Biology subjects

Uematsu, A.

Publications and source records attributed to Uematsu, A..

12 recordsLinked to original sources

bioRxiv2026

Iterative co-creation of harmonized human and non-human primate cellular and structural ontologies and 3D common coordinate frameworks for the basal ganglia

A major goal of the BRAIN Initiative Cell Atlas Network (BICAN) is to create a suite of foundational reference cell atlases and associated standards for human and non-human primate brains. Central to this goal is the creation of cross-species harmonized cellular taxonomies and structural parcellations with formal ontologies that can be mapped into 3D reference frameworks bridging neuroimaging and cellular and histological resolutions. We describe here an iterative approach, focused initially on the basal ganglia, to co-create structural and cellular ontologies in human, macaque and marmoset brains, including a Harmonized Ontology of Mammalian Brain Anatomy (HOMBA), and to map and refine structural parcellations into neuroimaging-based common coordinate frameworks. These references provide the framework for documenting and mapping all experimental sampling in BICAN, allowing analyses of cellular and molecular variation as a function of topographic position, and enabling comparisons of cellular, molecular and neuroimaging-based functional variation within and between primate species. HighlightsO_LIA hierarchical Harmonized Ontology of Mammalian Brain Anatomy (HOMBA) covering 2348 structures C_LIO_LIHOMBA-annotated 3D common coordinate frameworks (CCFs) of the basal ganglia across species C_LIO_LIHistologically informed 3D parcellation/atlas of 280 human subcortical structures indexed by HOMBA C_LIO_LIMapping and integration of structural, cellular and functional data with HOMBA and CCFs C_LI

neuroscience↗

bioRxiv2026

Postweaning social isolation induces gene expression alterations and histone modification dysregulations in nucleus accumbens (NAc) neurons

Lack of social interaction results in various behavioral abnormalities in rodents, including increased anxiety levels, altered sociability, and impaired cognitive ability. Epigenetic factors regulate gene expression, however, how they are involved in juvenile social isolation (jSI)-induced behavioral alterations remains largely unknown. Here, we focused on the nucleus accumbens (NAc), a critical brain region of the reward system that regulates motivation-related behaviors. We first performed RNA-seq on neuronal nuclei and found alterations in genes related to neuronal function, as well as in transcriptional and epigenetic regulation. Protein-protein interaction (PPI) analysis of differentially expressed genes (DEGs) showed that top key nodes among down-regulated genes include membrane receptors (Ntrk2, Grin3a, and Grik1) and an apoptosis regulator (Bcl2). To further investigate the association between jSI-induced gene expression alterations and histone modifications, we next performed CUT&Tag for four histone modifications (H3K4me1, H3K4me3, H3K27ac, and H3K27me3), and the results implied that epigenetic alterations may also play a role in neuronal function as well as transcriptional regulation. Reanalysis of previously published RNA-seq data on the manipulation of histone modification-associated factors (including Kdm6b, Brd4, and Setd1a) suggested that these enzymes are candidate regulators of jSI-induced gene expression alterations. Taken together, our comprehensive analysis characterizes the association between histone modification and jSI-related alterations of gene expression in the NAc of female mice.

neuroscience↗

bioRxiv2026

A neural substrate for resistance to change in the ventral hippocampus

Strong prior beliefs can render individuals resistant to change, even when outcomes contradict expectations, yet the neural mechanisms supporting such stability remain poorly understood. Here we show that the ventral hippocampus (vCA1) actively stabilizes inferred contextual state (belief) during aversive memory extinction in a behavior-dependent manner. Using in vivo calcium imaging, we identify a subset of vCA1 neurons that exhibit selective reductions in activity when expected aversive outcomes do not occur during extinction. Axonal calcium imaging further reveals that reduced signals are broadcast to basal amygdala, nucleus accumbens, and medial prefrontal cortex. Optogenetic manipulations demonstrate that these signals actively suppress extinction learning and promote persistence of defensive response. Computational modeling indicates that vCA1 omission-related signals reflect discrepancies between beliefs and observed omission of the expected outcome, thereby maintaining the aversive belief. Crucially, convergent evidence from calcium imaging, modelling, and closed-loop optogenetic manipulations reveals that vCA1 omission-related signals are specific to the period during which animals execute defensive behavior driven by their inferred aversive state. These findings identify a novel mechanism in vCA1 that stabilizes inferred aversive state despite changes in stimulus contingencies and suggest a key role of vCA1 in belief-based control of learning.

