Biology subjects

Onoe, H.

Publications and source records attributed to Onoe, H..

11 recordsLinked to original sources

bioRxiv2026

Adolescent prodromal phenotypes of psychiatric disorders: insights from a novel DISC1-perturbed monkey model

Neurodevelopmental deficits frequently lead to mild but significant adolescent social and cognitive changes, representing prodromal manifestations of adult-onset psychiatric disorders in a cross-disease manner. Although experimental medicine utilizes animal models to address the mechanisms, rodent brains lack critical structures for human higher brain functions such as the dorsolateral prefrontal cortex. To fill this translational gap, we generated monkeys with an impaired DISC1 gene locus, targeting the multifunctional protein essential for neurodevelopment and involved in transdiagnostic mental health risks. Here we analyze the F0 animals by minimizing mosaicism. At ages equivalent to human adolescence, these monkeys exhibited blunted responsiveness to social stimuli and increased internal drives, mirroring altered social behaviors in the prodromal stage in humans. Resting-state functional MRI data indicated disrupted global functional connectivity and reorganization of network topology, marked by a shift in the dominance of brain hubs from prefrontal regions to sensory areas. This primate model provides a unique platform for studying psychiatric disorders, such as schizophrenia, across the developmental trajectory.

neuroscience↗

bioRxiv2025

Bioengineered iPSC Vessels Recapitulate Human Vascular Physiological Function and Aging Phenotypes

Vascular aging contributes to multisystem diseases and limits health span. Although various animal models have contributed to aging research, their vasculatures poorly recapitulate human physiology. Even existing tissue-engineered blood vessels fail to mimic human vascular function and pathology, hindering translational advances in vascular aging studies. Here, we present a novel human physiological vascular model fabricated via the unique molding-induced circumferential alignment of human induced pluripotent stem cell (iPSC)-derived vascular smooth muscle cells with luminally seeded endothelial cells. This architecture enabled dynamic vasodiameter changes in response to vasoactive stimuli, including hormones and intraluminal pressure. Using iPSCs from a patient with Werner syndrome, the model recapitulated aging-associated phenotypes, such as hypercontractility and increased vascular compliance, possibly due to impaired nitric oxide bioavailability. Transcriptomic and metabolomic analyses revealed age-related dysregulation consistent with vascular senescence. As a key advantage of the vasculature, spatial transcriptomic analysis demonstrated upregulation of the aging marker CDKN1A near the lumen and downregulation of COL6A1 and TPM1 throughout the vessel. Treatment with mitochonic acid 5, a mitochondria-targeted compound, significantly reversed the aging phenotypes. These findings demonstrate that our engineered vascular model recapitulates key aspects of human vascular properties and provides a platform for mechanistic studies of vascular aging and drug discovery aimed at extending health span.

bioengineering↗

bioRxiv2023

Acquisition of Auditory Discrimination Mediated by Different Processes through Two Distinct Circuits Linked to the Lateral Striatum

The striatum, the central hub of cortico-basal ganglia loops, contains functionally heterogeneous subregions distinguished by the topographic patterns of structural connectivity. These subregions mediate various processes of procedural learning. However, it remains unclear when and how striatal subregions engage in the acquisition of sensory stimulus-based decision-making. A neuroimaging of regional brain activity shows that the anterior dorsolateral striatum (aDLS) and posterior ventrolateral striatum (pVLS) in rats are activated in a different temporal pattern during the acquisition phase of auditory discrimination. Chronic and transient pharmacologic manipulations show that the aDLS promotes the behavioral strategy driven by the stimulus- response association while suppressing that by the response-outcome association, and that the pVLS contributes to forming and maintaining the stimulus-response strategy. Electrophysiological recording indicates that subpopulations of aDLS neurons predominantly represent the outcome of specific behaviors at the initial period of discrimination learning, and that pVLS subpopulations encode the beginning and ending of each behavior according to the progress of learning. In addition, other subpopulations of striatal neurons indicate sustained activation after obtaining reward with distinct patterns reflecting the stimulus-response associations. Our findings demonstrate that aDLS and pVLS neurons integrate the new learning of auditory discrimination in spatiotemporally and functionally different manners.

