Development of a new viral vector strategy for a precise and selective control of transgene expression through Cre-dependent gene switch system
We developed a new strategy termed flip-excision switch (FLEX) system with unilateral spacer sequence (USS) by using AAV vector for a precise and selective control of transgene expression in target cell populations. The FLEX/USS system will enable us a detailed understanding of the structure and function of specific neural circuits.
Identification of the Production Mechanism of APP669-711 in Plasma for Early Detection of Amyloid-beta Deposition in the Brain
We found that ADAMTS4, a metalloproteinase, is involved in the production pathway of APP669-711, which is comprised of a composite plasma biomarker for the detection of amyloid-beta deposition in the human brain. This may lead to refined and early diagnostic techniques for Alzheimer ‘s pathology using plasma.
Parabrachial-to-parasubthalamic nucleus pathway mediates fear-induced suppression of feeding in male mice
Feeding and stress are deeply related, but the underlying neuronal mechanisms are not fully understood. We found that a neural pathway from the pontine lateral parabrachial nucleus (lPB) to the parasubthalamic nucleus (PSTN) in the hypothalamus plays an important role in fear-induced feeding suppression. The work has been published in Nature Communications.
Automated and parallelized spike collision tests to identify spike signal projections
We developed a novel method to identify spike signals of multiple projections among different brain areas. This method was realized by the automation and parallelization of spike collision tests with real-time processing of multi-channel recording and control of stimulations. Our result has been published in iScience.
Fluorochromized Tyramide-Glucose Oxidase as a multiplex fluorescent tyramide signal amplification system for histochemical analysis
The researchers have developed a novel multiplex fluorescent tyramide signal amplification system, namely, FT-GO (Fluorochromized Tyramide-Glucose Oxidase). FT-GO yielded 60 to 180 fold and 10 to 30 fold signal amplification compared with direct and indirect immunofluorescence detections, providing a versatile platform for histochemical analysis.
High-Contrast Imaging of α-Synuclein Pathologies in Living Patients with Multiple System Atrophy
We succeeded in imaging of α-synuclein lesions, protein aggregates supposed to play a crucial role in neurodegenerative disorders, in the brains of living patients with multiple system atrophy. This technology is expected to be applicable to Parkinson's disease and Lewy body dementia, contributing to elucidating the etiological mechanism of these diseases. This work has been published in Movement Disorders.
Lewy Body Disease Primate Model with α-Synuclein Propagation from the Olfactory Bulb
It is believed that α-synuclein propagation in the brain causes the disease progression in Lewy body diseases, including Parkinson's disease and dementia with Lewy bodies. We have inoculated α-synuclein aggregates into the olfactory bulb of marmosets, which induced the α-synuclein propagation via olfactory pathway, and the brain dysfunction was revealed using positron emission tomography (PET) imaging.
A Machine Learning–Based Approach to Discrimination of Tauopathies Using [18F]PM-PBB3 PET Images
We have developed a core technology that uses artificial intelligence (AI) to analyze positron emission tomography (PET) images of abnormal tau protein that accumulates in the brain in various types of dementia (tau lesions) and can automatically evaluate the accumulation pattern of tau lesions. The results of this research have been published in Movement Disorders.
Prenatal valproic acid-induced autism marmoset model exhibits higher salivary cortisol levels
This study revealed that both VPA-exposed ASD model marmosets and control marmosets showed similar diurnal changes in cortisol levels, which were lower in the afternoon than in the morning. However, heightened cortisol levels were observed in VPA-exposed marmosets at the times examined in this study. These results are consistent with those of ASD in humans.
Modular strategy for development of the hierarchical visual network in mice
A research team of the University of Tokyo has successfully elucidated a new mechanism of the brain by which a complex neural network, including interareal connections in the cerebral cortex, is efficiently formed during development. This is the first study investigating comprehensively how interareal connections among cortical and thalamic regions are formed during development. This study is expected to be applied in the future to treatments for diseases such as congenital blindness and to circuit formation algorithms to improve an artificial intelligence.
Exome sequencing analysis of Japanese autism spectrum disorder case-control sample supports an increased burden of synaptic function–related genes
Autism spectrum disorder (ASD) is a highly heritable, complex disorder in which rare variants contribute significantly to disease risk. This case-control exome study showed that rare variants related to synaptic function are associated with ASD susceptibility in the Japanese population. In particular, we strengthen the evidence regarding the role of ABCA13, a synaptic function-related gene. The results of this research have been published in Translational Psychiatry.
Reduced childhood social attention in autism model marmosets predicts impaired social skills and inflexible behavior in adulthood
This study found that the autism model marmoset showed a strong correlation between the time spent looking at adult marmosets during childhood and autism-like symptoms later in life. These results suggest that social attention to others at an early age may be a target for early treatment of autism and that autism model marmosets may be useful tool for early therapy development.
An isogenic panel of App knock-in mouse models: Profiling β-secretase inhibition and endosomal abnormalities
An Alzheimer’s disease (AD) mouse model that is useful for development of drugs such as BACE1 inhibitors is generated by genome editing technology. This AD mouse model recapitulated endosomal abnormality in neurons, one of characteristic changes in AD, indicating this model is also suitable to study cellular pathophysiology.
