Biology subjects

Ichinohe, N.

Publications and source records attributed to Ichinohe, N..

14 recordsLinked to original sources

bioRxiv2025

Prenatal valproic acid-exposed autism marmosets increase mutual gaze and reduce inter-individual distance during dyadic social interactions

Autism spectrum disorder (ASD) is associated with differences in social interaction, including alterations in gaze behavior and interpersonal distance. Although most assessments of ASD remain individual-centric, emerging human studies indicate that social difficulties may arise from atypical dyadic coordination rather than from reduced social interest alone. We examined dyadic coordination in a non-human primate model of ASD, focusing on gaze and inter-individual distance during minimally constrained first encounters between prenatal valproic acid-exposed marmosets (VPA) and unexposed conspecifics (UE). Markerless pose estimation quantified frame-by-frame gaze direction and spacing, comparing VPA-UE with UE-UE dyads. VPA-UE pairs exhibited a higher proportion of mutual-gaze events than UE-UE pairs. VPA individuals showed more rapid looks in response to the partners gaze, yet spent less time looking at the partner when unobserved. VPA-UE dyads maintained shorter inter-individual distances than UE-UE dyads, and closer spacing was associated with decreased stability of mutual gaze. These findings reveal a dyadic coordination pattern in VPA-UE pairs, with rapid responsiveness coupled with distance-dependent fragility, paralleling features reported in human ASD. Our dyad-centric, markerless framework yields ecologically grounded readouts and potential intervention targets that leverage intact social responsiveness while accommodating altered spatial coordination.

neuroscience↗

bioRxiv2025

Hyperactivity is linked to elevated cortisol levels: comprehensive behavioral analysis in the prenatal valproic acid-induced marmoset model of autism

Hyperactivity is frequently observed in individuals with autism spectrum disorder (ASD) and significantly affects various aspects of life. This underscores the critical need for effective intervention methods tailored to the needs of individuals with ASD. Non-human primate models offer a promising avenue for elucidating the intricate interplay between ASD characteristics and developing individualized therapeutic strategies. This study examined the activity levels and behavioral dynamics in a prenatal valproic acid-induced (VPA) common marmoset model of ASD using ultraminiature data loggers, employing a more detailed approach to behavioral pattern analysis than is traditionally utilized. Although the overall activity levels showed no significant differences, the VPA group exhibited increased activity during specific hours, which is consistent with human ASD studies. Sample Entropy, a statistical measure used to quantify the regularity and unpredictability of time-series data, was higher during daytime in the VPA group, indicating reduced regularity in activity patterns akin to impulsive behavior in ASD. Subtle patterns that were not discernible through simple group comparisons were identified, highlighting the potential of this method as a valuable tool for the behavioral analysis of human ASD. Associations between erratic activity patterns, brief resting intervals, and elevated cortisol levels were observed, all of which correspond to stress phenotypes in individuals with ASD. The findings revealed variations in activity among the adult VPA groups, potentially linked to stress responses. Additionally, VPA juvenile marmosets showed increased locomotor activity in the social interaction test, complementing the adult behavioral findings and suggesting age-dependent manifestations of hyperactivity in this model. This non-human primate model effectively replicates real-world scenarios encountered by individuals with ASD exhibiting hyperactivity, thus holding significant implications for the advancement of personalized therapeutic strategies.

neuroscience↗

bioRxiv2025

The Brain/MINDS 3D Digital Marmoset Brain Atlas Version 2.0: Population-based Cortical Region Parcellations with Multi-Modal Standard Templates

