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Prenatal exposure to buprenorphine renders offspring vulnerable to cerebral impairments. In this study, our data demonstrate, for the first time, that prenatal exposure to buprenorphine escalates astrocyte activation concurrent with indications of endoplasmic reticulum (ER) stress in the hippocampi of neonates, and this can be prevented by the coadministration of dextromethorphan with buprenorphine. Furthermore, dextromethorphan can inhibit the accumulation of GPR37 in the hippocampus of newborns caused by buprenorphine and is accompanied by the proapoptotic ER stress response that involves the procaspase-3/CHOP pathway. Primary astrocyte cultures derived from the neonates of the buprenorphine group also displayed aberrant ER calcium mobilization and elevated basal levels of cyclooxygenase-2 (COX-2) at 14 days in vitro while showing sensitivity to lipopolysaccharide-activated expression of COX-2. Similarly, these long-lasting defects in the hippocampus and astrocytes were abolished by dextromethorphan. Our findings suggest that prenatal exposure to buprenorphine might instigate long-lasting effects on hippocampal and astrocytic functions. The beneficial effects of prenatal coadministration of dextromethorphan might be, at least in part, attributed to its properties in attenuating astrocyte activation and hippocampal ER stress in neonates.

In magnetic resonance imaging (MRI), noise is a limiting factor for higher spatial resolution and a major cause of prolonged scan time, owing to the need for repeated scans. Improving the signal-to-noise ratio is therefore key to faster and higher-resolution MRI. Here we propose a method for mapping and reducing noise in MRI by leveraging the inherent redundancy in complex-valued multi-channel MRI data. Our method leverages a provably optimal strategy for shrinking the singular values of a data matrix, allowing it to outperform state-of-the-art methods such as Marchenko-Pastur PCA in noise reduction. Our method reduces the noise floor in brain diffusion MRI by 5-fold and remarkably improves the contrast of spiral lung \(^{19}\)F MRI. Our framework is fast and does not require training and hyper-parameter tuning, therefore providing a convenient means for improving SNR in MRI.

D-serine has attracted increasing attention for its possible role in depression. L-4-Fluorophenylglycine (L-4FPG), an inhibitor of the neutral amino acid transporter ASCT1/2, has been shown to regulate extracellular D-serine levels. The present study aimed to explore the potential antidepressant effects of L-4FPG. First, the acute effects of L-4FPG on the forced swimming test, elevated plus maze test, and novelty-suppressed feeding test were examined. L-4FPG showed antidepressant-like effects, which could be reversed by rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist. The phosphorylation levels of mTOR and GluR1 in the hippocampus were also increased after L-4FPG treatment. Next, the therapeutic effects of L-4FPG were examined in a chronic social defeat stress (CSDS) model of depression. L-4FPG ameliorated depression-like behaviors in mice subjected to CSDS. Furthermore, treatment with L-4FPG prior to each social defeat stress session not only decreased defensive behaviors but also prevented CSDS-induced social avoidance and anxiety-like and depression-like behaviors. These findings suggest that L-4FPG may be useful not only in alleviating depression but also in protecting against chronic stress-related psychiatric disorders.

Functional MRI (fMRI) has become an important translational tool for studying brain activity and connectivity in animal models and humans. For accurate and reliable measurement of functional connectivity, nuisance removal strategies developed for human brain, such as regressing motion parameters, cerebrospinal fluid (CSF)/white matter-derived signals and the global signal, have been applied to rodent. However, due to the very different anatomy, with the majority of the rodent brain being gray matter, and experimental conditions, in which animals are anesthetized and head-fixed, these methods may not be suitable for rodent fMRI. In this study, we assessed various nuisance regression methods and the effects of motion correction on a large dataset of both task and resting fMRI of anesthetized rat brain. Sensitivity and specificity were assessed in the somatosensory pathway under forepaw stimulation and resting state. Reproducibility at various sample sizes was simulated by randomly subsampling the dataset. To overcome the difficulty in extracting nuisance from the brain, a method using principal components estimated from tissues outside the brain was evaluated. Our results showed that neither detrend, motion correction, motion regression nor CSF signal regression could improve specificity despite increasing temporal signal-to-noise ratios. Although global signal regression increased the specificity of task activation and functional connectivity, the sensitivity and connectivity strength was drastically reduced, likely due to its strong correlation with the cortical signal. Motion parameters also correlated with task activation and the global signal, indicating that motion correction detected intensity variations in the brain. The nuisance estimated from tissues outside the brain produced a moderate improvement in specificity. In conclusion, nuisance removal suitable for human fMRI may not be optimal for rodents. While further development is needed, estimating nuisance from tissues outside the brain may be an alternative.