neuroscience↗

bioRxiv2026

A sensorimotor brain circuit for transforming aversive experiences into emotional states

Innately aversive experiences produce emotional states which control behavior as well as long term associative memories1-3. Brainstem regions engage innate defensive reactions1,3-7, but it is unclear how the nervous system transduces external aversive experiences into higher order, emotional representations in the forebrain to instruct learning and modulate behavior. The prevailing view is that the sensory properties of aversive experiences activate forebrain emotional processing1,3,8-10, but classical theories proposed that internal bodily reactions to unpleasant events produce feeling states11,12. Here we identify a brainstem cuneiform (CnF) circuit which conveys information about both the external sensory causes and internal motor reactions related to aversive events to the lateral/basal nuclei of the amygdala (LA/B), a brain region which stores emotional memories, to enhance ongoing defensive behaviors and regulate associative memory formation. Glutamatergic CnF neurons project directly to LA/B and receive afferent inputs from aversive-sensory and aversive-motor brain regions. Notably, LA/B neurons encode a sensorimotor state in response to noxious stimuli, with both sensory and motor features transmitted through the CnF-to-LA/B pathway. Finally, optogenetic perturbation experiments showed that during aversive experiences, the CnF-LA/B circuit instructs emotional memory formation and enhances the intensity of ongoing defensive behaviors. These findings reveal how the nervous system constructs an aversive sensorimotor state in the amygdala used for regulating the strength of emotional behaviors and producing memory formation. This demonstrates a clinically relevant brain mechanism for the regulation of emotional processing by both external traumatic events and the accompanying bodily reactions.

neuroscience↗

bioRxiv2025

Dietary amino acid manipulations in the common marmoset Callithrix jacchus impacts serum metabolites and FGF21 levels

Restricting dietary protein intake has metabolic and physiological benefits for animals. Rodent studies have identified the involvement of a hormone fibroblast growth factor 21 (FGF21), which is upregulated by sensing amino acid scarcity. However, to what extent this mechanism is conserved in primates remains elusive. Using common marmosets Callithrix jacchus as a non-human primate model, we demonstrate a protocol for protein restriction and dietary amino acid manipulation. Low protein diet induces a decrease in blood urea nitrogen, altered plasma amino acid profiles, and an increase in plasma FGF21. Supplementation of purified amino acids to the diet suppresses plasma features of protein restriction. Our data provide a dietary intervention technique in marmosets and an insight into the evolutionarily conserved mechanism of FGF21 induction during protein restriction.

physiology↗

bioRxiv2025

A neural circuit targeting technique for investigating functional input-output organization in the nervous system

Neurons communicate information across circuits and the function of cells in these circuits is determined by both the afferent inputs they receive and the efferent outputs they send to other brain regions1,2. To study the activity and function of specific neuronal populations, transneuronal anterograde3 and retrograde4-6 viral approaches have been employed to define neural circuit elements by inputs or outputs, respectively. However, what is missing is a way to study the function of neurons based on both their inputs and outputs. Applying a combination of multiple recombinases and transneuronal anterograde/retrograde viruses, we developed a technique called input-output Projection-based INtersectional Circuit-tagging Enabled by Recombinases (PINCER) to target specific neuronal cell types and investigate functional input-output organization in neural circuits. We show the logic and application of this technique with in vivo calcium imaging and optogenetic approaches to reveal the distinct functions and neural dynamics of connectivity defined neuronal populations in the amygdala for emotional processing. Specifically, PINCER allowed the parsing of valence and salience functions of the amygdala to reveal an input-output cell type selectively mediating aversive memory formation. This technique allows neuroscientists to identify novel subclasses of cells based on their combinatorial input-output anatomical connectivity, providing a tool for fine dissection of the functional properties of neural circuits.

neuroscience↗

bioRxiv2024

Charting Cortical-Layer Specific Area Boundaries Using Gibbs Ringing Attenuated T1w/T2w-FLAIR Myelin MRI

