Biology subjects

Takumi, T.

Publications and source records attributed to Takumi, T..

14 recordsLinked to original sources

bioRxiv2026

Neonatal social communication and single genes predict the variability of post-pubertal social behavior in a mouse model of paternal 15q11-13 duplication

Mental illnesses associated with high-risk copy number variations (CNVs) are characterized by incomplete penetrance and variable severity, with their underlying mechanisms remaining inadequately understood. We hypothesized that such phenotypic variability is evident from the neonatal stage and is, at least in part, attributable to individual differences in the expression levels of CNV-encoded genes in the brain. We conducted an analysis of the quantitative and functional structure of neonatal social communication, assessed post-pubertal social interaction, and evaluated the brain expression levels of genes within the same cohort of a mouse model of paternal human 15q11-13 duplication, a high-risk factor variably associated with neurodevelopmental disorders. Subsequently, computational methods were utilized to identify predictive variables for the variability of post-pubertal social interaction. Mice harboring the 15q11-13 duplication exhibited distinctive call sequences characterized by diverse connections, which lacked the incentive value necessary for effective social communication with mother mice. The neonatal call sequences and the expression levels of Magel2, along with, to a lesser extent, Herc2 and Ndn, in the prefrontal cortex of the 15q11-13 duplication model were predictive of post-pubertal social interaction. Our findings demonstrate that variability in post-pubertal social interaction--a dimensional characteristic of neurodevelopmental disorders--can be predicted by the variability of neonatal social communication and is influenced by the expression levels of specific CNV-encoded genes in the prefrontal cortex. This computational approach has the potential to predict the developmental trajectories of various dimensions of mental illness among CNV carriers in humans and to identify CNV-encoded driver genes in preclinical models, thereby providing potential mechanistic bases for the development of gene-based therapeutic strategies.

neuroscience↗

bioRxiv2025

Thalamo-insular pathway regulates tic generation via motor-limbic crosstalk

Tic disorders accompanied by premonitory urges are hallmark symptoms of Tourette syndrome (TS), yet the underlying neuronal mechanisms remain elusive. Here, we establish a mouse model of motor tics by unilateral striatal injection of a GABAA receptor antagonist. This model induces c-Fos activation in both motor and limbic structures, including the insular cortex (IC). Fiber photometry reveals tic-associated activity in IC as well as the primary motor cortex (M1). Viral tracing demonstrates that basal ganglia outputs from the substantia nigra pars reticulata are transmitted to IC via the intralaminar thalamic nuclei (ITN). Chemogenetic inhibition of IC or the thalamo-insular pathway suppresses tic-related cortical activity and alleviates tic-like behaviors. These findings identify IC as a key node in tic generation and highlight ITN as critical relay stations linking motor and limbic circuits. Aberrant thalamo-insular signaling thus contributes to the pathophysiology of tic disorders and represents a potential therapeutic target in TS. HighlightsO_LIc-Fos activation occurs in both motor and limbic structures in a mouse tic model C_LIO_LIBasal ganglia outputs are transmitted to insula via intralaminar thalamic nuclei C_LIO_LIChemogenetic inhibition of thalamo-insular pathway suppresses motor tics C_LIO_LIThalamo-insular inhibition diminishes tic-associated activity in primary motor cortex C_LI In briefAbnormal basal ganglia activity originating from the striatum drives dysfunction of the insular cortex via the intralaminar thalamic nuclei, leading to motor tics. Chemogenetic inhibition of this pathway suppresses tic-like behaviors, highlighting motor-limbic circuit pathology in tic disorders.

neuroscience↗

bioRxiv2025

Prucalopride ameliorates delayed gastrointestinal transit and social behaviour in a mouse model of 15q duplication syndrome

IntroductionChromosome 15q duplication syndrome (Dup15q) is a neurodevelopmental disorder linked to autism spectrum disorder (ASD), involving increased copies of the 15q11.2-q13 region. About 80% of individuals with Dup15q experience gastrointestinal (GI) dysfunction, including constipation. The duplicated region encodes GABA receptor A subunits, affecting GABAergic signalling, while reduced serotonin (5-HT) levels impair neuronal activity and social behaviour in a mouse model of Dup15q (15q dup). Given the importance of GABA and serotonin in the enteric nervous system (ENS), this study investigates GI dysfunction and neurotransmission in a Dup15q mouse model. MethodsColon RNA extracts were analysed for GABA receptor subunit and serotonin-associated gene expression using quantitative PCR. Total GI transit was assessed by Carmine red dye gavage. Ex vivo colonic motility was analysed via video imaging. The GABA receptor A antagonist Bicuculline was used to assess GABAergic signalling. Prucalopride, a 5-HT4 receptor (5HT4R) agonist, was administered for six days, and its effects on GI transit and social interaction were evaluated. Results15q dup mice exhibited elevated GABA receptor gene expression and reduced Tph2 and Htr4 expression in the colon. Total GI transit was delayed, and ex vivo colonic motility was slower and less extensive. Bicuculline further impaired colonic contractions, indicating enhanced GABAergic sensitivity. Prucalopride restored GI transit delays and improved social interaction, as evidenced by increased contact duration in social tests. ConclusionPrucalopride effectively restores GI function and improves social behaviour in 15q dup mice, demonstrating its therapeutic potential for addressing both GI dysfunction and behavioural deficits in 15q duplication syndrome.

