Biology subjects

Hirabayashi, T.

Publications and source records attributed to Hirabayashi, T..

13 recordsLinked to original sources

bioRxiv2025

Remote Cortical Network for Frontal Cognitive Symptoms derived from Tau Accumulation in Progressive Supranuclear Palsy

Progressive Supranuclear Palsy (PSP) is a neurodegenerative disorder characterized by impaired movement and frontal cognitive dysfunctions. While motor symptoms have been linked with subcortical tau deposits, network mechanisms underlying the frontal cognitive symptoms remain unclear because pathological tau accumulation is quite limited within the frontal cortex and heterogeneously distributed primarily in the subcortical regions. Here, we combined tau-PET using a high-contrast probe we have recently developed with normative connectome to resolve this issue. Tau-deposition sites were connected to a common cortical network that could not be identified through similar analyses based on atrophy detected by structural MRI. This network was predominantly overlapped with canonical action-mode and frontoparietal networks, which jointly support adaptive and goal-directed behavior. Critically, while the degree of subcortical primary tau deposition correlated with motor symptoms, only the degree of connectivity from tau-deposition sites to the derived cortical network explained the frontal cognitive deficits of individual patients. These findings suggest a novel mechanism that frontal cognitive impairments, but not motor deficits, in PSP are derived from remote effects of tau deposits, independent of atrophy, through the convergent connectivity to the identified common cortical network.

neuroscience↗

bioRxiv2024

Longitudinal assessment of DREADD expression and efficacy in the monkey brain

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) offer a powerful means for reversible control of neuronal activity through systemic administration of inert actuators. Because chemogenetic control relies on DREADD expression levels, understanding and quantifying the temporal dynamics of their expression is crucial for planning long-term experiments in monkeys. In this study, we longitudinally quantified in vivo DREADD expression in macaque monkeys using positron emission tomography with the DREADD-selective tracer [11C]deschloroclozapine (DCZ), complemented by functional studies. Twenty macaque monkeys were evaluated after being injected with adeno-associated virus vectors expressing the DREADDs hM4Di or hM3Dq, whose expression was quantified as changes in [11C]DCZ binding potential from baseline levels. Expression levels of both hM4Di and hM3Dq peaked around 60 days post-injection, remained stable for about 1.5 years, and declined gradually after two years. Significant chemogenetic control of neural activity and behavior persisted for about two years. The presence of protein tags significantly influenced expression levels, with co-expressed protein tags reducing overall expression levels. These findings provide valuable insights and guidelines for optimizing the use of DREADDs in long-term primate studies and potential therapeutic applications.

neuroscience↗

bioRxiv2023

Distinct roles of monkey OFC-subcortical pathways in adaptive behavior

To be the most successful, primates must adapt to changing environments and optimize their behavior by making the most beneficial choices. At the core of adaptive behavior is the orbitofrontal cortex (OFC) of the brain, which updates choice value through direct experience or knowledge-based inference. Here, we identify distinct neural circuitry underlying these two separate abilities. We designed two behavioral tasks in which macaque monkeys updated the values of certain items, either by directly experiencing changes in stimulus-reward associations, or by inferring the value of unexperienced items based on the tasks rules. Chemogenetic silencing of bilateral OFC combined with mathematical model-fitting analysis revealed that monkey OFC is involved in updating item value based on both experience and inference. In vivo imaging of chemogenetic receptors by positron emission tomography allowed us to map projections from the OFC to the rostromedial caudate nucleus (rmCD) and the medial part of the mediodorsal thalamus (MDm). Chemogenetic silencing of the OFC-rmCD pathway impaired experience-based value updating, while silencing the OFC-MDm pathway impaired inference-based value updating. Our results thus demonstrate a dissociable contribution of distinct OFC projections to different behavioral strategies, and provide new insights into the neural basis of value-based adaptive decision-making in primates.

neuroscience↗

bioRxiv2023

Multimodal imaging for validation and optimization of ion channel-based chemogenetics in nonhuman primates

