Lithium has been the frontline treatment for bipolar disorder for over 60 years. However, its mode of action and distribution in the brain is still incompletely understood. The primary isotope of ...lithium, lithium-7 (
Li), is a magnetic resonance (MR) active, spin-3/2 nucleus. However, its low MR sensitivity and the small brain size of mice make
Li MR imaging (MRI) difficult in preclinical research. We tested four MRI sequences (FLASH, RARE, bSSFP, and SPIRAL) on lithium-containing phantoms, and bSSFP and SPIRAL on orally lithium-treated adult C57BL/6 mice.
Li MR spectroscopy was acquired weekly at 9.4T to monitor the lithium uptake. The in vivo T1 relaxation time of
Li was estimated in four mice. 4-h SPIRAL
Li MRI was acquired in ten mice at a resolution of 2 × 2 × 3 mm
. SPIRAL MRI provided the highest signal-to-noise ratio (SNR) per unit acquisition time and the best image quality. We observed a non-homogeneous distribution of lithium in the mouse brain, with the highest concentrations in the cortex, ventricles, and basal brain regions. Almost no lithium signal was detected in the olfactory bulb and the cerebellum. We showed that in vivo
Li MRI in mice is feasible, although with limited spatial resolution and SNR.
•The subcortical gray matter areas of macaque monkeys are reliably mapped by QSM, much as they are in humans.•Combining T1w and QSM images improves the visualization and segmentation of white matter, ...cortex, and subcortical structures in the macaque monkey.•The proposed dual contrast TQ-SILiCON provides a similar image quality also in humans.•TQ-SILiCON facilitates comparative and translational neuroscience studies investigating subcortical structures.
Recent progress in quantitative susceptibility mapping (QSM) has enabled the accurate delineation of submillimeter-scale subcortical brain structures in humans. However, the simultaneous visualization of cortical, subcortical, and white matter structure remains challenging, utilizing QSM data solely. Here we present TQ-SILiCON, a fusion method that enhances the contrast of cortex and subcortical structures and provides an excellent white matter delineation by combining QSM and conventional T1-weighted (T1w) images. In this study, we first applied QSM in the macaque monkey to map iron-rich subcortical structures. Implementing the same QSM acquisition and analysis methods allowed a similar accurate delineation of subcortical structures in humans. However, the QSM contrast of white and cortical gray matter was not sufficient for appropriate segmentation. Applying automatic brain tissue segmentation to TQ-SILiCON images of the macaque improved the classification of subcortical brain structures as compared to the single T1 contrast by maintaining an excellent white to cortical gray matter contrast. Furthermore, we validated our dual-contrast fusion approach in humans and similarly demonstrated improvements in automated segmentation of the cortex and subcortical structures. We believe the proposed contrast will facilitate translational studies in nonhuman primates to investigate the pathophysiology of neurodegenerative diseases that affect subcortical structures such as the basal ganglia in humans.
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Medetomidine has become a popular choice for anesthetizing rats during long-lasting sessions of blood-oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI). Despite this, it has ...not yet been thoroughly established how commonly reported fMRI readouts evolve over several hours of medetomidine anesthesia and how they are affected by the precise timing, dose, and route of administration. We used four different protocols of medetomidine administration to anesthetize rats for up to six hours and repeatedly evaluated somatosensory stimulus-evoked BOLD responses and resting state functional connectivity. We found that the temporal evolution of fMRI readouts strongly depended on the method of administration. Intravenous administration of a medetomidine bolus (0.05 mg/kg), combined with a subsequent continuous infusion (0.1 mg/kg/h), led to temporally stable measures of stimulus-evoked activity and functional connectivity throughout the anesthesia. Deviating from the above protocol-by omitting the bolus, lowering the medetomidine dose, or using the subcutaneous route-compromised the stability of these measures in the initial two-hour period. We conclude that both an appropriate protocol of medetomidine administration and a suitable timing of fMRI experiments are crucial for obtaining consistent results. These factors should be considered for the design and interpretation of future rat fMRI studies.