physiology↗

bioRxiv2024

Dynamic population coding of social novelty in the insular cortex

The familiarity of socially interacting peers has a profound impact on behavior1-3, but little is known about the neuronal representations distinguishing familiar from novel conspecifics. The insular cortex (IC) regulates social behavior4-9, and our previous study revealed that neurons in the agranular IC (aIC) encode ongoing social interactions10. To elucidate how these neurons discriminate between interactions with familiar and novel conspecifics, we monitored neuronal activity in mice by microendoscopic calcium imaging during social recognition memory (SRM) and linear chamber social discrimination (LCSD) tasks. In the SRM task, repeated interactions with the same target activated largely nonoverlapping cells during each session. The fraction of cells associated with social investigation (social cells) decreased as the subject repeatedly interacted with the same target, whereas substitution of a second novel target and subsequent exchange with the first familiar target recruited more new social cells. In the LCSD task, the addition of a novel target to an area containing a familiar target transiently increased the number of cells responding to both targets, followed by an eventual increase in the number of cells responding to the novel target. These results support the view that the aIC dynamically encodes social novelty, rather than consistently encode social identity, by rapidly reorganizing the neural representations of conspecific information.

neuroscience↗

bioRxiv2024

Aberrant axon initial segment is an indicator for task-independent neural activity in autism model mice

Autism spectrum disorder (ASD) is a developmental disorder characterized by impairments in several communicative behaviors. Identification of biomarkers for ASD based on task-independent neural activity has been elusive. The axonal initial segment (AIS), located at the proximal part of the axon, is crucial for initiating action potentials (APs) and adaptable through activity-dependent AIS plasticity. In our study, we discovered decrease in AIS length in layer V pyramidal neurons (PyNs) of the prelimbic cortex (PrL) and increase in layer II/III PyNs in the somatosensory cortex of duplicated human 15q11-13 region (15q dup) ASD model mice. Electrophysiological studies using whole-cell patch-clamp recordings in the PrL revealed diminished ability to generate APs. We discovered lack of AIS plasticity in 15q dup mice under conditions of elevated potassium chloride. Retrograde tracing demonstrated that AIS shortening depends on the projection targets. These results indicate that activity-dependent aberrant AIS structures can serve as indicators of altered task-independent neural activity in ASD mouse models.

neuroscience↗

bioRxiv2023

End-to-end deep learning approach to mouse behavior classification from cortex-wide calcium imaging

Deep learning is a powerful tool for neural decoding, broadly applied to systems neuroscience and clinical studies. Interpretable and transparent models which can explain neural decoding for intended behaviors are crucial to identify essential features of deep learning decoders in brain activity. In this study, we examine the performance of deep learning to classify mouse behavioral states from mesoscopic cortex-wide calcium imaging data. Our convolutional neural network (CNN)-based end-to-end decoder combined with recurrent neural network (RNN) classifies the behavioral states with high accuracy and robustness to individual differences on temporal scales of sub-seconds. Using the CNN-RNN decoder, we identify that the forelimb and hindlimb areas in the somatosensory cortex significantly contribute to behavioral classification. Our findings imply that the end-to-end approach has the potential to be an interpretable deep learning method with unbiased visualization of critical brain regions. Author SummaryDeep learning is used in neuroscience, and it has become possible to classify and predict behavior from massive data of neural signals from animals, including humans. However, little is known about how deep learning discriminates the features of neural signals. In this study, we perform behavioral classification from calcium imaging data of the mouse cortex and investigate brain regions important for the classification. By the end-to-end approach, an unbiased method without data pre-processing, we clarify that information on the somatosensory areas in the cortex is important for distinguishing between resting and moving states in mice. This study will contribute to the development of interpretable deep-learning technology.

neuroscience↗

bioRxiv2023

DRACC1, a major postsynaptic protein, regulates the condensation of postsynaptic proteins via liquid-liquid phase separation