Chemogenetic tools provide an opportunity to manipulate neuronal activity and behavior selectively and repeatedly in nonhuman primates (NHPs) with minimal invasiveness. Designer Receptors Exclusively Activated by Designer Drugs are one example that is based on mutated muscarinic acetylcholine receptors. Another channel-based chemogenetic system available for neuronal modulation in NHPs uses Pharmacologically Selective Actuator Modules (PSAMs), which are selectively activated by Pharmacologically Selective Effector Molecules (PSEMs). To facilitate the use of the PSAM/PSEM system, the selection and dosage of PSEMs should be validated and optimized for NHPs. To this end, we used a multimodal imaging approach. We virally expressed excitatory PSAM (PSAM4-5HT3) in the striatum and the primary motor cortex of two macaque monkeys, and visualized its location through positron emission tomography (PET) with the reporter ligand [18F]ASEM. Chemogenetic excitability of neurons triggered by two PSEMs (uPSEM817 and uPSEM792) was evaluated using [18F]fluorodeoxyglucose-PET imaging, with uPSEM817 being more efficient than uPSEM792. Pharmacological magnetic resonance imaging showed that increased brain activity in the PSAM4-expressing region began approximately 13 min after uPSEM817 administration and continued for at least 60 min. Our multimodal imaging data provide valuable information regarding the manipulation of neuronal activity using the PSAM/PSEM system in NHPs, facilitating future applications. Significance statementLike other chemogenetic tools, the ion channel-based system called Pharmacologically Selective Actuator Module/Pharmacologically Selective Effector Molecule (PSAM/PSEM) allows remote manipulation of neuronal activity and behavior in living animals. Nevertheless, its application in non-human primates (NHPs) is still limited. Here, we used multi-tracer positron emission tomography (PET) imaging and pharmacological magnetic resonance imaging (MRI) to visualize an excitatory chemogenetic ion channel (PSAM4-5HT3) and validate its chemometric function in macaque monkeys. Our results provide the optimal agonist, dose, and timing for chemogenetic neuronal manipulation, facilitating the use of the PSAM/PSEM system and expanding the flexibility and reliability of circuit manipulation in NHPs in a variety of situations.

neuroscience↗

bioRxiv2023

Visualization of trans homophilic interaction of clustered protocadherin in neurons

Clustered protocadherin (Pcdh) functions as a cell recognition molecule through the homophilic interaction in CNS. However, its interactions have yet not been visualized in neurons. We previously reported Pcdh{gamma}B2-FRET probes to be applicable only for cell lines. Herein, we newly designed Pcdh{gamma}B2-FRET probes by fusing FRET donor and acceptor fluorescent proteins to a single Pcdh{gamma}B2 molecule and succeeded in visualizing Pcdh{gamma}B2 homophilic interaction in cultured hippocampal neurons. The {gamma}B2-FRET probe localized in the soma and neurites, and FRET signals were observed at contact sites between neurites and eliminated by EGTA addition. Live imaging revealed that the FRET-negative {gamma}B2 signals were rapidly moving along neurites and soma, whereas the FRET-positive signals remained in place. We observed that the {gamma}B2 proteins at synapses rarely interact homophilically. The {gamma}B2-FRET probe would allow us to elucidate the function of the homophilic interaction and the cell recognition mechanism. Significance StatementWe visualize the Pcdh homophilic interaction using a novel FRET-based probe, and reveal that the homophilically interacting Pcdh proteins are found at contact sites between the neurites and roots of neurites from the soma, and are stable at a location. Additionally, in neurons, Pcdh proteins are located at synapses but rarely interact homophilically.

neuroscience↗

bioRxiv2023

Imbalanced expression of clustered protocadherins in pre- and post-synaptic compartments of CA1 pyramidal cells during hippocampal development

Clustered protocadherins (cPcdhs) are candidates for the neural circuit formation; however, the localization of cPcdhs in pre- and post-synaptic compartments has not been well characterized. Here we examined the localization of cPcdh{gamma} proteins in the mouse hippocampal CA1 region using light and electron microscopy. From postnatal day 7 to 21, cPcdh{gamma} immunosignals were detected in approximately 40-60% of spines of pyramidal cells. SDS-digested freeze-fracture replica labelling revealed that cPcdh{gamma} immunolabeling was found in 50% of PSD 95-positive postsynaptic profiles but only in less than 10% of vGluT1-positive pre-synaptic terminals. Interestingly, cPcdh{gamma}-positive pre-synaptic terminal was exclusively accompanied by cPcdh{gamma}-positive postsynaptic counterpart. In addition, electrophysiological investigations revealed that the miniature excitatory postsynaptic current frequency in cPcdh{gamma} cKO mice was significantly higher than that in wild-type mice. These results suggest that cPcdh{gamma} proteins are unequally distributed in the pre- and post-synaptic membrane during neural circuit development and regulate the number of excitatory synapses.