We present our new Brain/MINDS 3D digital marmoset brain atlas version 2.0 (BMA2.0), a population-based 3D digital brain atlas of the common marmoset (Callithrix jacchus), designed to overcome the limitations of previous single subject atlases that are prone to structural biases arising from individual variation. Here, manually delineated cortical regions from 10 myelin-stained brains were used to create a generalized cortical parcellation. Newly refined subcortical regions from a previous atlas and a completely new cerebellum parcellation were also incorporated, resulting in a comprehensive whole brain parcellation for both hemispheres. To facilitate multimodal data analysis, the atlas package includes co-registered average templates for myelin and Nissl staining from the same individuals, ex vivo MRI T2 (91 individuals), and in vivo MRI T2 (446 individuals). Cortical flat maps and pial, cortical mid-thickness, and white matter surfaces are also provided. BMA2.0 provides a central brain space for multimodal data integration, spatial analysis, and comparative neuroscience. Standard formats and transformations are provided for easy integration into existing workflows and interoperability with existing atlases.

neuroscience↗

bioRxiv2025

Altered kinship vocal dynamics in marmosets with valproic acid-induced model of autism

Autism spectrum disorder (ASD) is characterised by social communication impairments and repetitive behaviours. Language deficits, including echolalia and restricted vocabulary, heighten caregiver stress and negatively affect the familys quality of life. Although animal models have advanced the understanding of individual ASD traits, their influence on kinship dynamics remains underexplored. To address this issue, we developed a clinically relevant ASD model in common marmosets by prenatal exposure to valproic acid (VPA) to produce ASD-like pups alongside their typically developing parents. We analysed 28,418 kinship calls from nine VPA-exposed and seven unexposed (UE) pups, along with their parents. Kinship vocalisations in VPA families exhibited significant alterations, including increased isolation calls, decreased affiliative calls, disruption of structured repetition patterns, and reduced developmental maturations. These deviations intensified after weaning, suggesting a link between social communicative stressors and altered family dynamics. Parental weight loss was correlated with kinship vocal deviations, potentially reflecting increased caregiver stress. This observation aligns with clinical reports of heightened stress in families raising children with ASD. VPA pups also displayed premature locomotion independence, indicating broader social and communication disruptions. These findings suggest that VPA marmosets are valuable models for investigating ASD-like traits in individuals and kinship-level dynamics. Kinship vocalisations provide critical insights into the interplay between communication impairments and caregiver stress, offering a promising avenue for developing non-invasive biomarkers for ASD-related challenges.

neuroscience↗

bioRxiv2024

Serial Two-Photon Tomography Imaging of the whole marmoset brain for neuroanatomical analyses

Serial Two photon tomography (STPT) imaging is a technique to image a mass of tissue in its three-dimensional shape by combining two-photon imaging with automatic stage control and microtome slicing. We successfully implemented this technique for tracing the axonal projections in the marmoset brain. Here we describe the detailed experimental procedures that realized reliable volumetric imaging of the whole marmoset brain. We also introduce auxiliary histological techniques including visualization of myelin structure by simple light reflection, and immunological detection of non-fluorescent anterograde and retrograde tracers, which further enhance the utility of STPT data.

neuroscience↗

bioRxiv2023

A reappraisal of the default mode and frontoparietal networks in the common marmoset brain

In recent years the common marmoset homologue of the human default mode network (DMN) has been a hot topic of discussion in the marmoset research field. Previously, the posterior cingulate cortex regions (PGM, A19M) and posterior parietal cortex regions (LIP, MIP) were defined as the DMN, but some studies claim that these form the frontoparietal network (FPN). We restarted from a neuroanatomical point of view and identified two DMN candidates: Comp-A (which has been called both the DMN and FPN) and Comp-B. We performed GLM analysis on auditory task-fMRI and found Comp-B to be more appropriate as the DMN, and Comp-A as the FPN. Additionally, through fingerprint analysis, a DMN and FPN in the tasking human was closer to the resting common marmoset. The human DMN appears to have an advanced function that may be underdeveloped in the common marmoset brain.

neuroscience↗

bioRxiv2023

Diverse Configurations of Erroneous Predictive Coding Across Brain Hierarchies in a Non-Human Primate Model of Autism Spectrum Disorder

