Biology subjects

Isa, T.

Publications and source records attributed to Isa, T..

14 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↗

bioRxiv2026

Transient focal inactivation of the primary visual cortex abolishes saccadic inhibition

Most organisms are perpetually engaged in an active-perception cycle: at any moment, planning, executing, or recovering from a given own movement. In the oculomotor system, such a cycle is under a powerful, reflexive, and short-latency interruptive influence by exogenous sensory stimulation, but the multitude of possible pathways eventually converging on the final oculomotor control gateway make it unknown how reflexive oculomotor inhibition takes place. Here we show that transient focal inactivation of the primary visual cortex abolishes visually-driven saccadic inhibition, suggesting an unequivocal dominance of the geniculostriate visual pathway over this robust behavioral reflex. Using chronic lesions, computational modeling, and fine-grained eye-movement analyses, we then show that latent visual signals bypassing the geniculostriate pathway are still present, but may not be as central as previously anticipated. These results recast classic views on visual-motor reflexes, and motivate functional and theoretical investigations of the multiplicity of parallel input-output loops in the brain.

neuroscience↗

bioRxiv2023

Future spinal reflex is embedded in primary motor cortex output

Mammals can execute intended limb movements despite the fact that spinal reflexes involuntarily modulate muscle activity. To generate appropriate muscle activity, the cortical descending motor output must coordinate with spinal reflexes, yet the underlying neural mechanism remains unclear. We simultaneously recorded activities in motor-related cortical areas, afferent neurons, and forelimb muscles of monkeys performing reaching movements. Motor-related cortical areas, primarily the primary motor cortex (M1), encode subsequent afferent activities attributed to forelimb movements. M1 also encodes a subcomponent of muscle activity evoked by these afferent activities, corresponding to spinal reflexes. Furthermore, selective disruption of the afferent pathway specifically reduced this subcomponent of muscle activity, suggesting that M1 output drives muscle activity not only through direct descending pathways but also through the "transafferent" pathway composed of descending plus subsequent spinal reflex pathways. Thus, M1 provides optimal motor output based on an internal forward model that prospectively computes future spinal reflexes.

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↗

bioRxiv2022

FT-GO: a multiplex fluorescent tyramide signal amplification system for histochemical analysis

Tyramide signal amplification (TSA) is a highly sensitive method for histochemical analysis. Previously, we reported a TSA system, BT-GO, for bright-filed imaging. Here, we develop FT-GO (Fluorochromized Tyramide-Glucose Oxidase) as a multiplex fluorescent TSA system. FT-GO involves peroxidase-catalyzed deposition of FT with hydrogen peroxide produced in enzymatic reaction between glucose and glucose oxidase. We showed that FT-GO enhanced immunofluorescence signals while maintaining low background signals. Compared with indirect immunofluorescence detections, FT-GO demonstrated a more widespread distribution of monoaminergic projection systems in mouse and marmoset brains. For multiplex labeling with FT-GO, we quenched Ab-conjugated peroxidase using sodium azide. We applied FT-GO to multiplex fluorescent in situ hybridization, and succeeded in labeling neocortical interneuron subtypes by coupling with immunofluorescence. FT-GO immunofluorescence further increased the detectability of an adeno-associated virus tracer. Given its simplicity and a staining with a high signal-to-noise ratio, FT-GO would provide a versatile platform for histochemical analysis.

neuroscience↗

bioRxiv2022

Staphylococcus aureus Breast Implant Infection Isolates Display Recalcitrance to Antibiotic Pocket Irrigants