Phosphoproteomic of the acetylcholine pathway enables discovery of the PKC-β-PIX-Rac1-PAK cascade as a stimulatory signal for aversive learning
Acetylcholine is critical for learning, whose deficits is associated with Alzheimer’s disease (AD). This study unravels the acetylcholine intracellular signaling for aversive learning, a major preliminary test for AD drugs. Moreover, AD drug donepezil enhances aversive learning through this signal. The findings imply the signal’s therapeutic potential for AD.
Cerebro-cerebellar interactions in nonhuman primates examined by optogenetic functional magnetic resonance imaging
Opto-fMRI, which combines functional magnetic resonance imaging (fMRI) and optogenetics, has been widely used in rodents, but only a few successful cases have been reported in non-human primates. By conducting opto-fMRI with efficient optogenetics and ultra-high field 7 tesla MRI, this study succeeded in visualizing the brain network induced by optical stimulation of the monkey motor cortex.
Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder
Copy number variation (CNV) analysis of bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD) revealed that small (<100 kb) deletions are more common in BD and large (>500 kb) CNVs are more common in SCZ/ASD. Known risk CNVs for neurodevelopmental disorders were associated with the three disorders, but their impact on BD risk was relatively small. Chromatin function was involved in BD, while broader and overlapping molecular mechanisms were involved in SCZ/ASD. CNVs in non-coding regions were associated with risk of SCZ/ASD.
Subthalamic nucleus stabilizes movements by reducing neural spike variability in monkey basal ganglia
A chemogenetic tool was applied to macaque monkeys, and activity in the subthalamic nucleus, a part of the basal ganglia, was suppressed. During suppression, monkeys’ reaching movements became unstable, and involuntary movements were induced. In the output nucleus of the basal ganglia, the internal pallidum, neurons showed no firing rate change, but their spike train became variable. The subthalamic nucleus may stabilize neural activity in the basal ganglia for smooth movements.
Subthalamic nucleus deep brain stimulation driven by primary motor cortex γ2 activity in parkinsonian monkeys
Deep brain stimulation (DBS), applying electric stimulation to the subthalamic nucleus, can effectively treat advanced Parkinson’s disease. Both adaptive DBS (aDBS) driven by primary motor cortical activity and conventional constant DBS (cDBS) significantly decreased reaction and movement times in parkinsonian monkeys. The electric charge delivered with aDBS was lower than that with cDBS. aDBS is an effective therapeutic approach with lower electrical requirements.
Claustrum mediates bidirectional and reversible control of stress-induced anxiety responses
Researchers from Osaka University discovered a small group of brain cells in the claustrum of mice that bidirectionally controls stress-induced anxiety behaviors. Deactivation of these cells made mice more resilient against chronic stress. These findings could be the key to understanding the cause of stress-related disorders.
Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration
Tau present in the extracellular fluids has a critical role in the pathogenesis of tauopathies. The authors describe that glymphatic clearance of extracellular tau impacts tau accumulation and neurodegeneration. The study implicates glymphatic system in the pathophysiology of tauopathies.
A Flp-dependent G-CaMP9a transgenic mouse for neuronal imaging in vivo
The researchers developed a Rosa26 knockin mouse that expresses a green calcium indicator (G-CaMP9a) with fast kinetics and a high signal-to-noise ratio. This reporter mouse allows for the investigation of neuronal activity in defined cell populations and will facilitate dissecting complex dynamics of neural networks in vivo.
Brain/MINDS DATA PORTAL・Marmoset Gene Atlas: Notice of scheduled maintenance
Due to maintenance work, we will stop our system in following period:
Date (Japan time): February 24th (Thu), 1:30 p.m – 3:30 p.m
During the periods, Brain/MINDS DATA PORTAL・Marmoset Gene Atlas will not be available.
These schedules might vary depending on the situation.
Thank you for your understanding.
Multi-scale light microscopy/electron microscopy neuronal imaging from brain to synapse with a tissue clearing method, ScaleSF
The researchers have extended the applicability of tissue clearing techniques to EM. For this, they developed an ultrastructurally-preserved tissue clearing method, ScaleSF, and LM/EM dual labeling stable in the clearing protocol. Their imaging pipeline allows for deciphering brain-wide connectivity by simultaneous interrogation of the neural circuit structure and synaptic connectivity.
Distributed sensory coding by cerebellar complex spikes in units of cortical segments
With a fluorescence calcium sensor yellow cameleon, the researchers succeeded in measuring complex spike activity in over 20,000 Purkinje cells simultaneously in the mouse cerebellum. The results have shown that combining activity patterns in "olivocerebellar segments" as a whole performs distributed population coding, which represents sensory input in real-time.
Somatostatin-evoked Aβ catabolism in the brain: Mechanistic involvement of α-endosulfine-KATP channel pathway
The researchers identified a novel mechanism, by which amyloid β peptide (Aβ), a primary cause of Alzheimer’s disease (AD), is degraded in brain. This mechanism can be modified by diazoxide, a medication used to treat low blood sugar, implying a potential application of this mechanism to prevention and treatment of AD.
A genetically targeted reporter for PET imaging of deep neuronal circuits in mammalian brains
The researchers established a new method for PET imaging of the expression, chemogenetic manipulation, and intermolecular interaction of reporter proteins in the neural circuit of living animals. This technique may facilitate a broad spectrum of PET analyses of a mammalian brain circuit at molecular levels that were not previously applicable for technical reasons.