Cortical areas have traditionally been defined by their distinctive layer cyto- and/or myelo- architecture using postmortem histology. Recent studies have delineated many areas by measuring overall cortical myelin content and its spatial gradients using the T1w/T2w ratio MRI in living primates, including humans. While T1w/T2w studies of areal transitions might benefit from using the layer profile of this myelin-related contrast, a significant confound is Gibbs ringing artefact, which produces signal fluctuations resembling cortical layers. Here, we address these issues with a novel approach using cortical layer thickness-adjusted T1w/T2w-FLAIR imaging, which effectively cancels out Gibbs ringing artefacts while enhancing intra-cortical myelin contrast. Whole-brain MRI measures were mapped onto twelve equivolumetric layers, and layer-specific sharp myeloarchitectonic transitions were identified using spatial gradients resulting in a putative 182 area/subarea partition of the macaque cerebral cortex. The myelin maps exhibit notably high homology with those in humans, suggesting cortical myelin shares a similar developmental program across species. Comparison with histological Gallyas myelin stains explains over 80% of the variance in the laminar T1w/T2w-FLAIR profiles, substantiating the validity of the method. Altogether, our approach provides a novel, noninvasive means for precision mapping layer myeloarchitecture in the primate cerebral cortex, advancing the pioneering work of classical neuroanatomists.

neuroscience↗

bioRxiv2024

Bidirectional emotional regulation through prefrontal innervation of the locus coeruleus

Traumatic experiences produce powerful emotional memories which can subsequently be enhanced or reduced through cognitive control mechanisms. Noradrenaline from the brainstem locus coeruleus (LC) is activated during aversive emotion-inducing experiences and upregulated in individuals suffering from anxiety and trauma related disorders. The medial prefrontal cortex (mPFC) participates in cognitive and emotional control processes such as production of learned defensive responses and suppression of aversive memories through extinction. However, it is unclear whether or how distinct mPFC regions influence the LC to regulate learned emotional responding. Using viral based anatomical tracing techniques, we found that the LC receives topographically organized projections from the prelimbic (PL) and infralimbic (IL) subregions of mPFC. Furthermore, optogenetic approaches revealed that PL and IL inputs to LC are required to inhibit or facilitate, respectively, the extinction of aversive memories. Moreover, LC-projecting neurons in PL and IL exhibited distinct activity patterns during extinction learning, with IL-to-LC neurons displaying sustained, sensory cue-evoked activation, while activity in PL-to-LC inputs is elevated during periods of externally and internally generated aversive emotional responding. Together, these results demonstrate that mPFC subregions bidirectionally regulate extinction of emotional memories through differential modulation of the LC-noradrenaline system.

neuroscience↗

bioRxiv2022

Whole-brain afferent input mapping to functionally distinct brainstem noradrenaline cell types

The locus coeruleus (LC) is a small region in the pons and the main source of noradrenaline (NA) to the forebrain. While traditional models suggested that all LC-NA neurons project indiscriminately throughout the brain, accumulating evidence indicates that these cells can be heterogeneous based on their anatomical connectivity and behavioral functionality and exhibit distinct coding modes. How LC-NA neuronal subpopulations are endowed with unique functional properties is unclear. Here, we used a viral-genetic approach for mapping anatomical connectivity at different levels of organization based on inputs and outputs of defined cell classes. Specifically, we studied the whole-brain afferent inputs onto two functionally distinct LC-NA neuronal subpopulations which project to amygdala or medial prefrontal cortex (mPFC). We found that the global input distribution is similar for both LC-NA neuronal subpopulations. However, finer analysis demonstrated important differences in inputs from specific brain regions. Moreover, sex related differences were apparent, but only in inputs to amygdala-projecting LC-NA neurons. These findings reveal a cell type and sex specific afferent input organization which could allow for context dependent and target specific control of NA outflow to forebrain structures involved in emotional control and decision making.

neuroscience↗

bioRxiv2022

Multi-modal brain magnetic resonance imaging database covering marmosets with a wide age range

Magnetic resonance imaging (MRI) is a noninvasive neuroimaging method beneficial for the identification of normal developmental and aging processes and data sharing. Marmosets have a relatively shorter life expectancy (approximately 10 years) than other primates, including, humans because they grow and age faster. Hence, the common marmoset model is effective in aging research. The current study investigated the aging process of the marmoset brain and provided an open MRI database on marmosets with a wide age range. The Brain/MINDS Marmoset Brain MRI Dataset contains brain MRI information on 216 marmosets aged between 1 and 10 years. During its release date, it is the largest public dataset worldwide. Further, it comprises multi contrast MRI images. In addition, 91 of 216 animals have corresponding ex vivo high-resolution MRI datasets. Our MRI database, which is available at the Brain/MINDS Data portal might help understand the effects of different factors, such as age, sex, body size, and fixation, on the brain. Moreover, it can contribute to and accelerate brain science studies worldwide.