Numerous proteome analyses have been conducted on the postsynaptic density (PSD), a protein condensate beneath the postsynaptic membrane of excitatory synapses. Each has identified several hundred to thousands of proteins. While proteins with predictable functions have been well studied, functionally uncharacterized proteins are mostly overlooked. In this study, we perform a meta-analysis of the 35 PSD proteome datasets, including 5,869 proteins, identifying 97 uncharacterized proteins that appeared in multiple datasets. We focus on the top-ranked protein, FAM81A, renamed DRACC1. DRACC1 is expressed in forebrain neurons and enriched at the synapse. DRACC1 interacts with PSD proteins, including PSD-95, SynGAP, and NMDA receptors, and promotes liquid-liquid phase separation of those proteins. Consistently, the downregulation of DRACC1 in neurons causes a decrease in the size of PSD-95 puncta and the frequency of neuronal firing. Our results characterize DRACC1 as a novel synaptic protein facilitating the assembly of proteins within PSD. It also indicates the effectiveness of a meta-analytic approach of existing proteome datasets in identifying uncharacterized proteins.

neuroscience↗

bioRxiv2022

VR-based real-time imaging reveals abnormal cortical dynamics during behavioral transitions in a mouse model of autism

Functional connectivity (FC) can provide insight into cortical circuit dysfunction in neuropsychiatric disorders. However, dynamic changes in FC related to locomotion with sensory feedback remain unexplored. To investigate FC dynamics in locomoting mice, we developed mesoscopic Ca2+ imaging with a virtual reality (VR) environment. We find rapid reorganization of cortical FC in response to changing behavioral states. Using machine learning classification, behavioral states are accurately decoded. We then use our VR-based imaging system to study cortical FC in a mouse model of autism and find that locomotion states are associated with altered FC dynamics. Furthermore, we identify FC patterns involving the motor area as the most distinguishing features of the autism mice from wild-type mice during behavioral transitions, which might correlate with motor clumsiness in patients with autism. Our VR-based real-time imaging system provides invaluable information to understand FC dynamics linked to a behavioral abnormality of neuropsychiatric disorders.

neuroscience↗

bioRxiv2022

Developmental dynamics of the postsynaptic proteome to understand synaptic maturation and dysmaturation

The postsynaptic density (PSD) is a protein condensate composed of [~]1,000 proteins beneath the postsynaptic membrane of excitatory synapses. The number, shape, and plasticity of synapses are altered during development. However, the dynamics of synaptic protein composition across development have not been fully understood. Here we show alterations of PSD protein composition in mouse and primate brains during development. Proteins involved in synapse regulation are enriched in the differentially expressed (288 decreased and 267 increased) proteins on mouse PSD after a 2-week-old. We find that the changes in PSD protein abundance in mouse brains correlate with gene expression levels in postnatal mice and perinatal primates. This alteration of PSD composition is likely to be defective in the brains of mouse models or patients with autism spectrum disorder (ASD). Finally, we demonstrate that the brain of the common marmoset (Callithrix jacchus) changes PSD composition after the juvenile period. The alteration of PSD composition after 2-month-old is distinct from that observed in mice. Our results provide a comprehensive architecture of the remodeling of PSD composition across development, which may explain the molecular basics of synapse maturation and the pathology of psychiatric disorders, such as ASD.

neuroscience↗

bioRxiv2022

Species-Specific Formation of Paraspeckles in Intestinal Epithelium Revealed by Characterization of NEAT1 in Naked Mole-rat

Paraspeckles are mammalian-specific nuclear bodies built on the long noncoding RNA NEAT1_2. The molecular mechanisms of paraspeckle formation have been mainly studied using human or mouse cells, and it is not known if the same molecular components are involved in the formation of paraspeckles in other mammalian species. We thus investigated the expression pattern of NEAT1_2 in naked mole-rats (nNEAT1_2), which exhibit extreme longevity and lower susceptibility to cancer. In the intestine, nNEAT1_2 is widely expressed along the entire intestinal epithelium, which is different from the expression of mNeat1_2, that is restricted to the cells of the distal tip in mice. Notably, the expression of FUS, a FET family RNA binding protein, essential for the formation of paraspeckles both in humans and mice, was absent in the distal part of the intestinal epithelium in naked mole-rats. Instead, mRNAs of other FET family proteins EWSR1 and TAF15 were expressed in the distal region. Exogenous expression of these proteins in Fus-deficient murine embryonic fibroblast cells rescued the formation of paraspeckles. These observations suggest that nNEAT1_2 recruits different set of RNA binding proteins in a cell type-specific manner during the formation of paraspeckles in different organisms.