Functional and molecular characterization of a non-human primate model of autism spectrum disorder shows similarity with the human disease
In the cortex of a marmoset model of autism exposed to valproic acid in utero, genes associated with neurons and oligodendrocytes were down-regulated, and genes associated with microglia and astrocytes were up-regulated, as in human autism. However, the current major rodent models could only reproduce human autism in at most two of the four cell types of the brain. This confirms the prediction that primate autism models reproduce human autism better than rodent models by an objective method of transcriptome comparison.
Current Status of and Perspectives on the Application of Marmosets in Neurobiology
The common marmoset (Callithrix jacchus), a small New World primate, is receiving substantial attention in the neuroscience and biomedical science fields because its anatomical features, functional and behavioral characteristics, and reproductive features and its amenability to available genetic modification technologies make it an attractive experimental subject. This review outlines the progress of marmoset neuroscience research and summarizes both the current status (opportunities and limitations) of and the future perspectives on the application of marmosets in neuroscience and disease modeling.
A third-generation mouse model of Alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid β peptide
The researchers generated a new Alzheimer’s disease (AD) mouse model that more faithfully recapitulate pathology of AD patients compared to the previous ones. This new third-generation mouse model will help accelerate the elucidation of the disease mechanisms and development of disease-modifying therapies to treat AD.
Altered Dynamic Information Flow through the Cortico-Basal Ganglia Pathways Mediates Parkinson’s Disease Symptoms
By recording neuronal activity from a Japanese monkey model of Parkinson’s disease, the researchers have elucidated the neural mechanisms underlying parkinsonian symptoms. Disturbance of information flow through the “direct pathway” in the basal ganglia is responsible for parkinsonian symptoms, and its restoration has beneficial effects on the symptoms.
Global and Parallel Cortical Processing Based on Auditory Gamma Oscillatory Responses in Humans
The researchers demonstrated that auditory gamma oscillation is globally distributed among the temporal, parietal, and frontal cortices by using intracranial recordings implanted for the diagnostic purpose of the intractable epilepsy. Elucidation of the mechanism of gamma oscillation, which is decreased in psychiatric disorders such as schizophrenia, is expected to be useful for the development of future diagnosis and treatment.
Cellular-resolution gene expression profiling in the neonatal marmoset brain reveals dynamic species- and region-specific differences
Comprehensive expression analysis of genes associated with developmental disorders and psychiatric disorders in the common marmoset brain revealed that these genes are expressed in a specific brain region. Also, by comparing the expression patterns of the mouse and human brain, it was clarified that there are many common expression patterns between marmosets and humans.
Decreased DNA methylation at promoters and gene-specific neuronal hypermethylation in the prefrontal cortex of patients with bipolar disorder
The researchers performed comprehensive DNA methylation analyses of neurons from patients with bipolar disorder, and found that many genes were hypomethylated in patients, while genes important for neuronal function were hypermethylated. Differentially methylated regions in neurons were significantly enriched in genomic regions suggested by a genome-wide association study of bipolar disorder, indicating an association with genetic factors.
Cosmic dance in the awake brain – a cortical small-world network across multi-modal areas–
The researchers developed a fast and wide field-of-view two-photon microscopy with practically no optical aberrations. Combining high-performance large lenses and devices and a fast laser scanning mirror enables the recording of over 16,000 neurons in awake mice. Functional network analysis with single-cell resolution reveals the small-world behavior of the cortex.
Feature extraction to maximise generalisation capability – towards data prediction with high reliability and explainability
This work develops an unsupervised learning scheme that extracts the most informative components for predicting future inputs, which is called PredPCA (predictive principal component analysis). We demonstrate that PredPCA can extract hidden features important for predicting previously unseen videos. This scheme is potentially useful for automated driving and medical diagnosis.
Perampanel Inhibits α‐Synuclein Transmission in Parkinson's Disease Models
The researchers demonstrated that perampanel, an antiepileptic drug, inhibited the activity-dependent neuronal uptake of α-synuclein preformed fibrils via macropinocytosis and the subsequent development of α-synuclein inclusions in Parkinson’s disease models. Targeting neuronal activity with perampanel could represent a new therapeutic strategy for Parkinson’s disease.
Non-viral Induction of Transgene-free iPSCs from Somatic Fibroblasts of Multiple Mammalian Species
In this article, the researchers established a species-wide method for deriving transgene-free iPSCs, and discovered primary colony-forming cells showed a neural stem cell-like profile, named induced neural stem cell-like cells (iNSLCs).
GABAergic neuron-specific whole-brain transduction by AAV-PHP.B incorporated with a new GAD65 promoter
The researchers developed a new inhibitory neuron-specific promoter, GAD65 promoter. Intravenous infusion of blood-brain barrier-penetrating AAV-PHP.B expressing an enhanced green fluorescent protein under the control of the mGAD65 promoter transduced the whole brain in an inhibitory neuron-specific manner.
Optimization and Validation of Diffusion MRI-based Fiber Tracking with Neural Tracer Data as a Reference
The researchers utilized the diffusion MRI and neural tracer data of marmoset brains collected by the Brain/MINDS project to optimize the parameters of the algorithms for estimating whole-brain neural connections (connectome). The optimization allowed tracking of long-range fibers and raised an issue of parameter selection in connectomic studies.