neuroscience↗

bioRxiv2023

Unsupervised decomposition and description of nonhuman primate behavior

Nonhuman primates (NHPs) exhibit complex and diverse behavior that typifies advanced cognitive function and social communication, but quantitative and systematical measure of this natural nonverbal processing has been a technical challenge. Specifically, a method is required to automatically segment time series of behavior into elemental motion motifs, much like finding meaningful words in character strings. Here, we propose a solution called SyntacticMotionParser (SMP), a general-purpose unsupervised behavior parsing algorithm using a non-parametric Bayesian model. Using three-dimensional posture-tracking data from NHPs, SMP automatically outputs an optimized sequence of latent motion motifs classified into the most likely number of states. When applied to behavioral datasets from common marmosets and rhesus monkeys, SMP outperformed conventional posture-clustering models and detected a set of behavioral ethograms from publicly available data. SMP also quantified and visualized the behavioral effects of chemogenetic neural manipulations. SMP thus has the potential to dramatically improve our understanding of natural NHP behavior in a variety of contexts.

neuroscience↗

bioRxiv2023

Prefronto-subcortical hypoconnectivity in schizophrenia: translation of critical pathways for symptom-related functions in nonhuman primates

Recent advances in genetic neuromodulation technology have enabled circuit-specific interventions in nonhuman primates (NHPs), thereby revealing the causal functions of specific neural circuits. Going forward, an important step is to use these findings to better understand neuropsychiatric and neurological disorders in humans, in which alterations in functional connectivity between brain regions are demonstrated. We recently identified the causal roles of the pathways from the dorsolateral prefrontal cortex (DLPFC) to the lateral part of the mediodorsal thalamic nucleus (MDl) and dorsal caudate nucleus (dCD) in working memory and decision-making, respectively. In the present study, we examined the resting-state functional connectivity of these two prefronto-subcortical circuits in healthy controls (HCs) and patients with various neuropsychiatric disorders including schizophrenia (SCZ), major depressive disorder (MDD), and autism spectrum disorders (ASD) in humans. We found that the functional connectivity of two pathways, DLPFC-MDl and DLPFC-dCD, was significantly reduced in the SCZ groups compared to HCs; however, this hypoconnectivity was not observed in the ASD or MDD groups, suggesting a disease-specific profile of altered prefronto-subcortical connectivity at rest. These results suggest that causal findings of pathway-specific functions revealed in NHPs can be effectively translated to identify the altered connectivity in neuropsychiatric disorders with related symptoms in humans.

neuroscience↗

bioRxiv2021

Chronic behavioral manipulation via orally delivered chemogenetic actuator in macaques

The chemogenetic technology referred to as designer receptors exclusively activated by designer drugs (DREADDs) offers reversible means to control neuronal activity for investigating its functional correlation with behavioral action. Deschloroclozapine (DCZ), a recently-developed highly potent and selective DREADDs actuator, displays a capacity to expand the utility of DREADDs for chronic manipulation without side-effects in nonhuman primates, which has not yet been validated. Here we investigated the pharmacokinetics and behavioral effects of orally administered DCZ in macaque monkeys. Pharmacokinetic analysis and positron emission tomography (PET) occupancy examination demonstrated that oral administration of DCZ yielded slower and prolonged kinetics, and that its bioavailability was 10-20% of that in the case of systemic injection. Oral DCZ (300-1000 g/kg) induced significant working memory impairments for at least 4 h in monkeys with hM4Di expressed in the prefrontal cortex. Repeated daily oral doses of DCZ consistently caused similar impairments over two weeks without discernible desensitization. Our results indicate that orally delivered DCZ affords a less invasive strategy for chronic but reversible chemogenetic manipulation of neuronal activity in nonhuman primates, and this has potential for clinical application.

neuroscience↗

bioRxiv2021

Chemogenetic dissection of the primate prefronto-subcortical pathways for working memory and decision-making

The primate prefrontal cortex (PFC) is situated at the core of higher brain functions by linking and cooperating with the caudate nucleus (CD) and mediodorsal thalamus (MD) via neural circuits. However, the distinctive roles of these prefronto-subcortical pathways remain elusive. Combining in vivo neuronal projection mapping with chemogenetic synaptic silencing, we reversibly dissected key pathways from PFC to the CD and MD individually in single monkeys. We found that silencing the bilateral PFC-MD projections, but not the PFC-CD projections, impaired performance in a spatial working memory task. Conversely, silencing the unilateral PFC-CD projection, but not the PFC-MD projection, altered preference in a free-choice task. These results revealed dissociable roles of the prefronto-subcortical pathways in working memory and decision-making, representing the technical advantage of imaging-guided pathway-selective chemogenetic manipulation for dissecting neural circuits underlying cognitive functions in primates.

