediated receptor internalisation with chronic use. Experimental Approach: Male Sprague–Dawley rats received either monocrotaline to induce pulmonary arterial hypertension or saline and then daily i.p. injections of either MM07 or saline for 21 days. The extent of disease was assessed by right ventricular catheterisation, cardiac MRI, and histological analysis of the pulmonary vasculature. The effect of MM07 on signalling, proliferation, and apoptosis of human pulmonary artery endothelial cells was investigated. Key Results: MM07 significantly reduced the elevation of right ventricular systolic pressure and hypertrophy induced by monocrotaline. Monocrotaline-induced changes in cardiac structure and function, including right ventricular end-systolic and end-diastolic volumes, ejection fraction, and left ventricular end-diastolic volume, were attenuated by MM07. MM07 also significantly reduced monocrotaline-induced muscularisation of small pulmonary blood vessels. MM07 stimulated endothelial NOS phosphorylation and expression, promoted proliferation, and attenuated apoptosis of human pulmonary arterial endothelial cells in vitro. Conclusion and Implications: Our findings suggest that chronic treatment with MM07 is beneficial in this animal model of pulmonary arterial hypertension by addressing disease aetiology. These data support the development of G protein-biased apelin receptor agonists with improved pharmacokinetic profiles for use in human disease.

Amyotrophic lateral sclerosis and frontotemporal dementia are overlapping diseases in which MRI reveals brain structural changes in advance of symptom onset. Recapitulating these changes in preclinical models would help to improve our understanding of the molecular causes underlying regionally selective brain atrophy in early disease. We therefore investigated the translational potential of the TDP-43Q331K knock-in mouse model of amyotrophic lateral sclerosis-frontotemporal dementia using MRI. We performed in vivo MRI of TDP-43Q331K knock-in mice. Regions of significant volume change were chosen for post-mortem brain tissue analyses. Ex vivo computed tomography was performed to investigate skull shape. Parvalbumin neuron density was quantified in post-mortem amyotrophic lateral sclerosis frontal cortex. Adult mutants demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of amyotrophic lateral sclerosis-frontotemporal dementia. Subcortical, cerebellar and brain stem regions were also affected in line with observations in pre-symptomatic carriers of mutations in C9orf72, the commonest genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Volume loss was also observed in the dentate gyrus of the hippocampus, along with ventricular enlargement. Immunohistochemistry revealed reduced parvalbumin interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia was in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the dentate gyrus, indicative of impaired adult neurogenesis, while a paucity of parvalbumin interneurons in P14 mutant mice suggests that TDP-43Q331K disrupts neurodevelopment. Computerized tomography imaging showed altered skull morphology in mutants, further suggesting a role for TDP-43Q331K in development. Finally, analysis of human post-mortem brains confirmed a paucity of parvalbumin interneurons in the prefrontal cortex in sporadic amyotrophic lateral sclerosis and amyotrophic lateral sclerosis linked to C9orf72 mutations. Regional brain MRI changes seen in human amyotrophic lateral sclerosis-frontotemporal dementia are recapitulated in TDP-43Q331K knock-in mice. By marrying in vivo imaging with targeted histology, we can unravel cellular and molecular processes underlying selective brain vulnerability in human disease. As well as helping to understand the earliest causes of disease, our MRI and histological markers will be valuable in assessing the efficacy of putative therapeutics in TDP-43Q331K knock-in mice., Graphical Abstract Graphical Abstract

Functional magnetic resonance imaging (fMRI) can be seriously impaired by patient motion. The purpose of this study was to characterize the typical motion in a clinical population of patients in disorders of consciousness and compare the performance of retrospective correction with rigid-body realignment as implemented in widely used software packages. 63 subjects were scanned with an fMRI visual checkerboard paradigm using a 3 T scanner. Time series were corrected for motion, and the resulting transformations were used to calculate a motion score. SPM, FSL, AFNI and AIR were evaluated by comparing the motion obtained by re-running the tool on the corrected data. A publicly available sample fMRI dataset was modified with the motion detected in each patient with each tool. The performance of each tool was measured by comparing the number of supra-threshold voxels after standard fMRI analysis, both in the sample dataset and in simulated fMRI data. We assessed the effect of user-changeable parameters on motion correction in SPM. We found the equivalent motion in the patient population to be 1.4 mm on average. There was no significant difference in performance between SPM, FSL and AFNI. AIR was considerably worse, and took more time to run. We found that in SPM the quality factor and interpolation method have no effect on the cluster size, while higher separation and smoothing reduce it. We showed that the main packages SPM, FSL and AFNI are equally suitable for retrospective motion correction of fMRI time series. We show that typically only 80% of activated voxels are recovered by retrospective motion correction.