In autism spectrum disorder (ASD), atypical sensory experiences are often associated with irregularities in predictive coding, which proposes that the brain creates hierarchical sensory models via a bidirectional process of predictions and prediction errors. However, it remains unclear how these irregularities manifest across different functional hierarchies in the brain. To address this, we used high-density electrocorticography (ECoG) in a non-human primate model of ASD during an auditory task with two layers of temporal control, and applied a quantitative model to quantify the integrity of predictive coding across two distinct hierarchies. Our results demonstrate that ASD is characterized by sensory hypersensitivity and unstable predictions across two brain hierarchies, and reveal the associated spatio-spectro-temporal neural signatures. Importantly, we observe diverse configurations of underestimation or overestimation of sensory regularities within these hierarchies. This work provides a multi-layered biomarker for ASD, contributing to our understanding of its diverse symptoms.

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

Imbalance of circuit plasticity and consolidation in autism model marmosets is adjusted by oxytocin administration

Alterations in the experience-dependent and autonomous elaboration of neural circuits are assumed to underlie autism spectrum disorder (ASD), though it is unclear what synaptic traits are responsible. Here, we used a valproic acid-induced ASD marmoset model, which shares common molecular features with idiopathic ASD, to investigate the structural dynamics of tuft dendrites of upper-layer pyramidal neurons and adjacent axons in the dorsomedial prefrontal cortex using two-photon microscopy. In model marmosets, dendritic spine turnover was upregulated, and spines were actively generated in clusters and subsequently survived more often than in control marmosets. Presynaptic boutons in local axons but not in commissural long-range axons showed hyperdynamic turnover in model marmosets, suggesting alterations in projection-specific plasticity. Intriguingly, nasal administration of oxytocin reduced the clustered spine emergence. Enhanced clustered spine generation, possibly unique to certain presynaptic partners, may be associated with ASD and may be a potential therapeutic target.

neuroscience↗

bioRxiv2022

Prenatal valproic acid-induced autism marmoset model exhibits higher salivary cortisol levels

Individuals with autism spectrum disorder (ASD) are exposed to a variety of stressors owing to their behavioral traits. Cortisol is a hormone typically associated with stress, and its concentration and response to stress are higher in individuals with ASD than in controls. The mechanisms underlying cortisol dysregulation in ASD have been explored in rodents. Although rodent models have successfully replicated the major symptoms of autism (i.e., impaired vocal communication, social interaction deficits, and restricted/repetitive patterns of behavior), evidence suggests that the hypothalamic-pituitary-adrenal (HPA) axis system differs between rodents and primates. We developed an ASD model in the common marmoset (Callithrix jacchus), a New World monkey, utilizing prenatal exposure to valproic acid (VPA). In this study, we collected the salivary cortisol levels in VPA-exposed and unexposed marmosets in the morning and afternoon. Our results revealed that both VPA-exposed and unexposed 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 in the morning, but not in the afternoon. These results are consistent with those of ASD in humans. Our results suggest that VPA-exposed marmosets show similarities not only in their behavioral patterns and brain pathologies, which we have reported previously but also in hormonal regulation, validating the usefulness of VPA-exposed marmosets also as a tool for ASD stress research.

neuroscience↗

bioRxiv2022

Reduced childhood social attention in an autism model marmoset predicts impaired social skills and inflexible behavior in adulthood