We present a reconstruction scheme for diffusion MRI data acquired using slice-interleaved diffusion encoding (SIDE). We show that, when combined with multi-band imaging, the method is capable of reducing the amount of data that needs to be acquired by as much as 25 times, therefore remarkably speeding up acquisition and making high angular resolution diffusion imaging much more feasible, particularly for pediatric, elderly, and claustrophobic patients. In contrast to the conventional approach of acquiring a full diffusion-weighted (DW) volume for each diffusion wavevector, SIDE acquires for each repetition time (TR) a volume consisting of interleaved slice groups, each corresponding to a different diffusion wavevector. This allows SIDE to rapidly acquire information associated with a larger number of wavevectors within a short period of time. We formulate the inverse problem involved in recovering the full DW images as a constrained variational problem regularized by multidimensional total variation. The problem can be solved efficiently using the alternating direction method of multipliers (ADMM). Experiment results based on SIDE data of adults indicate that DW images can be recovered with high fidelity despite high undersampling for multifold acceleration.

The hippocampus is critical for learning and memory and may be separated into anatomically-defined hippocampal subfields (aHPSFs). Many studies have shown that aHPSFs, and their respective functional networks, are differentially vulnerable to a variety of disorders. Hippocampal functional networks, particularly during resting state, are generally analyzed using aHPSFs as seed regions, with the underlying assumption that the function within a subfield is homogeneous, yet heterogeneous between subfields. However, several prior studies that have utilized aHPSFs and assessed brain-wide cortical connectivity have observed similar resting-state functional connectivity profiles between aHPSFs. Alternatively, data-driven approaches offer a means to investigate hippocampal functional organization without a priori assumptions. However, insufficient spatial resolution may lead to partial volume effects at the boundaries of hippocampal subfields, resulting in a number of caveats concerning the reliability of the results. Hence, we developed a functional Magnetic Resonance Imaging (fMRI) sequence on a 7T MR scanner achieving 0.94 mm isotropic resolution with a TR of 2s and brain-wide coverage to 1) investigate whether hippocampal functional segmentation with ultrahigh-resolution data demonstrate similar anatomical, lamellar structures in the hippocampus, and 2) define and compare the brain-wide FC associated with fine-grained aHPSFs and functionally-defined hippocampal subfields (fHPSFs). Using a spatially restricted hippocampal Independent Component Analysis (ICA) approach, this study showed that fHPSFs were arranged along the longitudinal axis of the hippocampus that were not comparable to the lamellar structures of aHPSFs. Contrary to the anatomically defined hippocampal subfields which are bilaterally symmetrical, 13 out of 20 fHPSFs were unilateral. For brain-wide FC, the fHPSFs rather than aHPSFs revealed that a number of fHPSFs connected specifically with some of the functional networks. The visual and sensorimotor networks preferentially connected with different portions of CA1, CA3 and CA4/DG. The DMN was also found to connect more extensively with posterior subfields rather than anterior subfields. Finally, the frontoparietal network (FPN) was anticorrelated with the head portion of CA1. The investigation of functional networks associated with the fHPSFs may enhance the sensitivity of biomarkers for a range of neurological disorders, as network-based approaches take into account disease-related alterations in brain-wide interconnections rather than measuring the regional changes of hippocampus.

The ability to achieve submillimter isotropic resolution diffusion MR imaging (dMRI) is critically important to study fine-scale brain structures, particularly in the cortex. One of the major challenges in performing submillimeter dMRI is the inherently low signal-to-noise ratio (SNR). While approaches capable of mitigating the low SNR in high resolution dMRI have been proposed, namely simultaneous multi-slab (SMSlab) and generalized slice dithered enhanced resolution with simultaneous multislice (gSlider-SMS), limitations are associated with these approaches. The SMSlab sequences suffer from the slab boundary artifacts and require additional navigators for phase estimation. On the other hand, gSlider sequences require relatively high RF power and peak amplitude, which increase the SAR and complicate the RF excitation. In this work, we developed a navigator-free multishot-encoded simultaneous multi-slice (MUSIUM) imaging approach on a 3T MR scanner, achieving enhanced SNR, low RF power and peak amplitude, and being free from slab boundary artifacts. The dMRI with ultrahigh resolution (0.86 mm isotropic resolution), whole brain coverage and ~12.5 minute acquisition time were achieved, revealing detailed structures at cortical and white matter areas. The simulated and in vivo results also demonstrated that the MUSIUM imaging was minimally affected by the motion. Taken together, the MUSIUM imaging is a promising approach to achieve submillimeter diffusion imaging on 3T MR scanners within clinically feasible scan time., 6 Figures in the main text and 2 figures in the supplementary materials

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.

