Developmental Mouse Brain Common Coordinate Framework.

3D standard reference brains serve as key resources to understand the spatial organization of the brain and promote interoperability across different studies. However, unlike the adult mouse brain, the lack of standard 3D reference atlases for developing mouse brains has hindered advancement of our understanding of brain development. Here, we present a multimodal 3D developmental common coordinate framework (DevCCF) spanning mouse embryonic day (E) 11.5, E13.5, E15.5, E18.5, and postnatal day (P) 4, P14, and P56 with anatomical segmentations defined by a developmental ontology. At each age, the DevCCF features undistorted morphologically averaged atlas templates created from Magnetic Resonance Imaging and co-registered high-resolution templates from light sheet fluorescence microscopy. Expert-curated 3D anatomical segmentations at each age adhere to an updated prosomeric model and can be explored via an interactive 3D web-visualizer. As a use case, we employed the DevCCF to unveil the emergence of GABAergic neurons in embryonic brains. Moreover, we integrated the Allen CCFv3 into the P56 template with stereotaxic coordinates and mapped spatial transcriptome cell-type data with the developmental ontology. In summary, the DevCCF is an openly accessible resource that can be used for large-scale data integration to gain a comprehensive understanding of brain development.

Towards reliable reconstruction of the mouse brain corticothalamic connectivity using diffusion MRI.

Diffusion magnetic resonance imaging (dMRI) tractography has yielded intriguing insights into brain circuits and their relationship to behavior in response to gene mutations or neurological diseases across a number of species. Still, existing tractography approaches suffer from limited sensitivity and specificity, leading to uncertain interpretation of the reconstructed connections. Hence, in this study, we aimed to optimize the imaging and computational pipeline to achieve the best possible spatial overlaps between the tractography and tracer-based axonal projection maps within the mouse brain corticothalamic network. We developed a dMRI-based atlas of the mouse forebrain with structural labels imported from the Allen Mouse Brain Atlas (AMBA). Using the atlas and dMRI tractography, we first reconstructed detailed node-to-node mouse brain corticothalamic structural connectivity matrices using different imaging and tractography parameters. We then investigated the effects of each condition for accurate reconstruction of the corticothalamic projections by quantifying the similarities between the tractography and the tracer data from the Allen Mouse Brain Connectivity Atlas (AMBCA). Our results suggest that these parameters significantly affect tractography outcomes and our atlas can be used to investigate macroscopic structural connectivity in the mouse brain. Furthermore, tractography in mouse brain gray matter still face challenges and need improved imaging and tractography methods.

Inhomogeneous magnetization transfer MRI of white matter structures in the hypomyelinated shiverer mouse brain.

PURPOSE: Inhomogeneous magnetization transfer (ihMT) MRI is uniquely sensitive to myelin with lipids as a primary source of its contrast. In this study, we investigated whether ihMT can detect white matter structures in the hypomyelinated shiverer mouse brain, a model of dysmyelination. METHODS: Conventional MT and ihMT images were acquired from ex vivo Rag2-/- control and shiverer mouse brains at 7T using previously reported optimized saturation parameters. RESULTS: ihMT ratio (ihMTR) maps revealed hypomyelinated corpus callosum in the shiverer mouse brain, whereas conventional MT ratio (MTR) maps showed no clear contrast. The ihMTR values of the corpus callosum in the shiverer mice were reduced by approximately 40% compared to controls, but remained significantly higher than the ihMTR values of the cortex. CONCLUSION: The finding further confirms ihMT's high myelin specificity and suggests its use as a marker to detect early myelination or myelin repair.

Macroscopic Structural and Connectome Mapping of the Mouse Brain Using Diffusion Magnetic Resonance Imaging.

Translational work in rodents elucidates basic mechanisms that drive complex behaviors relevant to psychiatric and neurological conditions. Nonetheless, numerous promising studies in rodents later fail in clinical trials, highlighting the need for improving the translational utility of preclinical studies in rodents. Imaging of small rodents provides an important strategy to address this challenge, as it enables a whole-brain unbiased search for structural and dynamic changes that can be directly compared to human imaging. The functional significance of structural changes identified using imaging can then be further investigated using molecular and genetic tools available for the mouse. Here, we describe a pipeline for unbiased search and characterization of structural changes and network properties, based on diffusion MRI data covering the entire mouse brain at an isotropic resolution of 100 µm. We first used unbiased whole-brain voxel-based analyses to identify volumetric and microstructural alterations in the brain of adult mice exposed to unpredictable postnatal stress (UPS), which is a mouse model of complex early life stress (ELS). Brain regions showing structural abnormalities were used as nodes to generate a grid for assessing structural connectivity and network properties based on graph theory. The technique described here can be broadly applied to understand brain connectivity in other mouse models of human disorders, as well as in genetically modified mouse strains. Graphic abstract: Pipeline for characterizing structural connectome in the mouse brain using diffusion magnetic resonance imaging. Scale bar = 1 mm.