Chromosome 22q11.2 deletion causes PERK-dependent vulnerability in dopaminergic neurons
Patients with 22q11.2 deletion syndrome (22q11.2DS) suffer from the onset risk for neuropsychiatric disorders over their lifetime. In this study, the researchers revealed “PRKR-Like Endoplasmic Reticulum Kinase-dependent vulnerabilities in dopaminergic neurons” as one of the molecular pathologies in brains of 22q11.2DS.
Setd1a Insufficiency in Mice Attenuates Excitatory Synaptic Function and Recapitulates Schizophrenia-Related Behavioral Abnormalities
The researchers demonstrated that mimicking a de novo mutation of the schizophrenia-risk gene SETD1A in mice induced various abnormal behaviors relevant to schizophrenia. Setd1a in postsynaptic neurons positively regulates excitatory synaptic transmission and structure in the medial prefrontal cortex through histone modification and regulating the expression of diverse synaptic genes.
Overlapping Projections of Neighboring Direct and Indirect Pathway Neostriatal Neurons to Globus Pallidus External Segment
Direct and indirect pathway medium-sized spiny neurons (dMSNs and iMSNs) in the neostriatum were selectively labeled with green and red fluorescent proteins by an AAV vector. Both pathways formed two axonal arborizations in the globus pallidus external segment, and dMSN axons converged in the center of iMSN projection fields.
Efficient whole brain transduction by systemic infusion of minimally purified AAV-PHP.eB
The researchers developed a simplified method for the production of AAV vectors, which drastically shortens the purification time from 1.5 days to 2 – 4 h. Systemic infusion of AAV-PHP.eB prepared using this method transduced whole brain. Transduction efficacy is comparable to the conventional method.
Machine-learning classification using neuroimaging data in schizophrenia, autism, ultra-high risk and first-episode psychosis
A machine learning classifier using neuroimaging data in schizophrenia, autism, and healthy controls classifies people with ultra-high risk and first episode psychosis into schizophrenia or healthy controls, but not autism.
Aberrant interaction between FUS and SFPQ in neurons in a wide range of FTLD spectrum diseases
Disruption of the FUS-SFPQ interaction was observed in a wide-range of FTLD spectrum diseases. Imbalanced ratio of tau isoforms regulated by FUS/SFPQ was observed in a wide-range of FTLD spectrum diseases as well. These results were not observed in Alzheimer disease, or Pick disease, indicating that impaired interactions of FUS/SFPQ is a common pathogenesis in FTLD spectrum diseases.
Human-specific ARHGAP11B increases size and folding of primate neocortex in the fetal marmoset
In this study, we generated transgenic fetal marmosets that express ARHGAP11B, a human specific gene. In the fetus brain of the transgenic marmoset, the number of bRG cells, a type of neural progenitor cell, were increased and led to an enlarged neocortex with a folded brain surface. Our study demonstrates that ARHGAP11B drives the changes in marmoset development which reflects those in the evolution of human neocortex.
Promoter activity-based case-control association study on SLC6A4 highlighting hypermethylation and altered amygdala volume in male patients with schizophrenia
The researchers revealed that increased DNA methylation in the serotonin transporter gene in schizophrenia and bipolar patients. The methylation level is inversely correlated with volume of the amygdala in patients. This work is expected to lead to a better understanding of the pathophysiology of schizophrenia and bipolar disorder.
Spatiotemporal Differentiation of MMN From N1 Adaptation: A Human ECoG Study
Mismatch negativity (MMN) is an electrophysiological response to a deviation from regularity. This human ECoG study differentiated auditory MMN from N1 adaptation spatiotemporally, suggesting that MMN is not merely a product of the neural adaptation of N1 and instead represents higher-order processes in auditory deviance detection.
Association between duration of breastfeeding based on maternal reports and dorsal and ventral striatum and medial orbital gyrus volumes in early adolescence
In this population-neuroimaging study in early adolescence, breastfeeding duration, that was assessed based on maternal and child health handbooks, was correlated with striatum and medial orbital gyrus volumes. Our findings shed light upon the importance of maternal breastfeeding for brain development related to emotional and motivational processing in early adolescence.
Opposing ventral striatal medium spiny neuron activities are shaped by striatal parvalbumin-expressing interneurons during goal-directed behaviors
The research group found that the upstream insular cortical silencing is converted to the downstream ventrolateral striatal activation in behaving animals. Parvalbumin-expressing interneurons in the ventrolateral striatum mediate this conversion through feedforward disinhibition.
Visualizing and Modulating Mitophagy for Therapeutic Studies of Neurodegeneration
Through investigation of the behaviors/fates of fluorescent proteins inside lysosomes, we developed a signa-retaining autophagy indicator (SRAI). We localized SRAI into mitochondria (mito-SRAI) to quantitatively measure mitophagy. We apply the new tool in a high-throughput in vitro screen for chemical inducers of mitophagy and in a mouse model of Parkinsons disease.
Versatile whole-organ/body staining and imaging based on electrolyte-gel properties of biological tissues
The researchers have successfully designed a novel three-dimensional staining and imaging technique, CUBIC-HistoVIsion, based on the physicochemical properties of biological tissues as an electrolyte gel. They demonstrated the staining of whole mouse brains, human brains, and whole marmoset bodies. This technique thus allows detailed analysis of brain circuits with cellular resolution.