Breast implant-associated infections (BIAIs) are a common complication following breast prostheses placement and account for [~]100,000 infections annually. The frequency, high cost of treatment, and morbidity make BIAIs a significant health burden for women. Thus, effective BIAI prevention strategies are urgently needed. This study tests the efficacy of one infection prevention strategy: the use of a triple antibiotic pocket irrigant (TAPI) against Staphylococcus aureus, the most common cause of BIAIs. TAPI, which consists of 50,000 U bacitracin, 1 g cefazolin, and 80 mg gentamicin diluted in 500 mL of saline, is used to irrigate the breast implant pocket during surgery. We used in vitro and in vivo assays to test the efficacy of each antibiotic in TAPI, as well as TAPI at the concentration used during surgery. We found that planktonically grown S. aureus BIAI isolates displayed susceptibility to gentamicin, cefazolin, and TAPI. However, TAPI treatment enhanced biofilm formation of BIAI strains. Furthermore, we compared TAPI treatment of a S. aureus reference strain (JE2) to a BIAI isolate (117) in a mouse BIAI model. TAPI significantly reduced infection of JE2 at 1- and 7-days post infection (dpi). In contrast, BIAI strain 117 displayed high bacterial burdens in tissues and implants, which persisted out to 14-dpi despite TAPI treatment. Lastly, we demonstrated that TAPI was effective against P. aeruginosa reference (PAO1) and BIAI strains in vitro and in vivo. Together, these data suggest S. aureus BIAI strains employ unique mechanisms to resist antibiotic prophylaxis treatment and promote chronic infection.

microbiology↗

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↗

bioRxiv2021

Multi-Scale LM/EM Neuronal Imaging from Brain to Synapse with a Tissue Clearing Method, ScaleSF

The mammalian brain is organized over sizes that span several orders of magnitude, from synapses to the entire brain. Thus, a technique to visualize neural circuits across multiple spatial scales (multi-scale neuronal imaging) is vital for deciphering brain-wide connectivity. Here, we developed this technique by coupling successive light microscope/electron microscope (LM/EM) imaging with an ultrastructurally-preserved tissue clearing method, ScaleSF. Our multi-scale neuronal imaging incorporates 1) brain-wide macroscopic observation, 2) mesoscopic circuit mapping, 3) microscopic subcellular imaging, and 4) EM imaging of nanoscopic structures, allowing seamless integration of structural information from the brain to synapses. We applied the technique to three neural circuits of two different species, mouse striatofugal, mouse callosal, and marmoset corticostriatal projection systems, and succeeded in the simultaneous interrogation of their circuit structure and synaptic connectivity in a targeted way. Our multi-scale neuronal imaging will significantly advance the understanding of brain-wide connectivity by expanding the scales of objects.

neuroscience↗

bioRxiv2020

The primary motor cortex prospectively computes the spinal reflex

The spinal reflex transforms sensory signals to generate muscle activity. However, it is unknown how the motor cortex (MCx) takes the spinal reflex into account when performing voluntary limb movements. We simultaneously recorded the activity of the MCx, afferent neurons, and forelimb muscles in behaving monkeys. We decomposed muscle activity into subcomponents explained by the MCx or afferent activity using linear models. Long preceding activity in the MCx, which is responsible for subsequent afferent activity, had the same spatiotemporal contribution to muscle activity as afferent activity, indicating that the MCx drives muscle activity not only by direct descending activation but also by trans-afferent descending activation. Therefore, the MCx implements internal models that prospectively estimate muscle activation via the spinal reflex for precise movement control.

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

Difference in context-dependency between orienting and defense-like responses induced by the superior colliculus

Previous electrical stimulation and lesion experiments have suggested that the crossed descending output pathway from the deeper layers (SCd) of superior colliculus (SC) controls orienting responses, while the uncrossed pathway mediates defense-like behavior. Here we extended these investigations by using selective optogenetic activation of each pathway in mice with channelrhodopsin 2 expression by double viral vector techniques. Brief photo-stimulation of the crossed pathway evoked short latency contraversive orienting-like head turns, while extended stimulation induced contraversive circling responses. In contrast, stimulation of uncrossed pathway induced short-latency upward head movements followed by longer-latency defense-like behaviors including retreat and flight. The novel discovery was that the evoked defense-like responses varied depending on the environment, suggesting that uncrossed output can be influenced by top-down modification of the SC or its downstream. This further suggests that the SCd-defense system can be profoundly modulated by non-motor, affective and cognitive components, in addition to direct sensory inputs.

neuroscience↗