Contains fulltext : 219632.pdf (Publisher’s version ) (Open Access) Preclinical applications of resting-state functional magnetic resonance imaging (rsfMRI) offer the possibility to non-invasively probe whole-brain network dynamics and to investigate the determinants of altered network signatures observed in human studies. Mouse rsfMRI has been increasingly adopted by numerous laboratories worldwide. Here we describe a multi-centre comparison of 17 mouse rsfMRI datasets via a common image processing and analysis pipeline. Despite prominent cross-laboratory differences in equipment and imaging procedures, we report the reproducible identification of several large-scale resting-state networks (RSN), including a mouse default-mode network, in the majority of datasets. A combination of factors was associated with enhanced reproducibility in functional connectivity parameter estimation, including animal handling procedures and equipment performance. RSN spatial specificity was enhanced in datasets acquired at higher field strength, with cryoprobes, in ventilated animals, and under medetomidine-isoflurane combination sedation. Our work describes a set of representative RSNs in the mouse brain and highlights key experimental parameters that can critically guide the design and analysis of future rodent rsfMRI investigations.

In this paper, we introduce a technique for super-resolution reconstruction of diffusion MRI, harnessing fiber-continuity (FC) as a constraint in a global whole-brain optimization framework. FC is a biologically-motivated constraint that relates orientation information between neighboring voxels. We show that it can be used to effectively constrain the inverse problem of recovering high-resolution data from low-resolution data. Since voxels are inter-related by FC, we devise a global optimization framework that allows solutions pertaining to all voxels to be solved simultaneously. We demonstrate that the proposed super-resolution framework is effective for diffusion MRI data of a glioma patient, a healthy subject, and a macaque.

The antiobesity effects of quercetin-rich supplement (QRS), which contain quercetin, lycopene, taurine, and litchi flower extract, on a high-fat diet (HFD)-induced obese rats were investigated. The rats that consume HFD with QRS (185 mg/kg rat) have significantly modulated the final body weights [490 ± 11 (HFD) → 441 ± 11 (HFD+QRS) g], total body fat [112.9 ± 4.5 (HFD) → 86.6 ± 5.7 (HFD+QRS) g], liver weights [14.8 ± 0.4 (HFD) → 12.6 ± 0.4 (HFD+QRS) g/rat], and the serum TG [102.5 ± 7.3 (HFD) → 90.7 ± 6.5 (HFD+QRS) mg/dL] to a level that resembled the regular diet-consumed rats (p < 0.05). The excretion of lipid in the faeces augmented in QRS groups as compared with the nonsupplemented HFD group [faecal total lipid: 62.43 ± 2.80 (HFD) → 73.15 ± 0.88 (HFD+QRS) mg/g dried faeces, p < 0.05]. In the histological analysis, quercetin-rich formulation supplemented groups presented a much less lipid accumulation and smaller size of adipocytes. Moreover, a decreased serum thiobarbituric acid reactive substances [1.55 ± 0.17 (HFD) → 0.78 ± 0.04 (HFD+QRS) nmol MDA eq/mL serum] increased levels of serum Trolox equivalent antioxidant capacity [3.89 ± 0.08 (HFD) → 6.46 ± 0.20 (HFD+QRS) μmol/mL serum], and more active hepatic antioxidant enzymes were observed in the supplemented groups (p < 0.05). The result of this work is a good demonstration of how a combination of bioactive compounds could work synergistically and become very effective in disease prevention.