Brain extraction (a.k.a. skull stripping) is a fundamental step in the neuroimaging pipeline as it can affect the accuracy of downstream preprocess such as image registration, tissue classification, etc. Most brain extraction tools have been designed for and applied to human data and are often challenged by non-human primates (NHP) data. Amongst recent attempts to improve performance on NHP data, deep learning models appear to outperform the traditional tools. However, given the minimal sample size of most NHP studies and notable variations in data quality, the deep learning models are very rarely applied to multi-site samples in NHP imaging. To overcome this challenge, we used a transfer-learning framework that leverages a large human imaging dataset to pretrain a convolutional neural network (i.e. U-Net Model), and then transferred this to NHP data using a small NHP training sample. The resulting transfer-learning model converged faster and achieved more accurate performance than a similar U-Net Model trained exclusively on NHP samples. We improved the generalizability of the model by upgrading the transfer-learned model using additional training datasets from multiple research sites in the Primate Data-Exchange (PRIME-DE) consortium. Our final model outperformed brain extraction routines from popular MRI packages (AFNI, FSL, and FreeSurfer) across a heterogeneous sample from multiple sites in the PRIME-DE with less computational cost (20 s~10 min). We also demonstrated the transfer-learning process enables the macaque model to be updated for use with scans from chimpanzees, marmosets, and other mammals (e.g. pig). Our model, code, and the skull-stripped mask repository of 136 macaque monkeys are publicly available for unrestricted use by the neuroimaging community at https://github.com/HumanBrainED/NHP-BrainExtraction.

Brain extraction (a.k.a. skull stripping) is a fundamental step in the neuroimaging pipeline as it can affect the accuracy of downstream preprocess such as image registration, tissue classification, etc. Most brain extraction tools have been designed for and applied to human data and are often challenged by non-human primates (NHP) data. Amongst recent attempts to improve performance on NHP data, deep learning models appear to outperform the traditional tools. However, given the minimal sample size of most NHP studies and notable variations in data quality, the deep learning models are very rarely applied to multi-site samples in NHP imaging. To overcome this challenge, we used a transfer-learning framework that leverages a large human imaging dataset to pretrain a convolutional neural network (i.e. U-Net Model), and then transferred this to NHP data using a small NHP training sample. The resulting transfer-learning model converged faster and achieved more accurate performance than a similar U-Net Model trained exclusively on NHP samples. We improved the generalizability of the model by upgrading the transfer-learned model using additional training datasets from multiple research sites in the Primate Data-Exchange (PRIME-DE) consortium. Our final model outperformed brain extraction routines from popular MRI packages (AFNI, FSL, and FreeSurfer) across a heterogeneous sample from multiple sites in the PRIME-DE with less computational cost (20s~10min). We also demonstrated the transfer-learning process enables the macaque model to be updated for use with scans from chimpanzees, marmosets, and other mammals (e.g. pig). Our model, code, and the skull-stripped mask repository of 136 macaque monkeys are publicly available for unrestricted use by the neuroimaging community at https://github.com/HumanBrainED/NHP-BrainExtraction.

Stress-related disorders such as depression and anxiety are characterized by enhanced negative emotion and physiological dysfunction. Whilst elevated activity within area 25 of the subgenual anterior cingulate cortex (sgACC/25) has been implicated in these illnesses, it is unknown whether this over-activity is causal. By combining targeted intracerebral microinfusions with cardiovascular and behavioral monitoring in marmosets, we show that over-activation of sgACC/25 reduces vagal tone and heart rate variability, alters cortisol dynamics during stress and heightens reactivity to proximal and distal threat. 18F-FDG PET imaging shows these changes are accompanied by altered activity within a network of brain regions including the amygdala, hypothalamus and dorsolateral prefrontal cortex. Ketamine, shown to have rapid antidepressant effects, fails to reverse elevated arousal to distal threat contrary to the beneficial effects we have previously demonstrated on over-activation induced reward blunting, illustrating the symptom-specificity of its actions.

Aim Stimulation of the nitric oxide (NO) – soluble guanylate (sGC) - protein kinase G (PKG) pathway confers protection against acute ischaemia/reperfusion injury, but more chronic effects in reducing post-myocardial infarction (MI) heart failure are less defined. The aim of this study was to not only determine whether the sGC stimulator riociguat reduces infarct size but also whether it protects against the development of post-MI heart failure. Methods and Results Mice were subjected to 30 min ischaemia via ligation of the left main coronary artery to induce MI and either placebo or riociguat (1.2 µmol/l) were given as a bolus 5 min before and 5 min after onset of reperfusion. After 24 hours, both, late gadolinium-enhanced magnetic resonance imaging (LGE-MRI) and 18F-FDG-positron emission tomography (PET) were performed to determine infarct size. In the riociguat-treated mice, the resulting infarct size was smaller (8.5±2.5% of total LV mass vs. 21.8%±1.7%. in controls, p = 0.005) and LV systolic function analysed by MRI was better preserved (60.1%±3.4% of preischaemic vs. 44.2%±3.1% in controls, p = 0.005). After 28 days, LV systolic function by echocardiography treated group was still better preserved (63.5%±3.2% vs. 48.2%±2.2% in control, p = 0.004). Conclusion Taken together, mice treated acutely at the onset of reperfusion with the sGC stimulator riociguat have smaller infarct size and better long-term preservation of LV systolic function. These findings suggest that sGC stimulation during reperfusion therapy may be a powerful therapeutic treatment strategy for preventing post-MI heart failure.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping neurodegenerative diseases that are increasingly understood to have long prodromal periods. Investigation of these early stages promises to yield valuable biomarkers of disease and will be key to understanding mechanisms underlying the genesis of ALS-FTD. Here, we use in vivo magnetic resonance imaging (MRI), histology and computed tomography to identify structural and cellular readouts of early stage disease in the TDP-43Q331K knock-in mouse model of ALS-FTD. Adult mutant mice demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of ALS-FTD. Subcortical, cerebellar and brain stem regions were also affected in line with observations in presymptomatic carriers of mutations in C9orf72, the commonest genetic cause of both ALS and FTD. Volume loss, as measured by MRI, was also observed in the dentate gyrus (DG) of the hippocampus, along with ventricular enlargement. Guided by these imaging findings, detailed post-mortem brain tissue analysis revealed reduced parvalbumin-positive (PV+) interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia were in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the DG, indicative of impaired adult neurogenesis, while a paucity of PV+ interneurons in juvenile mutant mice (P14) suggests that TDP-43Q331K disrupts neurodevelopment. Computerised tomography imaging also showed altered skull morphology in mutants, further suggesting a role for TDP-43Q331K in development. Finally, analysis of human post-mortem prefrontal cortices confirmed a paucity of PV+ interneurons in the prefrontal cortex in cases with both sporadic ALS and ALS linked to C9orf72 mutations. This study suggests an important role for PV+ interneurons in regional brain vulnerability associated with ALS-FTD, and identifies novel MRI and histological biomarkers that will be of value in assessing the efficacy of putative therapeutics in TDP-43Q331K knock-in mice.