Centrosome anchoring regulates progenitor properties and cortical formation.

Radial glial progenitor cells (RGPs) are the major neural progenitor cells that generate neurons and glia in the developing mammalian cerebral cortex1-4. In RGPs, the centrosome is positioned away from the nucleus at the apical surface of the ventricular zone of the cerebral cortex5-8. However, the molecular basis and precise function of this distinctive subcellular organization of the centrosome are largely unknown. Here we show in mice that anchoring of the centrosome to the apical membrane controls the mechanical properties of cortical RGPs, and consequently their mitotic behaviour and the size and formation of the cortex. The mother centriole in RGPs develops distal appendages that anchor it to the apical membrane. Selective removal of centrosomal protein 83 (CEP83) eliminates these distal appendages and disrupts the anchorage of the centrosome to the apical membrane, resulting in the disorganization of microtubules and stretching and stiffening of the apical membrane. The elimination of CEP83 also activates the mechanically sensitive yes-associated protein (YAP) and promotes the excessive proliferation of RGPs, together with a subsequent overproduction of intermediate progenitor cells, which leads to the formation of an enlarged cortex with abnormal folding. Simultaneous elimination of YAP suppresses the cortical enlargement and folding that is induced by the removal of CEP83. Together, these results indicate a previously unknown role of the centrosome in regulating the mechanical features of neural progenitor cells and the size and configuration of the mammalian cerebral cortex.

Acceleration of three-dimensional diffusion magnetic resonance imaging using a kernel low-rank compressed sensing method.

Diffusion Magnetic Resonance Imaging (dMRI) has shown great potential in probing tissue microstructure and structural connectivity in the brain but is often limited by the lengthy scan time needed to sample the diffusion profile by acquiring multiple diffusion weighted images (DWIs). Although parallel imaging technique has improved the speed of dMRI acquisition, attaining high resolution three dimensional (3D) dMRI on preclinical MRI systems remained still time consuming. In this paper, kernel principal component analysis, a machine learning approach, was employed to estimate the correlation among DWIs. We demonstrated the feasibility of such correlation estimation from low-resolution training DWIs and used the correlation as a constraint to reconstruct high-resolution DWIs from highly under-sampled k-space data, which significantly reduced the scan time. Using full k-space 3D dMRI data of post-mortem mouse brains, we retrospectively compared the performance of the so-called kernel low rank (KLR) method with a conventional compressed sensing (CS) method in terms of image quality and ability to resolve complex fiber orientations and connectivity. The results demonstrated that the KLR-CS method outperformed the conventional CS method for acceleration factors up to 8 and was likely to enhance our ability to investigate brain microstructure and connectivity using high-resolution 3D dMRI.

PARD3 dysfunction in conjunction with dynamic HIPPO signaling drives cortical enlargement with massive heterotopia.

Proper organization and orderly mitosis of radial glial progenitors (RGPs) drive the formation of a laminated mammalian cortex in the correct size. However, the molecular underpinnings of the intricate process remain largely unclear. Here we show that RGP behavior and cortical development are controlled by temporally distinct actions of partitioning-defective 3 (PARD3) in concert with dynamic HIPPO signaling. RGPs lacking PARD3 exhibit developmental stage-dependent abnormal switches in division mode, resulting in an initial overproduction of RGPs located largely outside the ventricular zone at the expense of deep-layer neurons. Ectopically localized RGPs subsequently undergo accelerated and excessive neurogenesis, leading to the formation of an enlarged cortex with massive heterotopia and increased seizure susceptibility. Simultaneous removal of HIPPO pathway effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) suppresses cortical enlargement and heterotopia formation. These results define a dynamic regulatory program of mammalian cortical development and highlight a progenitor origin of megalencephaly with ribbon heterotopia and epilepsy.

Magnetic resonance microscopy of human and porcine neurons and cellular processes.