animal behavior and cognition↗

bioRxiv2023

Chemogenetic activation of target neurons expressing insect Ionotropic Receptors in the mammalian central nervous system by systemic administration of ligand precursors

The IR-mediated neuronal activation (IRNA) technology allows stimulation of neurons in the brain that heterologously-express members of the insect chemosensory IR repertoire in response to their cognate ligands. In the current protocol, a ligand against the complex consisting of IR84a and IR8a subunits, phenylacetic acid (PhAc), is locally injected into a brain region, because of a low efficiency of PhAc for the delivery into the brain across the blood-brain barrier. To circumvent this invasive injection, here we developed a strategy for activation of target neurons in the brain through peripheral administration with a precursor of PhAc, methyl ester of PhAc (PhAcM), which is efficiently transferred into the brain and converted to the mature ligand by endogenous esterase activities. Peripheral administration of with PhAcM activated IR84a/IR8a-expressing neurons in the locus coeruleus of mice and increased the release of neurotransmitters in their nerve terminal regions. (S)-2-phenylpropionic acid ((S)-PhPr) was newly identified as a ligand for IR84a/IR8a, and peripheral administration with the methyl ester of PhPr with the S-configuration [(S)-PhPrM] caused similar effects on the target neurons. In addition, cell-type specific expression of IR84a/IR8a complex in the striatum of rats was unilaterally induced with a viral vector based on the Cre-loxP system. Peripheral administration with PhAcM or (S)-PhPrM stimulated the neurotransmitter release in the ipsilateral terminal regions of the vector-injected striatum, and PhAcM administration resulted in rotational behavior. Finally, we demonstrated that the metabolites of the peripherally administered-radiolabeled (S)-PhPrM accumulated in the IR84a/IR8a-expressing region in the striatum of the vector-injected rats. These results demonstrate that the systemic IRNA technique provides a powerful strategy for remote manipulation of diverse types of target neurons in the mammalian central nervous system.

neuroscience↗

bioRxiv2023

State-dependent role of interhemispheric pathway for motor recovery in primates

Whether and how the interhemispheric pathway is involved in post-injury motor recovery is controversial. Unidirectional chemogenetic blockade of the interhemispheric pathway from the contralesional to ipsilesional premotor cortex impaired dexterous hand movements during the early recovery stage after lesioning the lateral corticospinal tract in macaques. Furthermore, electrocorticographical recording showed that the low frequency band activity of the ipsilesional premotor cortex around the movement onset was decreased by the blockade during the early recovery stage, while it was increased by blockade during the intact state and the late recovery stage. These results demonstrate that the action of the interhemispheric pathway changed from inhibition to facilitation, leading to the involvement of the ipsilesional sensorimotor cortex in hand movements during the early recovery stage. The present study offers new insights into the state-dependent role of the interhemispheric pathway and a therapeutic target in the early recovery stage after lesioning of the corticospinal tract.

neuroscience↗

bioRxiv2023

Global disinhibition and corticospinal plasticity for drastic recovery after spinal cord injury

The induction of large-scale plasticity in the adult brain should be key for recovery from severe damage of the central nervous system. Here, drastic motor recovery was observed after subhemisection spinal cord injury in macaques that received intensive training and cortical electrical stimulation. During recovery, movement-related activity increased in ipsilesional sensorimotor areas and functional connectivity from ipsilesional to contralesional areas was strengthened. Electrical stimulation applied widely across bilateral sensorimotor areas induced muscle twitches in affected and intact forelimbs. The interhemispheric inhibition observed before injury was switched to facilitation. Furthermore, massive re-routing occurred in corticospinal axons from the contralesional motor cortex. Such global disinhibition and massive plasticity would open the workspace for the reorganization of motor networks to recruit novel areas for recovery. One Sentence SummaryGlobal disinhibition and corticospinal plasticity for drastic recovery after spinal cord injury in macaque monkeys.

neuroscience↗

bioRxiv2023

Reorganization of corticospinal projections after prominent recovery of finger dexterity from partial spinal cord injury in macaque monkeys