Contains fulltext : 217200.pdf (Publisher’s version ) (Closed access) Nonhuman primate neuroimaging is on the cusp of a transformation, much in the same way its human counterpart was in 2010, when the Human Connectome Project was launched to accelerate progress. Inspired by an open data-sharing initiative, the global community recently met and, in this article, breaks through obstacles to define its ambitions. 4 p.

Background Mapping the hypoxic brain in acute ischemic stroke has considerable potential for both diagnosis and treatment monitoring. PET using 18F-fluoro-misonidazole (FMISO) is the reference method; however, it lacks clinical accessibility and involves radiation exposure. MR-based T2′ mapping may identify tissue hypoxia and holds clinical potential. However, its validation against FMISO imaging is lacking. Here we implemented back-to-back FMISO-PET and T2′ MR in rodents subjected to acute middle cerebral artery occlusion. For direct clinical relevance, regions of interest delineating reduced T2′ signal areas were manually drawn. Methods Wistar rats were subjected to filament middle cerebral artery occlusion, immediately followed by intravenous FMISO injection. Multi-echo T2 and T2* sequences were acquired twice during FMISO brain uptake, interleaved with diffusion-weighted imaging. Perfusion-weighted MR was also acquired whenever feasible. Immediately following MR, PET data reflecting the history of FMISO brain uptake during MR acquisition were acquired. T2′ maps were generated voxel-wise from T2 and T2*. Two raters independently drew T2′ lesion regions of interest. FMISO uptake and perfusion data were obtained within T2′ consensus regions of interest, and their overlap with the automatically generated FMISO lesion and apparent diffusion coefficient lesion regions of interest was computed. Results As predicted, consensus T2′ lesion regions of interest exhibited high FMISO uptake as well as substantial overlap with the FMISO lesion and significant hypoperfusion, but only small overlap with the apparent diffusion coefficient lesion. Overlap of the T2′ lesion regions of interest between the two raters was ∼50%. Conclusions This study provides formal validation of T2′ to map non-core hypoxic tissue in acute stroke. T2′ lesion delineation reproducibility was suboptimal, reflecting unclear lesion borders.

Alzheimer’s disease is characterized by cognitive alterations, cerebral atrophy and neuropathological lesions including neuronal loss, accumulation of misfolded and aggregated β-amyloid peptides (Aβ) and tau proteins. Iatrogenic induction of Aβ is suspected in patients exposed to pituitary-derived hormones, dural grafts, or surgical instruments, presumably contaminated with Aβ. Induction of Aβ and tau lesions has been demonstrated in transgenic mice after contamination with Alzheimer’s disease brain homogenates, with very limited functional consequences. Unlike rodents, primates naturally express Aβ or tau under normal conditions and attempts to transmit Alzheimer pathology to primates have been made for decades. However, none of earlier studies performed any detailed functional assessments. For the first time we demonstrate long term memory and learning impairments in a non-human primate (Microcebus murinus) following intracerebral injections with Alzheimer human brain extracts. Animals inoculated with Alzheimer brain homogenates displayed progressive cognitive impairments (clinical tests assessing cognitive and motor functions), modifications of neuronal activity (detected by electroencephalography), widespread and progressive cerebral atrophy (in vivo MRI assessing cerebral volume loss using automated voxel-based analysis), neuronal loss in the hippocampus and entorhinal cortex (post mortem stereology). They displayed parenchymal and vascular Aβ depositions and tau lesions for some of them, in regions close to the inoculation sites. Although these lesions were sparse, they were never detected in control animals. Tau-positive animals had the lowest performances in a memory task and displayed the greatest neuronal loss. Our study is timely and important as it is the first one to highlight neuronal and clinical dysfunction following inoculation of Alzheimer’s disease brain homogenates in a primate. Clinical signs in a chronic disease such as Alzheimer take a long time to be detectable. Documentation of clinical deterioration and/or dysfunction following intracerebral inoculations with Alzheimer human brain extracts could lead to important new insights about Alzheimer initiation processes. Electronic supplementary material The online version of this article (10.1186/s40478-019-0771-x) contains supplementary material, which is available to authorized users.

