Biology subjects

Wood, T. C.

Publications and source records attributed to Wood, T. C..

7 recordsLinked to original sources

bioRxiv2025

Oral octanoylcarnitine alleviates exercise intolerance in mouse models of long-chain fatty acid oxidation disorders

Long-chain fatty acid oxidation disorders (LC-FAODs) cause energy deficits in heart and skeletal muscle that is only partially corrected by current medium-chain lipid therapies such as triheptanoin. We find that heart and muscle lack medium-chain acyl-CoA synthetases, limiting the capacity for {beta}-oxidation of medium-chain fatty acids. Instead, heart and muscle mitochondria robustly respire on medium-chain acylcarnitines. The mitochondrial matrix enzyme carnitine acetyltransferase (CrAT) efficiently converts orally delivered octanoylcarnitine (C8-carnitine) to octanoyl-CoA for energy generation. C8-carnitine exhibits twice the oral bioavailability of triheptanoin and distributes to muscle and heart. A single oral dose markedly enhances grip strength, basal locomotion, and treadmill endurance while attenuating lactate and creatine kinase elevations in multiple mouse models of LC-FAODs. Thus, medium-chain acylcarnitines overcome a previously unrecognized metabolic bottleneck in LC-FAOD muscle and may represent an alternative to triglyceride-based therapies for bioenergetic disorders.

biochemistry↗

bioRxiv2024

Ultra-low-field brain MRI morphometry: test-retest reliability and correspondence to high-field MRI

Magnetic resonance imaging (MRI) enables non-invasive monitoring of healthy brain development and disease. Widely used higher field (>1.5 T) MRI systems are associated with high energy and infrastructure requirements, and high costs. Recent ultra-low-field (<0.1T) systems provide a more accessible and cost-effective alternative. However, it remains uncertain whether anatomical ultra-low-field neuroimaging can be used to reliably extract quantitative measures of brain morphometry, and to what extent such measures correspond to high-field MRI. Here we scanned 23 healthy adults aged 20-69 years on two identical 64 mT systems and a 3 T system, using T1w and T2w scans across a range of (64 mT) resolutions. We segmented brain images into 4 global tissue types and 98 local structures, and systematically evaluated between-scanner reliability of 64 mT morphometry and correspondence to 3 T measurements, using correlations of tissue volume and Dice spatial overlap of segmentations. We report high 64 mT reliability and correspondence to 3 T across 64 mT scan contrasts and resolutions, with highest performance shown by combining three T2w scans with low through-plane resolution into a single higher-resolution scan using multi-resolution registration. Larger structures show higher 64 mT reliability and correspondence to 3 T. Finally, we showcase the potential of ultra-low-field MRI for mapping neuroanatomical changes across the lifespan, and monitoring brain structures relevant to neurological disorders. Raw images are publicly available, enabling systematic validation of pre-processing and analysis approaches for ultra-low-field neuroimaging.

neuroscience↗

bioRxiv2022

Widespread, depth-dependent microstructural damage in the cortex of children with drug resistant focal epilepsy: A quantitative T1 and T2 mapping study

ObjectiveTissue abnormalities in focal epilepsy may extend beyond the presumed focus. The underlying pathophysiology of these broader changes is unclear, and it is not known whether they result from ongoing disease processes, treatment-related side-effects, or whether they emerge earlier. Few studies have focused on the period of onset for most focal epilepsies, childhood. Fewer still have utilised quantitative MRI, which may provide a more sensitive and interpretable measure of tissue microstructural change. Here, we aimed to determine common spatial modes of changes in cortical architecture in children with heterogeneous drug-resistant focal epilepsy and, secondarily, whether changes were related to disease severity. MethodsTo assess cortical microstructure, quantitative T1 and T2 relaxometry (qT1 and qT2) was measured in 43 children with drug-resistant focal epilepsy [age-range=4-18 years] and 46 typically-developing children [age-range=2-18 years]. We assessed depth-dependent qT1 and qT2 values across the neocortex, as well as their gradient of change across cortical depths. We also determined whether global changes seen in group analyses were driven by focal pathologies in individual patients. Finally, as a proof-of-concept, we trained a classifier using qT1 and qT2 gradient maps from patients with radiologically-defined abnormalities (MRI-positive) and healthy controls, and tested if this could classify patients without reported radiological abnormalities (MRI-negative). ResultsWe uncovered depth-dependent qT1 and qT2 increases in widespread cortical areas in patients, likely representing microstructural alterations in myelin or gliosis. Changes did not correlate with disease severity measures, suggesting they may represent antecedent neurobiological alterations. Using a classifier trained with MRI-positive patients and controls, sensitivity was 62% at 100% specificity on held-out MRI-negative patients. SignificanceThese findings suggest the presence of a potential imaging endophenotype of focal epilepsy, detectable irrespective of radiologically-identified abnormalities, and potentially evident pre-symptomatically. Key PointsO_LIWe assessed cortical microstructure in children with focal epilepsy C_LIO_LIQuantitative T1 and T2 relaxometry (qT1 and qT2) was measured in the neocortex C_LIO_LIPatients showed extensive qT1/qT2 increases and intracortical organization changes C_LIO_LIAlterations may appear during cerebral development, prior to disease onset C_LI

neuroscience↗

bioRxiv2022

Mapping neuroinflammation in vivo with diffusion-MRI in rats given a systemic lipopolysaccharide challenge