We investigated morphological changes in the corticospinal tract (CST) to understand the mechanism underlying recovery of hand function after lesion of the CST at the C4/C5 border in 7 macaque monkeys. All monkeys exhibited complete recovery of precision grip success ratio within a few months. The trajectories and terminals of CST from the contralesional (n = 4) and ipsilesional (n = 3) hand area of primary motor cortex (M1) were investigated at 5-29 months after the injury using an anterograde neural tracer, biotinylated dextran amine (BDA). Reorganization of the CST was assessed by counting the number of BDA-labeled axons and button-like swellings in the gray and white matters. Rostral to the lesion (at C3), the number of axon collaterals of the descending axons from both contralesional and ipsilesional M1 entering the ipsilesional and contralesional gray matter, respectively, were increased. Caudal to the lesion (at C8), axons originating from the contralesional M1, descending in the preserved gray matter around the lesion, and terminating in ipsilesional laminae VI/VII and IX were observed. In addition, axons and terminals from the ipsilesional M1 increased in the ipsilesional laminae VI/VII and IX after recrossing the midline, which were not observed in intact monkeys. Conversely, axons originating from the ipsilesional M1 and directed toward the contralesional laminae VI/VII and IX decreased. These results suggest that multiple reorganizations of the corticospinal projections to spinal segments both rostral and caudal to the lesion originating from bilateral M1 underlie a prominent recovery in long-term after spinal cord injury. SIGNIFICANCE STATEMENTPrevious studies have shown that dexterous finger movements recover prominently after lesion of the corticospinal tract (CST) at the mid-cervical segments through rehabilitative training in macaque monkeys. Here, we show reorganization of the CST including sprouting of axons originating from the contralesional and ipsilesional motor cortex in the gray matter both caudal and rostral to the lesion, including a re-direction of the CST to hand motoneurons in the monkeys 5-29 months after the lesion. Thus, multiple mechanisms of reorganization of CST axons underlie the recovery of impaired cortico-motoneuronal pathways for the long-term recovery of finger dexterity.

neuroscience↗

bioRxiv2023

Visuomotor activity associated with conditioned hand movements in premotor cortex of blindsight macaques

Some patients with damage to the primary visual cortex (V1) can respond to visual stimuli in their affected visual field, even though they report loss of visual awareness. This phenomenon is termed blindsight. To clarify the visuomotor transformation for hand movement control in the blindsight condition, we conducted multichannel electrocorticographical recordings from the ipsilesional frontal cortex including the frontal eye field, premotor, primary motor, and somatosensory areas during a delayed conditioned two-alternative forced choice manual response task with arbitrary assignment of push-pull manual responses in relation to the visual target cue locations before and after unilateral V1 lesioning in macaque monkeys. Before lesioning, the activity in the dorsal premotor cortex (PMd) showed short latency task-related {theta} ~ band responses that were significantly higher in the successful trials than in the error/miss trials at approximately 200 ms after target cue onset. At 2-3 months after lesioning, the monkeys regained a >80% success rate in response to appearance of the target cue in the lesion-affected visual field. At this stage, similar task-related {theta} ~ band target cue responses were observed in the PMd. Further, Granger causality from the PMd to the primary motor cortex was enhanced in the {theta} ~ , {gamma}, and high-{gamma} bands during the delay period of the task. These results suggested that the PMd plays a crucial role in mediating the visual signals for execution of hand movements in blindsight monkeys. Significant StatementBlindsight is a curious phenomenon in which the patients with damage to the primary visual cortex can still respond to visual stimulus in their blinded visual field despite loss of awareness. Previously we clarified the critical circuits for visually guided saccadic eye movements in blindsight macaques, however, those for the control of hand movements are still unclear. Here, we have recorded the multichannel electrocorticography in the frontal cortices during the conditioned manual response task and found that the dorsal premotor cortex exhibits task-related {theta} ~ band target cue responses at approximately 200 ms after the visual cue onset, similarly to the intact state. This is the first report of electrophysiological recordings in the frontal lobe of the blindsight subjects.

neuroscience↗

bioRxiv2021

Dissecting errors of the exogenously-driven and endogenously-driven saccadic tasks in the common marmoset