Organoids regenerate human bile ducts Bile ducts carry bile from the liver and gall bladder to the small intestine, where it aids digestion. Cholangiocytes are epithelial cells that line bile ducts and modify bile as its transported through the biliary tree. Chronic liver diseases involving cholangiocytes account for a large fraction of liver failure and the need for liver transplantation. Because liver donors are in short supply, Sampaziotis et al. used organoid technology to develop a cell-based therapy using human tissue (see the Perspective by Kurial and Willenbring). Cholangiocyte organoids were transplanted into the intrahepatic ducts of deceased human donor livers undergoing ex vivo normothermic perfusion. The livers could be maintained for up to 100 hours, and the transplanted organoids engrafted, exhibited function, and could repair bile ducts. Science , this issue p. 839 ; see also p. 786

Genetic variation in the serotonin transporter gene (SLC6A4) is associated with vulnerability to affective disorders and pharmacotherapy efficacy. We recently identified sequence polymorphisms in the common marmoset SLC6A4 repeat region (AC/C/G and CT/T/C) associated with individual differences in anxiety-like trait, gene expression, and response to antidepressants. The mechanisms underlying the effects of these polymorphisms are unknown, but a key mediator of serotonin action is the serotonin 2A receptor (5HT(2A)). Thus, we correlated 5HT(2A) binding potential (BP) and RNA gene expression in 16 SLC6A4 genotyped marmosets with responsivity to 5HT(2A) antagonism during the human intruder test of anxiety. Voxel-based analysis and RNA measurements showed a reduction in 5HT(2A) BP and gene expression specifically in the right posterior insula of individuals homozygous for the anxiety-related variant AC/C/G. These same marmosets displayed an anxiogenic, dose-dependent response to the human intruder after 5HT(2A) pharmacological antagonism, while CT/T/C individuals showed no effect. A voxel-based correlation analysis, independent of SLC6A4 genotype, revealed that 5HT(2A) BP in the adjacent right anterior insula and insula proisocortex was negatively correlated with trait anxiety scores. Moreover, 5HT(2A) BP in both regions was a good predictor of the size and direction of the acute emotional response to the human intruder threat after 5HT(2A) antagonism. Our findings suggest that genetic variation in the SLC6A4 repeat region may contribute to the trait anxious phenotype via neurochemical changes in brain areas implicated in interoceptive and emotional processing, with a critical role for the right insula 5HT(2A) in the regulation of affective responses to threat.

Summary Anhedonia is a core symptom of depression, but the underlying neurobiological mechanisms are unknown. Correlative neuroimaging studies implicate dysfunction within ventromedial prefrontal cortex, but the causal roles of specific subregions remain unidentified. We addressed these issues by combining intracerebral microinfusions with cardiovascular and behavioral monitoring in marmoset monkeys to show that over-activation of primate subgenual anterior cingulate cortex (sgACC, area 25) blunts appetitive anticipatory, but not consummatory, arousal, whereas manipulations of adjacent perigenual ACC (pgACC, area 32) have no effect. sgACC/25 over-activation also reduces the willingness to work for reward. 18F-FDG PET imaging reveals over-activation induced metabolic changes in circuits involved in reward processing and interoception. Ketamine treatment ameliorates the blunted anticipatory arousal and reverses associated metabolic changes. These results demonstrate a causal role for primate sgACC/25 over-activity in selective aspects of impaired reward processing translationally relevant to anhedonia, and ketamine’s modulation of an affective network to exert its action., Highlights • Primate sgACC/25 over-activation blunts reward anticipation, but not consumption • Over-activation of sgACC/25 also blunts willingness to work for reward • Anticipatory blunting involves metabolic changes in reward-related circuits • Acute ketamine reverses blunted anticipatory arousal and metabolic changes, Using intracerebral microinfusions in marmosets, Alexander et al. demonstrate a causal role for sgACC/25 over-activity in specific aspects of impaired reward processing associated with anhedonia. Ketamine successfully ameliorates related impairments by modulating activity within a dysfunctional neural circuit involved in reward processing and interoception.

'True' transient ischaemic attacks are characterized not only clinically, but also radiologically by a lack of corresponding changes on magnetic resonance imaging. During a transient ischaemic attack it is assumed that the affected tissue is penumbral but rescued by early spontaneous reperfusion. There is, however, evidence from rodent studies that even brief focal ischaemia not resulting in tissue infarction can cause extensive selective neuronal loss associated with long-lasting sensorimotor impairment but normal magnetic resonance imaging. Selective neuronal loss might therefore contribute to the increasingly recognized cognitive impairment occurring in patients with transient ischaemic attacks. It is therefore relevant to consider treatments to reduce brain damage occurring with transient ischaemic attacks. As penumbral neurons are threatened by markedly constrained oxygen delivery, improving the latter by increasing arterial O2 content would seem logical. Despite only small increases in arterial O2 content, normobaric oxygen therapy experimentally induces significant increases in penumbral O2 pressure and by such may maintain the penumbra alive until reperfusion. Nevertheless, the effects of normobaric oxygen therapy on infarct volume in rodent models have been conflicting, although duration of occlusion appeared an important factor. Likewise, in the single randomized trial published to date, early-administered normobaric oxygen therapy had no significant effect on clinical outcome despite reduced diffusion-weighted imaging lesion growth during therapy. Here we tested the hypothesis that normobaric oxygen therapy prevents both selective neuronal loss and sensorimotor deficits in a rodent model mimicking true transient ischaemic attack. Normobaric oxygen therapy was applied from the onset and until completion of 15 min distal middle cerebral artery occlusion in spontaneously hypertensive rats, a strain representative of the transient ischaemic attack-prone population. Whereas normoxic controls showed normal magnetic resonance imaging but extensive cortical selective neuronal loss associated with microglial activation (present both at Day 14 in vivo and at Day 28 post-mortem) and marked and long-lasting sensorimotor deficits, normobaric oxygen therapy completely prevented sensorimotor deficit (P < 0.02) and near-completely Day 28 selective neuronal loss (P < 0.005). Microglial activation was substantially reduced at Day 14 and completely prevented at Day 28 (P = 0.002). Our findings document that normobaric oxygen therapy administered during ischaemia nearly completely prevents the neuronal death, microglial inflammation and sensorimotor impairment that characterize this rodent true transient ischaemic attack model. Taken together with the available literature, normobaric oxygen therapy appears a promising therapy for short-lasting ischaemia, and is attractive clinically as it could be started at home in at-risk patients or in the ambulance in subjects suspected of transient ischaemic attack/early stroke. It may also be a straightforward adjunct to reperfusion therapies, and help prevent subtle brain damage potentially contributing to long-term cognitive and sensorimotor impairment in at-risk populations.