Black garlic (also called aged garlic) is a type of fermented garlic product from fresh garlic that is often used as a food ingredient and a functional food in Asian countries. The aim of this study was to investigate whether black garlic ameliorates obesity induced by a high-fat diet in rats. Male Wistar rats were fed a normal diet or a high-fat diet (HFD) (30% lard, w/w) combined with 0, 0.2, 0.6, or 1.2% black garlic (BG) (w/w) for a period of six weeks. The results demonstrated that body weight, tissue weights of liver, peritoneal fat, and epididymal fat, serum triglycerides, and hepatic lipid profiles (total lipids, triglycerides, and cholesterol) in the HFD+BG groups were significantly decreased compared with those in the HFD group. BG also reduced hepatic oxidative stress (reduced GSSG and enhanced TEAC, GSH, GRd, and GPx) in HFD-induced obese rats. These results suggest that black garlic may be useful for the treatment of obesity.

Phytochemicals have multifunctional bioactivities, such as anti-inflammatory and anti-obesity activities. However, there are still relatively few studies that have investigated the possible anti-fatigue of functional phytochemical compounds (such as resveratrol, triterpenoids, and catechins) in animal models. Therefore, the aim of this study was to develop of in vitro models as tools for cellular and molecular studies of anti-fatigue. C2C12 myotubes were used for evaluating in vitro the anti-fatigue of functional compounds. The results indicated that treatment with some functional compounds (including resveratrol, quercetin, epigallocatechin gallate, and epicatechin) significantly increased the expression of mitochondrial DNA genes (including cytochrome b and cytochrome c oxidase subunit II ) and the activities of mitochondrial enzymes (including citrate synthase and cytochrome c oxidase) in C2C12 myotubes. These results demonstrated that resveratrol, quercetin, epigallocatechin gallate, and epicatechin have great potential as novel mitochondrial-activating agents that may play an important role in anti-fatigue.

MR Fingerprinting (MRF) is a relatively new imaging framework capable of providing accurate and simultaneous quantification of multiple tissue properties for improved tissue characterization and disease diagnosis. While 2D MRF has been widely available, extending the method to 3D MRF has been an actively pursued area of research as a 3D approach can provide a higher spatial resolution and better tissue characterization with an inherently higher signal-to-noise ratio. However, 3D MRF with a high spatial resolution requires lengthy acquisition times, especially for a large volume, making it impractical for most clinical applications. In this study, a high-resolution 3D MR Fingerprinting technique, combining parallel imaging and deep learning, was developed for rapid and simultaneous quantification of T(1) and T(2) relaxation times. Parallel imaging was first applied along the partition-encoding direction to reduce the amount of acquired data. An advanced convolutional neural network was then integrated with the MRF framework to extract features from the MRF signal evolution for improved tissue characterization and accelerated mapping. A modified 3D-MRF sequence was also developed in the study to acquire data to train the deep learning model that can be directly applied to prospectively accelerate 3D MRF scans. Our results of quantitative T(1) and T(2) maps demonstrate that improved tissue characterization can be achieved using the proposed method as compared to prior methods. With the integration of parallel imaging and deep learning techniques, whole-brain (26 × 26 × 18 cm(3)) quantitative T(1) and T(2) mapping with 1-mm isotropic resolution were achieved in ~7 min. In addition, a ~7-fold improvement in processing time to extract tissue properties was also accomplished with the deep learning approach as compared to the standard template matching method. All of these improvements make high-resolution whole-brain quantitative MR imaging feasible for clinical applications.

Objectives: The neuroprotective effects of resveratrol against excitatory neurotoxicity have been associated with N-methyl-D-aspartate receptor (NMDAR) inhibition. This study examined the different...

Preclinical applications of resting-state functional magnetic resonance imaging (rsfMRI) offer the possibility to non-invasively probe whole-brain network dynamics and to investigate the determinants of altered network signatures observed in human studies. Mouse rsfMRI has been increasingly adopted by numerous laboratories worldwide. Here we describe a multi-centre comparison of 17 mouse rsfMRI datasets via a common image processing and analysis pipeline. Despite prominent cross-laboratory differences in equipment and imaging procedures, we report the reproducible identification of several large-scale resting-state networks (RSN), including a mouse default-mode network, in the majority of datasets. A combination of factors was associated with enhanced reproducibility in functional connectivity parameter estimation, including animal handling procedures and equipment performance. RSN spatial specificity was enhanced in datasets acquired at higher field strength, with cryoprobes, in ventilated animals, and under medetomidine-isoflurane combination sedation. Our work describes a set of representative RSNs in the mouse brain and highlights key experimental parameters that can critically guide the design and analysis of future rodent rsfMRI investigations.