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication impairments and restricted and repetitive behavior. Although currently no established cure exists for ASD, early intervention to the deficits of attention to other individuals is expected to reduce the progression of ASD symptoms in later life. In order to confirm this hypothesis and improve early therapeutic interventions, it is desirable to develop an animal model of ASD in which social attention is impaired in childhood and ASD-like social behavior is observed in adulthood. However, rodent models of ASD have difficulty in recapitulating the deficit of gaze-based social attention. In this study, we examined the direction of gaze towards other conspecifics during childhood and puberty in a three-chamber test setting using an ASD model of marmoset produced by maternal exposure to valproic acid (VPA). We also conducted a reversal learning test in an adult VPA-exposed marmoset as an indicator of perseveration, a core symptom of ASD that has not previously been investigated in this model. The results showed that time spent gazing at other conspecifics was reduced in VPA-exposed marmosets in childhood, and adults displayed rigidity of response. In a longitudinal study using the same animals, deficits in social attention in childhood correlated well with ASD-like social disturbance (inequity aversion and third-party reciprocity) and inflexible behavior in adulthood. Since VPA-exposed marmosets exhibit these diverse ASD-like behaviors that are coherent from childhood to adulthood, VPA-exposed marmosets will provide a valuable opportunity to elucidate mechanisms for early intervention and contribute to the development of early therapies.

neuroscience↗

bioRxiv2022

Connectional architecture of the prefrontal cortex in the marmoset brain

Prefrontal cortex (PFC) has dramatically expanded in primates, but its organization and interactions with other brain regions are only partially understood. We performed high-resolution connectomic mapping of marmoset PFC and found two contrasting corticocortical and corticostriatal projection patterns: "patchy" projections that formed many columns of submillimeter scale in nearby and distant regions and "diffuse" projections that spread widely across the cortex and striatum. Parcellation-free analyses revealed representations of PFC gradients in these projections local and global distribution patterns. We also demonstrated column-scale precision of reciprocal cortico-cortical connectivity, suggesting that PFC contains a mosaic of discrete columns. Diffuse projections showed considerable diversity in the laminar patterns of axonal spread. In mice, columnar projections were much less conspicuous, underscoring the importance of the primate model. Altogether, these fine-grained analyses reveal important principles of local and long-distance PFC circuits in marmosets and provide insights into the functional organization of the primate brain.

neuroscience↗

bioRxiv2020

Distinct synaptic and related transcriptional abnormalities in neonatal, childhood and mature autism model of primate: implications for early-age therapeutic intervention

Autism spectrum disorder (ASD) is a synapse-related disorder that is diagnosed at around 3 years of age. Earlier intervention is desirable for better ASD prognosis; however, there is limited biological literature regarding early-age ASD. This study aimed to assess altered cortical synapses and gene expression in the ASD model marmoset. There were distinct phenotypes in the model animals across the neonate, childhood, and mature stages in the dorsomedial prefrontal cortex (Brodmann area 8b/9). At the neonate stage, synapses were underdeveloped and modulated genes were enriched with synaptogenesis- and ASD-related genes. At the childhood stage, synaptic features and gene expressions associated with experience-dependent circuit remodeling were altered in model animals. At the mature stage, there were synapse overdevelopment and altered gene expression similar to those in human ASD. These early synaptic phenotypes and altered gene expressions could be novel targets of efficient therapy from a young age.

neuroscience↗

bioRxiv2019

The NanoZoomer Connectomics Pipeline for Tracer Injection Studies of the Marmoset Brain

We describe our connectomics pipeline for processing tracer injection data for the brain of the common marmoset (Callithrix jacchus). Brain sections were imaged using a batch slide scanner (NanoZoomer 2.0-HT) and we used artificial intelligence to precisely segment the anterograde tracer signal from the background in the fluorescence images. The shape of each brain was reconstructed by reference to a block-face and all data was mapped into a common 3D brain space with atlas and 2D cortical flat map. To overcome the effect of using a single template atlas to specify cortical boundaries, each brain was cytoarchitectonically annotated and used for making an individual 3D atlas. Registration between the individual and common brain cortical boundaries in the flat map space was done to absorb the variation of each brain and precisely map all tracer injection data into one cortical brain space. We describe the methodology of our pipeline and analyze tracer segmentation and brain registration accuracy. Results show our pipeline can successfully process and normalize tracer injection experiments into a common space, making it suitable for large-scale connectomics studies with a focus on the cerebral cortex.

neuroscience↗