PURPOSE: MR fingerprinting (MRF) can be used for quantitative estimation of physical parameters in MRI. Here, we extend the method to incorporate B1 estimation. METHODS: The acquisition is based on steady state free precession MR fingerprinting with a Cartesian trajectory. To increase the sensitivity to the B1 profile, abrupt changes in flip angle were introduced in the sequence. Slice profile and B1 effects were included in the dictionary and the results from two- and three-dimensional (3D) acquisitions were compared. Acceleration was demonstrated using retrospective undersampling in the phase encode directions of 3D data exploiting redundancy between MRF frames at the edges of k-space. RESULTS: Without B1 estimation, T2 and B1 were inaccurate by more than 20%. Abrupt changes in flip angle improved B1 maps. T1 and T2 values obtained with the new MRF methods agree with classical spin echo measurements and are independent of the B1 field profile. When using view sharing reconstruction, results remained accurate (error

Objective Although the underlying cause of Huntington's disease (HD) is well established, the actual pathophysiological processes involved remain to be fully elucidated. In other proteinopathies such as Alzheimer's and Parkinson's diseases, there is evidence for impairments of the cerebral vasculature as well as the blood–brain barrier (BBB), which have been suggested to contribute to their pathophysiology. We investigated whether similar changes are also present in HD. Methods We used 3- and 7-Tesla magnetic resonance imaging as well as postmortem tissue analyses to assess blood vessel impairments in HD patients. Our findings were further investigated in the R6/2 mouse model using in situ cerebral perfusion, histological analysis, Western blotting, as well as transmission and scanning electron microscopy. Results We found mutant huntingtin protein (mHtt) aggregates to be present in all major components of the neurovascular unit of both R6/2 mice and HD patients. This was accompanied by an increase in blood vessel density, a reduction in blood vessel diameter, as well as BBB leakage in the striatum of R6/2 mice, which correlated with a reduced expression of tight junction-associated proteins and increased numbers of transcytotic vesicles, which occasionally contained mHtt aggregates. We confirmed the existence of similar vascular and BBB changes in HD patients. Interpretation Taken together, our results provide evidence for alterations in the cerebral vasculature in HD leading to BBB leakage, both in the R6/2 mouse model and in HD patients, a phenomenon that may, in turn, have important pathophysiological implications. Ann Neurol 2015;78:160–177

The treatment of common bile duct (CBD) disorders, such as biliary atresia or ischemic strictures, is restricted by the lack of biliary tissue from healthy donors suitable for surgical reconstruction. Here we report a new method for the isolation and propagation of human cholangiocytes from the extrahepatic biliary tree in the form of extrahepatic cholangiocyte organoids (ECOs) for regenerative medicine applications. The resulting ECOs closely resemble primary cholangiocytes in terms of their transcriptomic profile and functional properties. We explore the regenerative potential of these organoids $\textit{in vivo}$ and demonstrate that ECOs self-organize into bile duct–like tubes expressing biliary markers following transplantation under the kidney capsule of immunocompromised mice. In addition, when seeded on biodegradable scaffolds, ECOs form tissue-like structures retaining biliary characteristics. The resulting bioengineered tissue can reconstruct the gallbladder wall and repair the biliary epithelium following transplantation into a mouse model of injury. Furthermore, bioengineered artificial ducts can replace the native CBD, with no evidence of cholestasis or occlusion of the lumen. In conclusion, ECOs can successfully reconstruct the biliary tree, providing proof of principle for organ regeneration using human primary cholangiocytes expanded $\textit{in vitro}$.

Background Mapping the hypoxic brain in acute ischemic stroke has considerable potential for both diagnosis and treatment monitoring. PET using

In vivo assessment of heart function in mice is important for basic and translational research in cardiology. MRI is an accurate tool for the investigation of the anatomy and function in the preclinical setting; however, the long scan duration limits its usage. We aimed to reduce the acquisition time of cine MRI to 1 min. We employed spatiotemporal compressed sensing and parallel imaging to accelerate retrospectively gated cine MRI. We compared the functional parameters derived from full and undersampled data in Cartesian and radial MRI by means of Bland–Altman plots. We found that the scan time for the whole heart could be reduced to 2 min with Cartesian sampling and to 1 min with radial sampling. Despite a reduction in the signal-to-noise ratio, the accuracy in the estimation of left and right ventricular volumes was preserved for all tested subjects. This method can be used to perform accurate functional MRI examinations in mice for high-throughput phenotyping or translational studies. Copyright © 2014 John Wiley & Sons, Ltd.