neuroscience↗

bioRxiv2020

The Japan Monkey Centre Primates Brain Imaging Repository of high-resolution postmortem magnetic resonance imaging: the second phase of the archive of digital records

A comparison of neuroanatomical features of the brain between humans and our evolutionary relatives, nonhuman primates, is key to understanding the human brain system and the neural basis of mental and neurological disorders. Although most comparative MRI studies of human and nonhuman primate brains have been based on brains of primates that had been used as subjects in experiments, it is essential to investigate various species of nonhuman primates in order to elucidate and interpret the diversity of neuroanatomy features among humans and nonhuman primates. To develop a research platform for this purpose, it is necessary to harmonize the scientific contributions of studies with the standards of animal ethics, animal welfare, and the conservation of brain information for long-term continuation of the field. In previous research, we first developed an open-resource repository of anatomical images obtained using 9.4-T ex vivo MRI of postmortem brain samples from 12 nonhuman primate species, and which are stored at the Japan Monkey Centre. In the present study, as a second phase, we released a collection of T2-weighted images and diffusion tensor images obtained in nine species: white-throated capuchin, Bolivian squirrel monkey, stump-tailed macaque, Tibet monkey, Sykes monkey, Assamese macaque, pig-tailed macaque, crested macaque, and chimpanzee. Our image repository should facilitate scientific discoveries in the field of comparative neuroscience. This repository can also promote animal ethics and animal welfare in experiments with nonhuman primate models by optimizing methods for in vivo and ex vivo MRI scanning of brains and supporting veterinary neuroradiological education. In addition, the repository is expected to contribute to conservation, preserving information about the brains of various primates, including endangered species, in a permanent digital form.

neuroscience↗

bioRxiv2019

Deschloroclozapine: a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys

The chemogenetic technology Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) affords remotely reversible control of cellular signaling, neuronal activity and behavior. Although the combination of muscarinic-based DREADDs with clozapine-N-oxide (CNO) has been widely used, sluggish kinetics, metabolic liabilities, and potential off-target effects of CNO represent areas for improvement. Here we provide a new high affinity and selective agonist deschloroclozapine (DCZ) for muscarinic-based DREADDs. Positron emission tomography revealed that DCZ selectively bound to and occupied DREADDs in both mice and monkeys. Systemic delivery of low doses of DCZ (1 or 3 g/kg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injections of DCZ (100 g/kg) reversibly induced spatial working memory deficits in monkeys expressing hM4Di in the prefrontal cortex. DCZ represents the most potent, selective, metabolically stable and fast-acting DREADD agonist reported with utility in both mice and non-human primates for a variety of applications.

neuroscience↗

bioRxiv2019

Cold Vacuum Extracts of Double Cherry Blossom (Gosen-Sakura) Leaves Show Antitumor Activity

The present research examines the possibility of finding bio-molecular compounds from the double cherry blossom (termed as Gosen-Sakura of Gosen-city, Niigata-prefecture, Japan) leaves, which have been long used in the preparation of the traditional Japanese sweet (wagashi) - sakura-mochi. Based on its indicated anti-microbial properties historically, our study provides a new low temperature vacuum extraction method for extracting near natural form of water soluble leaf (cell) extracts from the Gosen-Sakura, and demonstrates the presence of some novel compound(s) with anti-tumor cell lines proliferation inhibitory affects through the MTT assay. To our knowledge, no reports exist on the sakura tree leaf (cell) extracts inhibiting tumor cell line growth. We further examined and compared the effects of known compounds with anti-tumor activity, coumarin and benzyl alcohol with Gosen-Sakura leaf extract; results lead us to hypothesize that the Gosen-Sakura leaf extract contains substance(s) other than the above 2 known compounds, with antitumor effect. Additionally, we speculate on the underlying mechanism of action of the Gosen-Sakura leaf extract by targeting cell division at the point of DNA synthesis and causing apoptosis. In conclusion, we present scientific evidence on the presence of a certain novel biomolecule(s), with anti-tumor activity, in the Gosen-Sakura leaf which has been long used as a Japanese - the sakura-mochi.

plant biology↗