We present a fully reversible and highly efficient on-off photoswitching of magnetic resonance imaging (MRI) contrast with green (500 nm) and violet-blue (435 nm) light. The contrast change is based ...on intramolecular light-driven coordination-induced spin state switch (LD-CISSS), performed with azopyridine-substituted Ni-porphyrins. The relaxation time of the solvent protons in 3 mM solutions of the azoporphyrins in DMSO was switched between 3.5 and 1.7 s. The relaxivity of the contrast agent changes by a factor of 6.7. No fatigue or side reaction was observed, even after >100,000 switching cycles in air at room temperature. Electron-donating substituents at the pyridine improve the LD-CISSS in two ways: better photostationary states are achieved, and intramolecular binding is enhanced.
Increased cortical size is essential to the enhanced intellectual capacity of primates during mammalian evolution. The mechanisms that control cortical size are largely unknown. Here, we show that ...mammalian BAF170, a subunit of the chromatin remodeling complex mSWI/SNF, is an intrinsic factor that controls cortical size. We find that conditional deletion of BAF170 promotes indirect neurogenesis by increasing the pool of intermediate progenitors (IPs) and results in an enlarged cortex, whereas cortex-specific BAF170 overexpression results in the opposite phenotype. Mechanistically, BAF170 competes with BAF155 subunit in the BAF complex, affecting euchromatin structure and thereby modulating the binding efficiency of the Pax6/REST-corepressor complex to Pax6 target genes that regulate the generation of IPs and late cortical progenitors. Our findings reveal a molecular mechanism mediated by the mSWI/SNF chromatin-remodeling complex that controls cortical architecture.
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•BAF170 regulates cortical size and thickness•BAF170 controls the mode of cortical neurogenesis•Interaction of BAF170, Pax6, and REST controls the timing of cortical layer generation•Competition between BAF155 and BAF170 subunits controls chromatin structure
Tuoc et al. show that BAF chromatin remodeling complex component BAF170 controls cortical size via cortical neurogenesis. BAF170 competes with BAF155 subunit in the complex. The BAF170-containing complex interacts with Pax6 and modulates Pax6 target gene expression via REST corepressor complex recruitment to control intermediate and later cortical progenitor generation.
During deep anesthesia, the electroencephalographic (EEG) signal of the brain alternates between bursts of activity and periods of relative silence (suppressions). The origin of burst-suppression and ...its distribution across the brain remain matters of debate. In this work, we used functional magnetic resonance imaging (fMRI) to map the brain areas involved in anesthesia-induced burst-suppression across four mammalian species: humans, long-tailed macaques, common marmosets, and rats. At first, we determined the fMRI signatures of burst-suppression in human EEG-fMRI data. Applying this method to animal fMRI datasets, we found distinct burst-suppression signatures in all species. The burst-suppression maps revealed a marked inter-species difference: in rats, the entire neocortex engaged in burst-suppression, while in primates most sensory areas were excluded-predominantly the primary visual cortex. We anticipate that the identified species-specific fMRI signatures and whole-brain maps will guide future targeted studies investigating the cellular and molecular mechanisms of burst-suppression in unconscious states.
Autism spectrum conditions (ASCs) are heritable conditions characterized by impaired reciprocal social interactions, deficits in language acquisition, and repetitive and restricted behaviors and ...interests. In addition to more complex genetic susceptibilities, even mutation of a single gene can lead to ASC. Several such monogenic heritable ASC forms are caused by loss-of-function mutations in genes encoding regulators of synapse function in neurons, including NLGN4. We report that mice with a loss-of-function mutation in the murine NLGN4 ortholog Nlgn4, which encodes the synaptic cell adhesion protein Neuroligin-4, exhibit highly selective deficits in reciprocal social interactions and communication that are reminiscent of ASCs in humans. Our findings indicate that a protein network that regulates the maturation and function of synapses in the brain is at the core of a major ASC susceptibility pathway, and establish Neuroligin-4-deficient mice as genetic models for the exploration of the complex neurobiological disorders in ASCs.