neuroscience↗

bioRxiv2022

Anatomical variability, multi-modal coordinate systems, and precision targeting in the marmoset brain

Localising accurate brain regions needs careful evaluation in each experimental species due to their individual variability. However, the function and connectivity of brain areas is commonly studied using a single-subject cranial landmark-based stereotactic atlas in animal neuroscience. Here, we address this issue in a small primate, the common marmoset, which is increasingly widely used in systems neuroscience. We developed a non-invasive multi-modal neuroimaging-based targeting pipeline, which accounts for intersubject anatomical variability in cranial and cortical landmarks in marmosets. This methodology allowed creation of multi-modal templates (MarmosetRIKEN20) including head CT and brain MR images, embedded in coordinate systems of anterior and posterior commissures (AC-PC) and CIFTI grayordinates. We found that the horizontal plane of the stereotactic coordinate was significantly rotated in pitch relative to the AC-PC coordinate system (10 degrees, frontal downwards), and had a significant bias and uncertainty due to positioning procedures. We also found that many common cranial and brain landmarks (e.g., bregma, intraparietal sulcus) vary in location across subjects and are substantial relative to average marmoset cortical area dimensions. Combining the neuroimaging-based targeting pipeline with robot-guided surgery enabled proof-of-concept targeting of deep brain structures with an accuracy of 0.2 mm. Altogether, our findings demonstrate substantial intersubject variability in marmoset brain and cranial landmarks, implying that subject-specific neuroimaging-based localization is needed for precision targeting in marmosets. The population-based templates and atlases in grayordinates, created for the first time in marmoset monkeys, should help bridging between macroscale and microscale analyses. HighlightsO_LIAchieved sub-millimeter localization accuracy of subject-wise brain region C_LIO_LIPropose a dedicated non-invasive multi-modal subject-specific registration pipeline C_LIO_LIConstruct brain coordinate system in AC-PC and grayordinate spaces C_LIO_LIEstablish multi-modal MRI and CT brain and cortical templates, MarmosetRIKEN20 C_LIO_LIQuantify intersubject variabilities in marmoset brain C_LIO_LISignificant bias and uncertainty exist in marmoset stereotactic positioning C_LI

neuroscience↗

bioRxiv2020

Brain/MINDS Beyond Human Brain MRI Study: Multi-Site Harmonization for Brain Disorders Throughout the Lifespan

Psychiatric and neurological disorders are afflictions of the brain that can affect individuals throughout their lifespan. Many brain magnetic resonance imaging (MRI) studies have been conducted; however, imaging-based biomarkers are not yet well established for diagnostic and therapeutic use. This article describes an outline of the planned study, the Brain/MINDS Beyond human brain MRI project (FY2018 [~] FY2023), which aims to establish clinically-relevant imaging biomarkers with multi-site harmonization by collecting data from healthy traveling subjects (TS) at 13 research sites. Collection of data in psychiatric and neurological disorders across the lifespan is also scheduled at 13 sites, whereas designing measurement procedures, developing and analyzing neuroimaging protocols, and databasing are done at three research sites. The Harmonization protocol (HARP) was established for five high-quality 3T scanners to obtain multimodal brain images including T1 and T2-weighted, resting state and task functional and diffusion-weighted MRI. Data are preprocessed and analyzed using approaches developed by the Human Connectome Project. Preliminary results in 30 TS demonstrated cortical thickness, myelin, functional connectivity measures are comparable across 5 scanners, providing high reproducibility and sensitivity to subject-specific connectome. A total of 75 TS, as well as patients with various psychiatric and neurological disorders, are scheduled to participate in the project, allowing a mixed model statistical harmonization. The HARP protocols are publicly available online, and all the imaging, demographic and clinical information, harmonizing database will also be made available by 2024. To the best of our knowledge, this is the first project to implement a rigorous, prospective harmonization protocol with multi-site TS data. It explores intractable brain disorders across the lifespan and may help to identify the disease-specific pathophysiology and imaging biomarkers for clinical practice.

neuroscience↗