Glucocerebrosidases catalyze a transgalactosylation reaction that yields a newly-identified brain sterol metabolite, galactosylated cholesterol
In this study, we discovered galactosylated cholesterol as a novel brain sterol metabolite. We found that glucocerebrosidases, whose involvement in galactose metabolism was not previously reported, catalyze a transgalactosylation reaction from galactosylceramide to cholesterol to synthesize galactosylated cholesterol.
Identification of calcium and integrin-binding protein 1 as a novel regulator of production of amyloid β peptide using CRISPR/Cas9-based screening system
Production and deposition of amyloid β peptide (Aβ) are the initial steps of pathogenesis of Alzheimer disease (AD). This study successfully identified CIB1 as a negative regulator of Aβ production by CRISPR/Cas9 screening. Furthermore, single-cell RNA-seq revealed the decreased CIB1 mRNA in early stage of AD patients, indicating that CIB1 is involved in AD pathogenesis.
Variants in saposin D domain of prosaposin gene linked to Parkinson’s disease
This study revealed the association between Parkinson’s disease (PD) and the prosaposin saposin D domain (PSAP-D). iPS cells from patients with PSAP-D mutation showed an accumulation of alpha-synuclein. Mouse with PSAP-D mutation showed dopaminergic neurodegeneration. Furthermore, two variants in the intronic regions of the PSAP-D in sporadic PD had significantly higher allele frequencies.
Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes
This study shows that POGZ, one of the most recurrently de novo mutated gene products in patients with ASD, regulates neuronal development and that ASD-related mutations on POGZ impair the POGZ function. These results provide insight into how de novo mutations on POGZ lead to impaired mature cortical network function.
Reduced auditory mismatch negativity reflects impaired deviance detection in schizophrenia
Patients with schizophrenia showed a selective impairment in deviance detection component of the mismatch negativity compared to healthy comparison subjects in the current study. Future investigation of the neural mechanisms underlying deviance detection will be important for clarifying the pathophysiology of schizophrenia and developing new treatments.
International Brain Initiative： An Innovative Framework for Coordinated Global Brain Research Efforts
The International Brain Initiative (IBI) has been established to coordinate efforts across existing and emerging national and regional brain initiatives. A NeuroView has been published in the Neuron highlighting the involvement and the new opportunities for global collaboration that are emerging between scientists, scientific societies, funders, industry, government, and society.
Visualization of AMPA receptors in living human brain with positron emission tomography
Research group led by professor Takuya Takahashi at Yokohama City University developed a positron emission tomography (PET) tracer for AMPA receptor, a most important synaptic protein, which enables us to visualize AMPA receptors in living human brain. This can lead to the elucidation of neuropsychiatric disorders, providing novel diagnostics and therapeutics.
Resting-state EEG beta band power predicts quality of life outcomes in patients with depressive disorders: a longitudinal investigation
In this study, resting-state electroencephalograms were taken in patients with depressive disorders. The high beta band power predicted quality of life 3 years later in the patients. The high beta band power may be a useful biomarker for depressive disorders.
Store-operated calcium channels are involved in spontaneous slow calcium oscillations in striatal neurons
Striatal neurons exhibit spontaneous slow Ca2+ oscillations due to Ca2+ release from the Ca2+-store. We show that store-operated calcium channels (SOCCs) exert a functional role and are involved in the slow Ca2+ oscillations in striatal GABAergic neurons. The present results indicate that SOCCs contribute to Ca2+ signaling in striatal GABAergic neurons.
α-Synuclein BAC transgenic mice exhibited RBD-like behaviour and hyposmia: a prodromal Parkinson’s disease model
We created prodromal Parkinson’s disease (PD) mice model exhibiting hyposmia and REM sleep behavior disorders (RBD) as well as α-synuclein deposition and mild dopaminergic cell loss. This mice model can contribute to the development of disease-modifying therapies and preventive treatments in the prodromal stage of PD.
Study finds common abnormalities in the white matter across multiple psychiatric disorders―schizophrenia and bipolar disorder share similar abnormalities
Mega-analyses indicated similar white matter microstructural abnormalities between schizophrenia and bipolar disorder in the limbic system, while autism spectrum disorder also shared abnormalities in the corpus callosum. Major depression showed a relative lack of white matter microstructural defects. Schizophrenia was unique in having defects in discrete neocortical tracks. This study was published in 『Molecular Psychiatry』
Visualization of brain activity in a neuropathic pain model using quantitative activity-dependent manganese magnetic resonance imaging
To elucidate brain regions associated with neuropathic pain, we conducted an activity mapping of a mouse model of neuropathic pain using quantitative activation-induced manganese-enhanced magnetic resonance imaging (qAIM-MRI). qAIM-MRI revealed increased neural activity in the limbic system and sensory-motor, piriform, and insular cortex. This is the first study to demonstrate whole-brain activity mapping in a neuropathic pain model.
Arm movements induced by noninvasive optogenetic stimulation of the motor cortex in the common marmoset
We improved a method of optogenetic cortical stimulation and induced overt forelimb movements in the common marmoset, a New World monkey. Our results open doors for noninvasive interrogation of motor circuits in behaving nonhuman primates to address which brain area drives hand/arm movements after learning or brain injury.