With its unparalleled ability to safely generate high-contrast images of soft tissues, magnetic resonance imaging (MRI) has remained at the forefront of diagnostic clinical medicine. Unfortunately due to resolution limitations, clinical scans are most useful for detecting macroscopic structural changes associated with a small number of pathologies. Moreover, due to a longstanding inability to directly observe magnetic resonance (MR) signal behavior at the cellular level, such information is poorly characterized and generally must be inferred. With the advent of the MR microscope in 1986 came the ability to measure MR signal properties of theretofore unobservable tissue structures. Recently, further improvements in hardware technology have made possible the ability to visualize mammalian cellular structure. In the current study, we expand upon previous work by imaging the neuronal cell bodies and processes of human and porcine α-motor neurons. Complimentary imaging studies are conducted in pig tissue in order to demonstrate qualitative similarities to human samples. Also, apparent diffusion coefficient (ADC) maps were generated inside porcine α-motor neuron cell bodies and portions of their largest processes (mean=1.7 ± 0.5 µm²/ms based on 53 pixels) as well as in areas containing a mixture of extracellular space, microvasculature, and neuropil (0.59 ± 0.37 µm²/ms based on 33 pixels). Three-dimensional reconstruction of MR images containing α-motor neurons shows the spatial arrangement of neuronal projections between adjacent cells. Such advancements in imaging portend the ability to construct accurate models of MR signal behavior based on direct observation and measurement of the components which comprise functional tissues. These tools would not only be useful for improving our interpretation of macroscopic MRI performed in the clinic, but they could potentially be used to develop new methods of differential diagnosis to aid in the early detection of a multitude of neuropathologies.

Differences of photographs inducing craving between alcoholics and non-alcoholics.

Many researchers have used cue reactivity paradigm to study alcohol craving. But the difference of craving response to drinks between alcoholic patients and social drinkers was little evaluated. To investigate characteristics of alcohol-related visual cues which induce alcohol craving in alcoholism, we examined the response of subjects to alcohol-related cues considering qualitative aspects. The authors developed 27 photographs related to alcohol as candidate visual cues. Thirty five patients with alcohol dependence, 35 heavy drinkers and 35 social drinkers were shown these pictures and asked to rate these 6 pictures in order of inducing alcohol craving the most. 'A glass of Soju' and 'A Party scene' were chosen as the alcohol-related visual cues which induced craving the most in the patients and heavy drinkers, respectively. The results suggest that the patients with alcohol dependence are more absorbed by alcohol without drinking context such as an atmosphere or situation involving drinking. Heavy drinkers may experience craving in anticipation of being in a drinking situation.

Increased P3 amplitudes induced by alcohol-related pictures in patients with alcohol dependence.

BACKGROUND: Alcohol craving, a key element in alcohol dependence, is recognized as being a kind of motivational or emotional state. It is meaningful in research and clinical practice involving alcohol dependence to explore ways of measuring alcohol craving. The aim of this study was to measure the P3 event-related potentials induced by alcohol-related pictures in patients with alcohol dependence; these potentials are considered to constitute a neuronal correlate of alcohol craving. METHODS: On the basis of our previous study, six alcohol-related pictures and six neutral pictures were chosen as the visual stimuli. Each set of stimuli consisted of alcohol-related or neutral pictures as the target stimuli and same-sized checkerboards as the nontarget stimuli. The stimuli were presented by using the oddball paradigm for 300 msec, with an interstimulus interval of 1000 msec, in 12 controls and 16 abstinent patients with alcohol dependence. Each electroencephalography session consisted of three blocks: a practice block, a neutral block, and an alcohol-craving block. RESULTS: The amplitudes of P3 elicited by the alcohol-related pictures were significantly larger than those elicited by the neutral pictures in the patients with alcohol dependence, whereas there was no significant difference according to the stimuli in the P3 amplitudes of controls. Repeated-measures ANOVA on the amplitudes of P3 revealed that there was a significant interaction effect of block by subject group. CONCLUSIONS: These results suggest that event-related potentials can be used as a neuronal correlate of alcohol craving in alcohol-dependent patients. Future investigations will be needed to assess the frequency of relapse in the patients included in this study, to elucidate the meaning of the observed results with regard to the therapeutic outcomes.

Reduced P3 amplitudes by negative facial emotional photographs in schizophrenia.

Event-related potentials (ERPs), mostly P3, were measured in 20 schizophrenia and 20 healthy control subjects, in order to determine whether patients with schizophrenia have greater impairment in the processing of negative emotions. Study subjects were instructed to feel and respond to rare targets of facial photographs placed between frequent nontarget checkerboards. We found that P3 amplitudes associated with negative emotional photographs, in normal controls, were significantly larger than those of positive stimuli. Unlike the controls, in patients with schizophrenia, P3 amplitudes generated by negative emotional targets were significantly smaller than those of positive stimuli. We conclude that schizophrenia patients might be neurophysiologically different from healthy controls in terms of the manner in which they process facial emotion. Our findings are in line with previous neurobehavioral studies, in which patients with schizophrenia showed greater impairment in the recognition of negative emotions.