It is becoming increasingly apparent that neuroinflammation plays a critical role in an array of neurological and psychiatric disorders. Recent studies have demonstrated the potential of diffusion MRI (dMRI) to characterize changes in microglial density and morphology associated with neuroinflammation, but these were conducted mostly ex vivo and/or in extreme, non-physiological animal models. Here, we build upon these studies by investigating the utility of well-established dMRI methods to detect neuroinflammation in vivo in a more clinically relevant animal model of sickness behavior. We show that diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) indicate widespread increases in diffusivity in the brains of rats given a systemic lipopolysaccharide challenge (n=20) vs. vehicle-treated controls (n=12). These diffusivity changes correlated with histologically measured changes in microglial morphology, confirming the sensitivity of dMRI to neuroinflammatory processes. This study marks a further step towards establishing a noninvasive indicator of neuroinflammation, which would greatly facilitate early diagnosis and treatment monitoring in various neurological and psychiatric diseases.

neuroscience↗

bioRxiv2021

Tissue Optimisation Strategies for High Quality Ex Vivo Diffusion Imaging

Ex vivo diffusion imaging can be used to study healthy and pathological tissue microstructure in the rodent brain with microscopic resolution, providing a link between in vivo MRI and ex vivo microscopy techniques. A major challenge for the successful acquisition of ex vivo diffusion imaging data however are changes in the relaxivity and diffusivity of brain tissue following perfusion fixation. In this study we address this question by examining the combined effects of tissue preparation factors that influence image quality, including tissue rehydration time, fixative concentration and contrast agent concentration. We present an optimisation strategy combining these factors to manipulate the T1 and T2 of fixed tissue and maximise signal-to-noise ratio (SNR) efficiency. Applying this strategy in the rat brain resulted in a doubling of SNR and an increase in SNR per unit time by 135% in grey matter and 88% in white matter. This enabled the acquisition of excellent quality high-resolution (78 {micro}m isotropic voxel size) diffusion data in less than 4 days, with a b-value of 4000 s/mm2, 30 diffusion directions and a field of view of 40 x 13 x 18 mm, using a 9.4 Tesla scanner with a standard 39 mm volume coil and a 660 mT/m 114 mm gradient insert. It was also possible to achieve comparable data quality for a standard resolution (150 {micro}m) diffusion dataset in 21/4 hours. In conclusion, the optimisation strategy presented here may be used to improve signal quality, increase spatial resolution and/or allow faster acquisitions in preclinical ex vivo diffusion MRI experiments.

neuroscience↗

bioRxiv2019

The Innate Immune Toll-Like Receptor-2 modulates the Depressogenic and Anorexiolytic Neuroinflammatory Response in Obstructive Sleep Apnoea

BackgroundThe neurological mechanisms of the disease process of obstructive sleep apnea, the second most frequent sleep disorder, remain unclear whilst its links with several major neuropsychiatric disorders, such as depression, anxiety and even Alzheimers disorder, are increasingly recognised. A radical theory, that inflammation in the brain may underlie certain phenotypes of many of these disorders, has been proposed, and the microglial TLR2 system may serve as an important crossroad at the borderlands of several pathogenesis. This study undertook to investigate whether a neuroinflammatory response occurs under conditions of OSA, and whether it might be related to a modulated response due to TLR2 functionality in an established rodent model of OSA. MethodsThe effects of three weeks exposure to chronic intermittent hypoxia were monitored in mice with or without functional TLR2 (C57BL/6-Tyrc-Brd-Tg(Tlr2-luc/gfp)Kri/Gaj; TLR2-/-, C57BL/6-Tlr2tm1Kir), that were investigated by multimodal in vivo and ex vivo imaging, combining magnetic resonance and bioluminescence imaging and a variety of functional tests. ResultsAn acute neuroinflammatory response was demonstrated following the three days in the basal forebrain of mice, and more chronically in other parts of the frontal cortex. Adaptive changes in specific neurocircuitry were demonstrated, with significant links to agitated (mal)adaptive behaviour under episodes of stress, and an increased ability to gain weight. ConclusionsOur results suggest that microglial activation and an innate immune response might be the missing link underlying the pathogenesis of well known structural, psychologic and metabolic changes experienced by some patients with OSA.

neuroscience↗

bioRxiv2018

Maternal immune activation specifically increases diagonal domain volume in the rat brain during early postnatal development

Maternal immune activation (MIA) is consistently associated with elevated risk for multiple psychiatric and neurological disorders in the affected offspring. Converging lines of evidence from humans and animal models suggest a link between MIA and early entry into an atypical neurodevelopmental trajectory characterised by time- and sex-dependent abnormalities in brain structure and function. However to date, no such studies have investigated the brain-wide impact of MIA in the early post-weaning period, a critical and dynamic window of brain development. To address this, we acquired high-resolution ex vivo structural and diffusion tensor imaging (DTI) images from Wistar rat brains on postnatal day (PD) 21 following exposure to the viral mimetic poly (I:C) or sterile saline on gestational day (GD) 15 using a recently validated protocol. Using a combination of atlas-based segmentation and tensor based morphometry analysis we observed that MIA resulted in a significant increase in the relative volume of the diagonal domain (FDR q<0.1). Additional trend-level volume increases (p<0.05 uncorrected) were also found for the olfactory structures and preoptic area. Although not significant after FDR correction, we found trend-level evidence (p<0.05 uncorrected) for MIA x sex interactions in the volume of the diagonal domain, nucleus accumbens, pineal gland and anterior commissure. In contrast to volume, we found no evidence for microstructural alterations in our DTI dataset at PD21. These data provide new insights into the specific effects of MIA early in development, highlighting in particular, the diagonal domain as a target for future studies.

neuroscience↗