The objective of this study was to evaluate the performance of the built-in MR-based attenuation correction (MRAC) included in the combined whole-body Ingenuity TF PET/MR scanner and compare it to the performance of CT-based attenuation correction (CTAC) as the gold standard. Included in the study were 26 patients who underwent clinical whole-body FDG PET/CT imaging and subsequently PET/MR imaging (mean delay 100 min). Patients were separated into two groups: the alpha group (14 patients) without MR coils during PET/MR imaging and the beta group (12 patients) with MR coils present (neurovascular, spine, cardiac and torso coils). All images were coregistered to the same space (PET/MR). The two PET images from PET/MR reconstructed using MRAC and CTAC were compared by voxel-based and region-based methods (with ten regions of interest, ROIs). Lesions were also compared by an experienced clinician. Body mass index and lung density showed significant differences between the alpha and beta groups. Right and left lung densities were also significantly different within each group. The percentage differences in uptake values using MRAC in relation to those using CTAC were greater in the beta group than in the alpha group (alpha group −0.2 ± 33.6 %, R 2 = 0.98, p

Background: Increasingly, evidence from studies in both animal models and patients suggests that cardiovascular dysfunction is important in HD. Previous studies measuring function of the left ventricle (LV) in the R6/2 mouse model have found a clear cardiac abnormality, albeit with preserved LV systolic function. It was hypothesized that an impairment of RV function might play a role in this condition via mechanisms of ventricular interdependence.Objective: To investigate RV function in the R6/2 mouse model of Huntington's disease (HD).Methods: Cardiac cine- magnetic resonance imaging (MRI) was used to determine functional parameters in R6/2 mice. In a first experiment, these parameters were derived longitudinally to determine deterioration of cardiac function with disease progression. A second experiment compared the response to a stress test (using dobutamine) of wildtype and early-symptomatic R6/2 mice. Results: There was progressive deterioration of RV systolic function with age in R6/2 mice. Furthermore, beta-adrenergic stimulation with dobutamine revealed RV dysfunction in R6/2 mice before any overt symptoms of the disease were apparent.Conclusions: This work adds to accumulating evidence of cardiovascular dysfunction in R6/2 mice, describing for the first time the involvement of the right ventricle. Cardiovascular dysfunction should be considered, both when treatment strategies are being designed, and when searching for biomarkers for HD.

Introduction Severe brain hypoxia in the territory of the occluded artery is a key feature of ischemic stroke. This region can be imaged using positron emission tomography (PET) and the standard hypoxia radiotracer 18 F-fluoromisonidazole ( 18 F-FMISO). However, the utility of 18 F-FMISO is limited by its slow accumulation in the lesion. Therefore, this study investigated three hypoxia-sensitive radiotracers, namely the nitroimidazole 18 F-fluoroazomycin arabinoside ( 18 F-FAZA) and two 64 Cu bis(thiosemicarbazone) complexes ( 64 Cu-ATSM and 64 Cu-ATSE), expected to have improved pharmacokinetic profiles relative to 18 F-FMISO, in a rodent model of ischemic stroke. Methods In anaesthetised Wistar rats, the distal middle cerebral artery was permanently occluded by electrocoagulation, the radiotracers administered intravenously and animals PET scanned for up to 3hours, followed by T2-weighted magnetic resonance imaging to map the infarct. Results As expected, late and prominent 18 F-FMISO retention was observed despite lower tracer delivery into the affected region. Time-activity curves revealed that both 64 Cu-ATSM and 64 Cu-ATSE showed rapid entry and efflux from the brain, but did not show significant accumulation in the lesion. 18 F-FAZA showed limited brain penetration, and accumulation in the lesion was inconsistent, low and as slow as 18 F-FMISO. Conclusions This study suggests further development of these radiotracers as hypoxia markers for ischemic stroke may not be warranted.

We have previously shown that impulsivity in rats predicts the emergence of compulsive cocaine seeking and taking, and is coupled to decreased D2/3 receptor availability in the ventral striatum. As withdrawal from cocaine normalises high impulsivity in rats, we investigated, using positron emission tomography (PET), the effects of response-contingent cocaine administration on D2/3 receptor availability in the striatum. Rats were screened for impulsive behavior on the five-choice serial reaction time task. After a baseline PET scan with the D2/3 ligand [(18)F]fallypride, rats were trained to self-administer cocaine for 15 days under a long-access schedule. As a follow-up, rats were assessed for impulsivity and underwent a second [(18)F]fallypride PET scan. At baseline, we found that D2/3 receptor availability was significantly lower in the left, but not right, ventral striatum of high-impulsive rats compared with low-impulsive rats. While the number of self-administered cocaine infusions was not different between the two impulsivity groups, impulsivity selectively decreased in high-impulsive rats withdrawn from cocaine. This effect was accompanied by a significant increase in D2/3 receptor availability in the left, but not right, ventral striatum. We further report that D2/3 receptor availability was inversely related to baseline D2/3 receptor availability in the ventral striatum of high-impulsive rats, as well as to the left and right dorsal striatum of both low-impulsive and high-impulsive rats. These findings indicate that the reduction in impulsivity in high-impulsive rats by prior cocaine exposure may be mediated by a selective correction of deficient D2/3 receptor availability in the ventral striatum. A similar baseline-dependent mechanism may account for the therapeutic effects of stimulant drugs in clinical disorders such as ADHD.