Various visual paradigms in oculomotor research have been used for studying the neural processes of eye movement, cognitive control, attention and neurological disorders. However, we usually analyse data collected from humans or over-trained non-human primates (NHPs), focusing only on successful trials, whereas error trials are usually excluded. These errors may repetitively show up in diseases, but their interpretation would be difficult due to the absence of records taken from healthy controls. In the current study, we aimed to analyse both correctly and incorrectly performed trials in both marmosets and humans. We trained marmosets to perform the gap saccade task and the oculomotor delayed response task. We also collected data from human subjects who performed identical tasks. We categorised error trials into three different groups, based on the time when an incorrect response occurred. We also interpreted possible causes by analysing saccade reaction time, saccade landing position and task history. Despite the rareness of human error, we found that marmosets and humans showed remarkably similar behaviour in error and success. We also found that successful saccades in the gap saccade task had always the highest peak velocity in both species, reflecting faster sensorimotor processing for correct responses. Our results suggest that marmosets and humans might share similar neural processing for successful and unsuccessful oculomotor behaviour, making them a suitable model for studying human behaviour. More importantly, analysing error trials in sync with successful ones will provide further insights into the cognitive and sensorimotor processes. NEW AND NOTEWORTHYThis is the first detailed report focusing on analysing both error and successful trials in oculomotor tasks. We proposed nomenclatures and a generalizable way of grouping and analysing error trials. Our results also indicate that marmosets can be a promising experimental candidate for oculomotor research because they replicate the saccade properties of error and success seen in humans. This will help set the baseline measurements to study brain disorders using NHP and understand the neural mechanisms from a different perspective.

neuroscience↗

bioRxiv2020

Common properties of visually-guided saccadic behavior and bottom-up attention in marmoset, macaque, and human

The saccade is a stereotypic behavior whose investigation improves our understanding of how primate brains implement precise motor control. Furthermore, saccades offer an important window into the cognitive and attentional state of the brain. Historically, saccade studies have largely relied on macaque. However, the cortical network giving rise to the saccadic command is difficult to study in macaque because relevant cortical areas lie in sulci and are difficult to access. Recently, a New World monkey - the marmoset - has garnered attention as an attractive alternative to macaque because of its smooth cortical surface, its smaller body, and its amenability to transgenic technology. However, adoption of marmoset for oculomotor research has been limited due to a lack of in-depth descriptions of marmoset saccade kinematics and their ability to perform psychophysical and cognitive tasks. Here, we directly compare free-viewing and visually-guided behavior of marmoset, macaque, and human engaged in identical tasks under similar conditions. In video free-viewing task, all species exhibited qualitatively similar saccade kinematics including saccade main sequence up to 25{degrees} in amplitude. Furthermore, the conventional bottom-up saliency model predicted gaze targets at similar rates for all species. We further verified their visually-guided behavior by training them with step and gap saccade tasks. All species showed similar gap effect and express saccades in the gap paradigm. Our results suggest that the three species have similar natural and task-guided visuomotor behavior. The marmoset can be trained on saccadic tasks and thus can serve as a model for oculomotor, attention, and cognitive research. New & noteworthyWe directly compared the results of video free-viewing task and visually-guided saccade tasks (step and gap) among three different species: the marmoset, macaque and human. We found that all species exhibit qualitatively similar saccadic behavior and bottom-up saliency albeit with small differences. Our results suggest that the marmoset possesses similar neural mechanisms to macaque and human for saccadic control, and it is an appropriate model animal to study neural mechanisms for active vision and attention.

animal behavior and cognition↗

bioRxiv2019

Enhanced emotional memory retrieval by chemogenetic activation of locus coeruleus norepinephrine neurons

The ability to retrieve memory store in response to the environment is essential for animal behavioral adaptation. Norepinephrine (NE)-containing neurons in the brain play a key role in the modulation of synaptic plasticity underlying various processes of memory formation. However, the role of the central NE system in memory retrieval remains unclear. In this study, we developed a neural chemogenetic activation strategy using insect olfactory Ionotropic Receptors (IRs), and used it for selective stimulation of NE neurons in the locus coeruleus (LC) in transgenic mice. Ligand-induced activation of LC NE neurons resulted in enhancement of the retrieval process of conditioned taste aversion, which was mediated through at least partly adrenergic receptors in the amygdala. Pharmacological blockade of LC activity confirmed the facilitative role of these neurons in memory retrieval. Our findings indicate that the LC-amygdalar pathway is required and sufficient for enhancing the recall of taste associative memory.

neuroscience↗