Abstract
Cardiac MRI in rhesus macaques, a species of major relevance for preclinical studies on biological therapies, requires artificial ventilation to realize breath holding. To overcome this ...limitation of standard cine MRI, the feasibility of Real-Time (RT) cardiac MRI has been tested in a cohort of ten adult rhesus macaques using a clinical MR-system. In spite of lower tissue contrast and sharpness of RT-MRI, cardiac functions were similarly well assessed by RT-MRI compared to cine MRI (similar intra-subject repeatability). However, systematic underestimation of the end-diastolic volume (31 ± 9%), end-systolic volume (20 ± 11%), stroke volume (40 ± 12%) and ejection fraction (13 ± 9%) hamper the comparability of RT-MRI results with those of other cardiac MRI methods. Yet, the underestimations were very consistent (< 5% variability) for repetitive measurements, making RT-MRI an appropriate alternative to cine MRI for longitudinal studies. In addition, RT-MRI enabled the analysis of cardio-respiratory coupling. All functional parameters showed lower values during expiration compared to inspiration, most likely due to the pressure-controlled artificial ventilation. In conclusion, despite systematic underestimation of the functional parameters, RT-MRI allowed the assessment of left ventricular function in macaques with significantly less experimental effort, measurement time, risk and burden for the animals compared to cine MRI.
Magnetic resonance imaging (MRI) is the gold standard for the detection of multiple sclerosis (MS) lesions. However, current MRI techniques provide little information about the structural features of ...a brain lesion with inflammatory cell infiltration, demyelination, gliosis, acute axonal damage and axonal loss. To identify methods for a differentiation of demyelination, inflammation, and axonal damage we developed a novel mouse model combining cuprizone-induced demyelination and experimental autoimmune encephalomyelitis. MS-like brain lesions were assessed by T1-weighted, T2-weighted, and magnetization transfer MRI as well as by diffusion tensor imaging (DTI). T2-weighted MRI differentiated control and diseased mice, while T1-weighted MRI better reflected the extent of inflammation and axonal damage. In DTI, axonal damage and cellular infiltration led to a reduction of the axial diffusivity, whereas primary demyelination after cuprizone treatment was reflected by changes in radial but not axial diffusivity. Importantly, alterations in radial diffusivity were less pronounced in mice with demyelination, inflammation, and acute axonal damage, indicating that radial diffusivity may underestimate demyelination in acute MS lesions. In conclusion, the combined information from different DTI parameters allows for a more precise identification of solely demyelinated lesions versus demyelinated and acutely inflamed lesions. These findings are of relevance for offering individualized, stage-adapted therapies for MS patients.
The aim of this study was to establish a feasible and robust magnetic resonance imaging protocol for the quantitative assessment of cardiac function in marmosets and to present normal values of ...cardiac function across different ages from young adult, middle-aged, to very old clinically healthy animals. Cardiac MRI of 33 anesthetized marmosets at the age of 2-15 years was performed at 9.4 T using IntraGate-FLASH that operates without any ECG-triggering and breath holding. Normalized to post-mortem heart weight, the left ventricular end-diastolic volume (LV-EDV) was significantly reduced in older marmosets. The LV end-systolic volume (LV-ESV) and the LV stroke volume (LV-SV) showed a similar trend while the LV ejection fraction (LV-EF) and wall thickening remained unchanged. Similar observations were made for the right ventricle. Moreover, the total ventricular myocardial volume was lower in older monkeys while no significant difference in heart weight was found. In conclusion, IntraGate-FLASH allowed for quantification of left ventricular cardiac function but seems to underestimate the volumes of the right ventricle. Although less strong and without significant sex differences, the observed age related changes were similar to previously reported findings in humans supporting marmosets as a model system for age related cardiovascular human diseases.
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