A Bayesian psychophysics model of sense of agency
Sense of agency (SoA) refers to the experience that one's own actions caused an external event. Here, the authors present a model of SoA in terms of optimal Bayesian cue integration taking into account reliability of action and outcome sensory signals and judging if the action caused the outcome.
Parkinson’s disease is a type of amyloidosis featuring accumulation of amyloid fibrils of α-synuclein
We confirmed, for the first time, that Lewy bodies contained amyloid fibrils using autopsied brains of Parkinson's disease patients. Collaborative research with the large-scale synchrotron radiation facility, SPring-8, enabled ultrastructural analysis of aggregates in brain sections. These new findings are expected to be applied to the development of diagnostic and therapeutic approaches for Parkinson's disease.
Alzheimer’s disease protein links plaques to cell death in mice
A new protein involved in Alzheimer’s disease (AD) has been identified by researchers at the RIKEN Center for Brain Science (CBS). CAPON may facilitate the connection between the two most well-known AD culprits, amyloid plaques and tau pathology, whose interactions cause brain cell death and symptoms of dementia. This latest finding from the Takaomi Saido group at RIKEN CBS uses a novel mouse model of AD.
The study was published in Nature Communications on June 3.
Rational Engineering of XCaMPs, a Multicolor GECI Suite for In Vivo Imaging of Complex Brain Circuit Dynamics
We here developed a multicolor GECI suite, "XCaMP", which enables to image high-frequency firing patterns, non-invasively measure hippocampal CA1 dynamics, and simultaneously record pre- and postsynaptic firing, or co-image neuronal activities in 4 distinct celltypes. XCaMPs will be useful for elucidating complex brain circuit dynamics in health and neuropsychiatric diseases.
Common Marmosets (Callithrix jacchus) Evaluate Third-Party Social Interactions of Human Actors But Japanese Monkeys (Macaca fuscata) Do Not
Human, who has cooperative society, can tell who has reciprocity and who does not, by observing others' interaction. This study showed that highly prosocial common marmosets have this ability, but despotic Japanese monkeys do not. These results suggest that common marmoset is a suitable animal model for studying human social disorder, such as autism.
Abnormal axon guidance signals and reduced interhemispheric connection via anterior commissure in neonates of marmoset ASD model
In the neonatal autism-model marmoset, we showed a significant reduction of anterior commissure, which connected bilateral social brains. Abnormal expression of axon guidance molecules mediating formation of anterior commissure were also observed in this animal-model. These features might be useful for early diagnosis and early intervention/ therapy of human autism.
Neuroethical Issues of the Brain/MINDS Project of Japan
The Brain/MINDS project aims to further understand the human brain and neuropsychiatric disorders through ‘‘translatable’’ biomarkers. Here, we describe the neuroethical issues of the project that have arisen from clinical data collection and the use of biological models of neuropsychiatric disorders.
Mismatch negativity (MMN) as a tool for translational investigations into early psychosis: a review
Mismatch negativity (MMN) reduction is one of the most robust findings in schizophrenia that is related with early psychosis, functional abilities and translatable into animal models. We reviewed clinical MMN research and basic research in animal models and human intracranial recording for understanding neural mechanism of MMN.
Gamma-band auditory steady-state response is associated with plasma levels of D-serine in schizophrenia: an exploratory study
We demonstrated that the gamma-band auditory steady-state response (ASSR), which is significantly impaired in patients with schizophrenia compared with healthy controls, is significantly correlated with plasma levels of D-serine, a co-agonist of the glycine binding site of N-methyl-D-aspartate (NMDA) receptor, in the schizophrenia group. These findings suggest that the gamma-band ASSR may reflect NMDA receptor function in schizophrenia.
A high-throughput neurohistological pipeline for brain-wide mesoscale connectivity mapping of the common marmoset
We developed a high-throughput neurohistological and computational pipeline to accurately map individual brains into a common reference atlas. This method uses a grid-based tracer injection strategy for systematic mesoscale connectivity mapping, providing the first detailed and large-scale presentation of a full resolution microscopic online database (http://marmoset.brainarchitecture.org/). Our method will lay a foundation for subsequent scientific outputs and help others establish their own workflows in the future.
Comparative Evaluation of Genetically Encoded Voltage Indicators
We compare the performance of recently developed genetically encoded voltage indicators (GEVIs) under multiple experimental conditions in vitro and in vivo. Each indicator has advantages and disadvantages, and no single GEVI is ideal for every experiment. The results provide a guide for choosing optimal GEVIs for specific applications.
Super-wide-field two-photon imaging with a micro-optical device moving in post-objective space
Recording the activity of neurons over large brain regions requires expanding the field of view of the optics without losing on spatial and temporal resolution. Here, this team reports a micro-opto-mechanical device that enables two-photon imaging across distant cortical areas around 6 mm apart in the mouse.
Monitoring and Updating of Action Selection for Goal-Directed Behavior through the Striatal Direct and Indirect Pathways
It remains unclear how direct and indirect pathways of the basal ganglia signal functional information for a goal-directed adaptive behavior. Combining electrophysiology and optogenetics in behaving rats, we found the direct pathway neurons reselect the same action after reward outcome, whereas indirect pathway neurons switch to the other action after no-reward outcome.