Purpose To demonstrate and validate a late gadolinium enhancement (LGE) imaging protocol, optimized for tissue viability assessment in interventional mouse models of myocardial infarction. Materials and Methods The method uses an efficient sampling scheme using multiple slices in a single heartbeat interleaving slice packages between alternate TRs. Sampling multiple slices instead of multiple echoes or multiple k-lines achieves higher SNR efficiency, and images covering the whole heart can be obtained in 3 min. Saturation effects are exploited for an optimum compromise between contrast and speed. Results The images obtained show high hyperenhancement with good contrast-to-noise. It is shown that inversion time optimization can be reliably omitted with this scheme, and that measured infarct sizes correlate well with histological measures. Conclusion Our protocol offers a new efficient tool for the measurement of infarct size in mouse models of heart disease. J. Magn. Reson. Imaging 2013;38:468–473. © 2012 Wiley Periodicals, Inc.

Highlights • Maternal immune activation leads to brain structural changes. • Cortical volume decreases between post-natal day 50 and 100 and is static thereafter. • Hippocampus volume decreases early and is maintained into adulthood. • TBM reveals previously unappreciated changes in grey and white matter., Genetic and environmental risk factors for psychiatric disorders are suggested to disrupt the trajectory of brain maturation during adolescence, leading to the development of psychopathology in adulthood. Rodent models are powerful tools to dissect the specific effects of such risk factors on brain maturational profiles, particularly when combined with Magnetic Resonance Imaging (MRI; clinically comparable technology). We therefore investigated the effect of maternal immune activation (MIA), an epidemiological risk factor for adult-onset psychiatric disorders, on rat brain maturation using atlas and tensor-based morphometry analysis of longitudinal in vivo MR images. Exposure to MIA resulted in decreases in the volume of several cortical regions, the hippocampus, amygdala, striatum, nucleus accumbens and unexpectedly, the lateral ventricles, relative to controls. In contrast, the volumes of the thalamus, ventral mesencephalon, brain stem and major white matter tracts were larger, relative to controls. These volumetric changes were maximal between post-natal day 50 and 100 with no differences between the groups thereafter. These data are consistent with and extend prior studies of brain structure in MIA-exposed rodents. Apart from the ventricular findings, these data have robust face validity to clinical imaging findings reported in studies of individuals at high clinical risk for a psychiatric disorder. Further work is now required to address the relationship of these MRI changes to behavioral dysfunction and to establish thier cellular correlates.

BACKGROUND: Huntington's disease (HD) is caused by an unstable polyglutamine (CAG) repeat in the HD gene, whereby a CAG repeat length greater than ∼36 leads to the disease. In HD patients, longer repeats correlate with more severe disease and earlier death. This is also seen in R6/2 mice carrying repeat lengths up to ∼200. Paradoxically, R6/2 mice with repeat lengths >300 have a less aggressive phenotype and longer lifespan than those with shorter repeats. The mechanism underlying this phenomenon is unknown. OBJECTIVE: To investigate the consequences of longer repeat lengths on structural changes in the brains of R6/2 mice, especially with regard to progressive atrophy. METHODS: We used longitudinal in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS) to compare pathological changes in two strains of R6/2 mice, one with a rapidly progressing disease (250 CAG repeats), and the other with a less aggressive phenotype (350 CAG repeats). RESULTS: We found significant progressive brain atrophy in both 250 and 350 CAG repeat mice, as well as changes in metabolites (glutamine/glutamate, choline and aspartate). Although similar in magnitude, atrophy in the brains of 350 CAG R6/2 mice progressed more slowly than that seen in 250 CAG mice, in line with the milder phenotype and longer lifespan. Interestingly, significant atrophy was detectable in 350 CAG mice as early as 8-12 weeks of age, although behavioural abnormalities in these mice are not apparent before 25-30 weeks. This finding fits well with human data from the PREDICT-HD and TRACK-HD project, where reductions in brain volume were found 10 years in advance of the onset of symptoms. CONCLUSIONS: The similar brain atrophy with a mismatch between onset of brain atrophy and behavioural phenotype in HD mice with 350 repeats will make this mouse particularly useful for modelling early stages of HD pathology.

