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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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) 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.
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.
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.
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.
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. 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.
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.
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.
ORIGINAL ARTICLE Abe, H. et al.
CRMP2‑binding compound, edonerpic maleate, accelerates motor function recovery from brain damage. Science 360, 50–57 (2018)
This article was published in "Biochemical and Biophysical Research Communications, Volume 500, Issue 2".
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.
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".
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.
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.
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
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.
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.
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.
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.
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
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
The special issue "Marmoset Neuroscience" has been published as the April issue of Neuroscience Research
Brain/MINDS was relegated to Japan Agency for Medical Research and Development From April, 2015
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