Calcium Transient Dynamics of Neural Ensembles in the Primary Motor Cortex of Naturally Behaving Monkeys
The research team led by Hideyuki Okano and Junichi Ushiba (Keio University) demonstrate calcium imaging from neuronal populations using a miniature fluorescence microscope in naturally behaving non-human primates (NHPs), common marmosets. This technique marks an advance beyond methods using fixed head positioning, which limits the study of complex, self-determined behaviors such as social interactions or fear/anxiety.
Ser46-Phosphorylated MARCKS Is a Marker of Neurite Degeneration at the Pre-Aggregation Stage in PD/DLB Pathology
MARCKS Phosphorylation at Ser46 reflects neurite degeneration and is a candidate marker for presymptomatic and preaggretaion pathology of Alzheimer’s disease. Here, we demonstrate the similar change in Parkinson’s disease and Dementia with Lewy body prior to alpha-synuclein aggregation, and suggest an ultra-early stage pathology shared by different groups of neurodegenerative diseases.
Anatomical templates of the midbrain ventral tegmental area and
substantia nigra for Asian populations
The ventral tegmental area (VTA) and substantia nigra (SN) are involved in dopaminergic brain functions. Given that there are no VTA or SN anatomical MRI templates for Asian people, we created these templates and showed suitability for Asian brains using anatomical and resting state functional MRI data.
Single-cell trajectory analysis of human homogenous neurons carrying a rare RELN variant
The research team led by Profs. Norio Ozaki (Nagoya University) and Hideyuki Okano (Keio University) revealed that a rare RELN variant, initially identified in a schizophrenic patient, causes a loss of directional stability during neuronal migration using human iPSCs generated from the patient. These findings are expected to contribute to understanding the molecular pathophysiology and/or developing drugs for mental disorders.
Arioka Y, Shishido E, Kubo H, Kushima I, Yoshimi A, Kimura H, Ishizuka K, Aleksic B, Maeda T, Ishikawa M, Kuzumaki N, Okano H, Mori D, Ozaki N: Single-cell trajectory analysis of human homogenous neurons carrying a rare RELN variant. Transl Psychiatry 8 (1):129, 2018
The 41st Annual Meeting of the Japan Neurosciene Society - International Symposium on Global Neuroscience Cooperation sponsored by Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS)
The 41st Annual Meeting of the Japan Neurosciene Society - International Symposium on Global Neuroscience Cooperation will take place on the following schedule.
Date: Sunday, July 29th , 2018
Location: Kobe Convention Center Kobe International Conference Center 3F Venue 7(504+505)
Norihiro Sadato (Department of System Neuroscience, National Institute for Physiological Sciences)
Kiyoto Kasai (Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo)
Hideyuki Okano (Department of Physiology, Keio University School of Medicine)
Takuya Hayashi (Division of Bio-Function Dynamics Imaging, RIKEN Center for Life Science Technologies)
Intellectual deterioration may play a key role in work disturbances in patients with schizophrenia.(in Japanese only)
Intellectual deterioration may play a key role in work disturbances in patients with schizophrenia. The study demonstrated probabilistic models to estimate work status in patients with schizophrenia based on relevant factors including intellectual deterioration. Feedback on work status would support social rehabilitation in patients with schizophrenia.
Tau steal the motivation in patients with Alzheimer’s disease.
The present study demonstrated that tau pathology in orbitofrontal cortex (OFC) may provoke focal neurotoxicity in OFC and the following disruption of the OFC-uncinate fasciculus network, leading to the emergence and progression of apathy in Alzheimer’s disease. The current data also raise the possibility that emerging antitau drugs would be efficacious for suppressing apathy.
In vivo wide-field calcium imaging of mouse thalamocortical synapses
with an 8K ultra-high-definition camera
By combining an 8K ultra-high-definition camera with spinning-disk one-photon confocal microscopy, we succeeded in imaging of activity of presynaptic axonal boutons of neurons projecting to the motor cortex in a behaving mouse. We detected axonal boutons with highly correlated activity over the 1 mm2 field.
News A research article "CRMP2-binding compound, edonerpic maleate, accelerates motor function recovery from brain damage. Science 360, 50–57 (2018)" was cited by Nature Reviews Drug Discovery.
ORIGINAL ARTICLE Abe, H. et al.
CRMP2‑binding compound, edonerpic maleate, accelerates motor function recovery from brain damage. Science 360, 50–57 (2018)
A spherical aberration-free microscopy system for live brain imaging
This article was published in "Biochemical and Biophysical Research Communications, Volume 500, Issue 2".
CRMP2-binding compound, edonerpic maleate, accelerates motor function recovery from brain damage
Brain damage such as stroke is a devastating neurological condition, which may severely compromise patient quality of life. No effective medication-mediated intervention to accelerate rehabilitation has been established. We found that a small compound, edonerpic-maleate, facilitated experience-driven synaptic glutamate AMPAreceptor delivery and resulted in the acceleration of motor function recovery after brain damage in a training-dependent manner.
Single-cell bioluminescence imaging of deep tissue in freely moving animals.
Bioluminescence is a natural light source based on luciferase catalysis of its substrate luciferin. We performed directed evolution on firefly luciferase using a red-shifted and highly deliverable luciferin analog to establish AkaBLI, an all-engineered bioluminescence in vivo imaging system.
This research result was published in "Science 23 Feb 2018".
Targeting Tyro3 ameliorates a model of PGRN-mutant FTLD-TDP via tau-mediated synaptic pathology.