Supplemental Digital Content is available in the text., Background: Elabela/toddler (ELA) is a critical cardiac developmental peptide that acts through the G-protein–coupled apelin receptor, despite lack of sequence similarity to the established ligand apelin. Our aim was to investigate the receptor pharmacology, expression pattern, and in vivo function of ELA peptides in the adult cardiovascular system, to seek evidence for alteration in pulmonary arterial hypertension (PAH) in which apelin signaling is downregulated, and to demonstrate attenuation of PAH severity with exogenous administration of ELA in a rat model. Methods: In silico docking analysis, competition binding experiments, and downstream assays were used to characterize ELA receptor binding in human heart and signaling in cells expressing the apelin receptor. ELA expression in human cardiovascular tissues and plasma was determined using real-time quantitative polymerase chain reaction, dual-labeling immunofluorescent staining, and immunoassays. Acute cardiac effects of ELA-32 and [Pyr1]apelin-13 were assessed by MRI and cardiac catheterization in anesthetized rats. Cardiopulmonary human and rat tissues from PAH patients and monocrotaline- and Sugen/hypoxia-exposed rats were used to show changes in ELA expression in PAH. The effect of ELA treatment on cardiopulmonary remodeling in PAH was investigated in the monocrotaline rat model. Results: ELA competed for binding of apelin in human heart with overlap for the 2 peptides indicated by in silico modeling. ELA activated G-protein– and β-arrestin–dependent pathways. We detected ELA expression in human vascular endothelium and plasma. Comparable to apelin, ELA increased cardiac contractility, ejection fraction, and cardiac output and elicited vasodilatation in rat in vivo. ELA expression was reduced in cardiopulmonary tissues from PAH patients and PAH rat models, respectively. ELA treatment significantly attenuated elevation of right ventricular systolic pressure and right ventricular hypertrophy and pulmonary vascular remodeling in monocrotaline-exposed rats. Conclusions: These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin, and is downregulated in human disease and rodent PAH models, and exogenous peptide can reduce the severity of cardiopulmonary remodeling and function in PAH in rats. This study provides additional proof of principle that an apelin receptor agonist may be of therapeutic use in PAH in humans.

International audience; Impulsivity is an endophenotype of vulnerability for compulsive behaviors. However, the neural mechanisms whereby impulsivity facilitates the development of compulsive disorders, such as addiction or obsessive compulsive disorder, remain unknown. We first investigated, in rats, anatomical and functional correlates of impulsivity in the anterior insular (AI) cortex by measuring both the thickness of, and cellular plasticity markers in, the AI with magnetic resonance imaging and in situ hybridization of the immediate early gene zif268, respectively. We then investigated the influence of bilateral AI cortex lesions on the high impulsivity trait, as measured in the five-choice serial reaction time task (5-CSRTT), and the associated propensity to develop compulsivity as measured by high drinking levels in a schedule-induced polydipsia procedure (SIP). We demonstrate that the AI cortex causally contributes to individual vulnerability to impulsive-compulsive behavior in rats. Motor impulsivity, as measured by premature responses in the 5-CSRTT, was shown to correlate with the thinness of the anterior region of the insular cortex, in which highly impulsive (HI) rats expressed lower zif268 mRNA levels. Lesions of AI reduced impulsive behavior in HI rats, which were also highly susceptible to develop compulsive behavior as measured in a SIP procedure. AI lesions also attenuated both the development and the expression of SIP. This study thus identifies the AI as a novel neural substrate of maladaptive impulse control mechanisms that may facilitate the development of compulsive disorders.

Contains fulltext : 167380.pdf (Publisher’s version ) (Open Access) Intellectual disability (ID) is a common condition with considerable genetic heterogeneity. Next-generation sequencing of large cohorts has identified an increasing number of genes implicated in ID, but their roles in neurodevelopment remain largely unexplored. Here we report an ID syndrome caused by de novo heterozygous missense, nonsense, and frameshift mutations in BCL11A, encoding a transcription factor that is a putative member of the BAF swi/snf chromatin-remodeling complex. Using a comprehensive integrated approach to ID disease modeling, involving human cellular analyses coupled to mouse behavioral, neuroanatomical, and molecular phenotyping, we provide multiple lines of functional evidence for phenotypic effects. The etiological missense variants cluster in the amino-terminal region of human BCL11A, and we demonstrate that they all disrupt its localization, dimerization, and transcriptional regulatory activity, consistent with a loss of function. We show that Bcl11a haploinsufficiency in mice causes impaired cognition, abnormal social behavior, and microcephaly in accordance with the human phenotype. Furthermore, we identify shared aberrant transcriptional profiles in the cortex and hippocampus of these mouse models. Thus, our work implicates BCL11A haploinsufficiency in neurodevelopmental disorders and defines additional targets regulated by this gene, with broad relevance for our understanding of ID and related syndromes. 22 p.

HD is a progressive genetic neurological disorder, characterized by motor as well as cognitive impairments. The gene carrying the mutation causing Huntington's disease (HD) is not brain specific, and there is increasing evidence for peripheral, as well as brain pathology in this disorder. Here, we used in vivo and ex vivo techniques to assess the cardiac function of mice transgenic for the HD mutation. Using magnetic resonance imaging (MRI) of the beating heart, we show that abnormalities previously reported in end-stage mice are present by mid-stages of the disease. We also found abnormalities that have not been hitherto reported, including changes in cardiac efficiency and a mechanical distortion of the beating heart. Using the Langendorff preparation, we show reduced coronary blood flow, impaired myocardial contractility and reduced left ventricular developed pressure in HD mouse hearts. Together, our findings suggest that there is significant pathology of the HD mouse heart, even by mid stages of disease. Previous clinical research has demonstrated that the risk of cognitive symptoms increases markedly in patients with heart failure. R6/2 mice show significant progressive cognitive abnormalities, so we hypothesize that cardiac pathology in the R6/2 mouse may contribute, not only to their progressive decline and death, but also to their cognitive dysfunction. We suggest that closer attention should be paid to cardiovascular symptoms in HD patients.