molecular biology↗

bioRxiv2022

Autism in a dish: ES cell models of autism with copy number variations reveal cell-type-specific vulnerability

Human genetics has identified numerous single nucleotide variations (SNVs) and copy number variations (CNVs) associated with autism spectrum disorders (ASD) and other psychiatric disorders. However, the lack of standardized biological resources impedes understanding of the common pathophysiology of ASD. Here, using next-generation chromosome engineering based on the CRISPR/Cas9 system, we established a biological resource including 65 genetically modified mouse embryonic stem cell (mESC) lines as genetic models of human SNVs and CNVs. To illustrate cell-type and CNV specific molecular features of ASD, we performed single-cell RNA sequencing (37,397 cells in total), morphological, and physiological analyses using 12 representative cell lines with CNVs highly associated with ASD. These results uncover gene ontology (GO) terms, canonical pathways, upstream regulators, and related neuropsychiatric disorders in a cell-type and CNV specific manner.

neuroscience↗

bioRxiv2021

Reciprocal differentiation via GABAergic components and ASD-related phenotypes in hES with 1q21.1 CNV

Copy number variations (CNVs) in the distal 1q21.1 region, both deletion (1q del) and duplication (1q dup), are associated with autism spectrum disorder, epilepsy and schizophrenia. Besides common phenotypes, 1q del and 1q dup manifest opposite clinical phenotypes--e.g., microcephaly in 1q del and macrocephaly in 1q dup. However, molecular and cellular mechanisms are still elusive. We generate isogenic human ES (hES) cell lines with reciprocal 1q21.1 CNVs using CRISPR/Cas9 system and differentiate them into 2-dimensional (2-D) neurons and 3-D cortical organoids. Our study recapitulates opposite organoid size and shows dosage-dependent differentiation changes i.e., more mature and GABAergic components in 1q del and more proliferative state in 1q dup. In contrast, both CNVs show hyperexcitability and altered expressions of glutamate system as common features. These results demonstrate that 1q21.1 CNVs dramatically affect cell fate in the early neurodevelopmental periods. This is the first isogenic model of hES CNVs and our findings provide new insights into the underlying mechanisms of neurodevelopmental disorders.

genomics↗

bioRxiv2020

Comprehensive Topographical Map of the Serotonergic Fibers in the Mouse Brain

It is well established that serotonergic fibers distribute throughout the brain. Abnormal densities or patterns of serotonergic fibers have been implicated in neuropsychiatric disorders. Although many classical studies have examined the distribution pattern of serotonergic fibers, most of them were either limited to specific brain areas or had limitations in demonstrating the fine axonal morphology. In this study, we utilize transgenic mice expressing GFP under the SERT promoter to map the topography of serotonergic fibers across the rostro-caudal extent of each brain area. We demonstrate previously unreported regional density and fine-grained anatomy of serotonergic fibers. Our findings include: 1) SERT fibers distribute abundantly in the thalamic nuclei close to the midline and dorsolateral areas, in most of the hypothalamic nuclei with few exceptions such as the median eminence and arcuate nuclei, and within the basal amygdaloid complex and lateral septal nuclei, 2) the source fibers of innervation of the hippocampus traverse through the septal nuclei before reaching its destination, 3) unique, filamentous type of straight terminal fibers within the nucleus accumbens, 4) laminar pattern of innervation in the hippocampus, olfactory bulb and cortex with heterogenicity in innervation density among the layers, 5) cortical labelling density gradually decreases rostro-caudally, 6) fibers traverse and distribute mostly within the gray matter, leaving the white fiber bundles uninnervated, and 7) most of the highly labelled nuclei and cortical areas have predominant anatomical connection to limbic structures. In conclusion, we provide novel, regionally specific insights on the distribution map of serotonergic fibers using transgenic mouse.

neuroscience↗

bioRxiv2019

Encoding of social exploration by neural ensembles in the insular cortex

The insular cortex participates in diverse complex brain functions including sociality, yet little is known about their cellular bases. Using microendoscopic calcium imaging of the agranular insular cortex (AI) in mice interacting with freely-moving and restrained social targets, we identified two subsets of AI neurons -a larger fraction of Social-ON cells and a smaller fraction of Social-OFF cells- that change their activity in opposite directions during social exploration. Social-ON cells included those that represented social investigation independent of location and consisted of multiple subsets, each of which were preferentially active during exploration under particular behavioral state or with a particular target of physical contact. These results uncover a previously unknown function of AI neurons in encoding conjunctive information on social behavior and suggest that AI may act to monitor the ongoing status of social exploration while an animal interacts with unfamiliar conspecifics.

neuroscience↗