Mutations in the progranulin (PGRN) gene cause a tau pathology-negative and TDP43 pathology-positive form of frontotemporal lobar degeneration (FTLD-TDP). We generated a knock-in mouse harboring the R504X mutation (PGRN-KI).
This research result was published on Nature Communications, 30 January 2018.
Role of subcortical structures on cognitive and social function in schizophrenia
Subcortical regions have a pivotal role in cognitive, affective, and social functions in humans, and the structural and functional abnormalities of the regions have been associated with various psychiatric disorders.
This research result was published on Scientific Reports, volume 8, 19 January 2018.
The Neural Basis of Changing Social Norms through Persuasion
We examined the neural basis of persuasion-induced changes in attitude toward and away from norms using fMRI. We measured brain activity while human participants were exposed to persuasive messages directed toward specific norms.
This research result was published on Scientific Reports volume 7, Article number: 16295, 24 November 2017.
Brain/MINDS Data Portal has been launched
“Neurobiology: learning from marmosets” in nature methods
Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) was introduced on Nature Methods
Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) was introduced by Newton
“Worldwide initiatives to advance brain research” in Nature Neuroscience
Brain/MINDS updated brochure
Press Release Calcium imaging reveals glial involvement in transcranial direct current stimulation-induced plasticity in mouse brain
Researchers at the RIKEN Brain Science Institute and collaborative project have discovered that the benefits of stimulating the brain with direct current come from its effects on astrocytes — not neurons — in the mouse brain. Published in Nature Communications, the work shows that applying direct current to the head releases synchronized waves of calcium from astrocytes that can reduce depressive symptoms and lead to a general increase in neural plasticity — the ability of neuronal connections to change when we try to learn or form memories.
Press Release Territories of heterologous inputs onto Purkinje cell dendrites are segregated by mGluR1-dependent parallel fiber synapse elimination
In cerebellar Purkinje cells (PCs), dendritic territories by climbing and parallel fiber (PF) innervations are segregated. Here, we show that the segregation of territories occurs as a result of elimination of PF synapses from the proximal dendrites, and that PF synapse elimination is controlled by the type 1 metabotropic glutamate receptor to protein kinase Cg signaling pathway in PCs.
Press Release Mirror Neurons in a New World Monkey, Common Marmoset
The research team including researchers from NCNP and RIKEN BSI found neurons in the ventrolateral frontal cortex with characteristic “mirror” properties quite similar to those in macaques. This finding suggests that mirror neurons occur in a common ancestor of New and Old World monkeys and its common properties are preserved during the course of primate evolution.
Press Release Long-term two-photon calcium imaging of neuronal populations with subcellular resolution in adult non-human primate
Researchers at the RIKEN Brain Science Institute in Japan have developed a new system for imaging the activity of individual neurons in the marmoset brain. Published in Cell Reports, the study shows how amplifying genetically encoded fluorescent signals with TET-inducible gene expression allows hundreds of individual neurons in the primate brain to be imaged simultaneously over a period of several months.
Press Release Two-photon fluorescence lifetime imaging of primed SNARE complexes in presynaptic terminals and β cells
It remains unclear how readiness for Ca2+ -dependent exocytosis depends on varying degrees of SNARE complex assembly. We demonstrated the SNARE assembly using ﬂuorescence lifetime imaging (FLIM) of Forster resonance energy transfer (FRET) between three pairs of neuronal SNAREs in presynaptic boutons and pancreatic beta cells in the islets of Langerhans.
Press Release In vivo two-photon imaging of dendritic spines in marmoset neocortex
The research team including researchers from RIKEN BSI and NIPS established a new method to visualize dendritic spines in the living marmoset brain. The method that utilizes two-photon microscopy in combination with virus vectors to enhance the expression of fluorescent signals makes it possible to study neural circuits in primate brains.
Press Release Real x-ray vision: see-through brains ready for study
Researchers at the RIKEN Brain Science Institute in Japan have developed a new technique for creating transparent tissue that can be used to illuminate 3D brain anatomy at very high resolutions. Published in Nature Neuroscience, the work showcases the new technology and its practical importance in clinical science by showing how it has given new insights into Alzheimer’s disease plaques.
Brain/MINDS Symposium in Neuroscience 2015 has been concluded successfully
Brain/MINDS Symposium in Neuroscience 2015
Fasting activates macroautophagy in neurons of Alzheimer’s disease mouse model but is insufficient to degrade amyloid-beta
The research team led by Prof. Okazawa (Tokyo Medical and Dental University) developed a new technique for observation
of autophagy in the brain in vivo, and revealed unexpected roles of autophagy in Alzheimer's disease
including the increase of intracellular Amyloid beta by starvation and circadian rhythm of neuronal autophagy activity.
Dr. H. Okano published the papaer “Brains, Genes, and Primates” in Neuron
Brains, Genes, and Primates
The special issue "Marmoset Neuroscience" has been published as the April issue of Neuroscience Research
Brain/MINDS: brain-mapping project in Japan- Philosophical Transactions B
Hideyuki Okano, Atsushi Miyawaki, Kiyoto Kasai
Brain/MINDS was relegated to Japan Agency for Medical Research and Development From April, 2015
Welcome! Our website is now open to the world.
Brain-mapping projects using the common marmoset
Hideyuki Okano, Partha Mitra