Biology subjects

Nakahara, K.

Publications and source records attributed to Nakahara, K..

12 recordsLinked to original sources

bioRxiv2026

Human parietal retrieval states prioritize an absent temporal reference to reconstruct event order

How the brain judges when something happened is thought to involve reconstruction--deriving temporal judgments from information recovered from memory rather than simply reading out a fixed temporal code. Testing this has been difficult because conventional tasks present both compared items at retrieval, so reinstatement could reflect cue processing as much as memory recovery. Here we dissociated what a judgment requires from what its cue supplies: during fMRI scanning, participants (n = 55) judged a targets temporal position relative to a milestone that was never shown at retrieval. We found that retrieval patterns in the precuneus and angular gyrus resembled the absent milestone more than the target, a bias strongest in the precuneus. Moreover, trial-by-trial similarity to the encoded path linking milestone to target--rather than to either alone--predicted correct judgments independently of retrieval activation. Human parietal retrieval is thus configured more by what a judgment requires than by what the cue supplies, providing content-specific representational evidence for reconstructive temporal-order memory.

neuroscience↗

bioRxiv2026

Beyond Temporary Scaffolding: Persistent Hippocampal Engagement and Brain-Wide Network Reorganization in Remote Memory Consolidation

The standard model of memory consolidation posits a temporary role for the hippocampus. We challenge this view by combining a novel face-name associative memory task with cross-modal decoding of fMRI data. We demonstrate that the hippocampus remains persistently engaged in representing both recent and remote memories, with distinct subregional contributions: recent memories were represented in the right posterior hippocampus, whereas remote memories additionally recruited the left anterior hippocampus. This sustained hippocampal involvement occurred alongside a large-scale network reorganization. Remote memory retrieval was accompanied by increased global connectivity among semantic regions, yet the hippocampus itself did not emerge as a major hub. Instead, network hubs shifted from the medial prefrontal cortex (mPFC) for recent memories to the mPFC and bilateral inferior parietal lobule for remote memories. These findings reveal a dynamic process in which the hippocampus preserves long-lasting representational functions while the broader memory network undergoes extensive reorganization.

neuroscience↗

bioRxiv2026

Hippocampal-midcingulate connectivity is associated with representational integration during cognitive map updating

Cognitive maps organize experience into structured internal models that support goal-directed behavior. Although map formation has been extensively studied in the human hippocampus, the neural mechanisms supporting flexible updating of established maps remain unclear. We used fMRI to track the formation and updating of a spatial cognitive map across three days. Participants learned object-location associations and later updated them by remapping objects among fixed locations. Representational similarity analysis revealed two concurrent signatures in the right hippocampus: prior relational structure remained differentiated, whereas updated associations became integrated. Map updating engaged a frontoparietal network and modulated hippocampal-cortical connectivity. Critically, hippocampal-midcingulate connectivity was associated with the integration of updated associations, but not with the differentiation of prior relational structure. These results suggest that cognitive map updating involves coordinated hippocampal-cortical interactions that incorporate new information while preserving prior relational structure, reflecting a balance of stability and plasticity in internal models.

neuroscience↗

bioRxiv2026

Asynchronous cortical recovery from sleep inertia: region- and frequency-specific dynamics following deep NREM sleep

Sleep inertia (SI) is a transient state of impaired alertness and cognition after awakening, typically exacerbated by prior deep sleep. Despite its prevalence, the fine-grained temporal dynamics of brain activity during this transition remains poorly understood. We employed trial-by-trial behavioral assessment (20-second resolution) to map the recovery trajectories of 44 participants following awakenings from either shallow (N1/N2) or deep (N3) NREM sleep. We found that awakening from deep NREM sleep resulted in a significantly slower return to baseline working-memory performance. This behavioral deficit was mirrored by specific EEG signatures: frontal low-frequency activity (delta/theta) returned to baseline levels within minutes, whereas posterior high-frequency activity (alpha/beta) remained altered for a prolonged period. These findings reveal that the human brain reboots asynchronously following deep NREM sleep, with a "frontal-first, posterior-last" gradient that dictates the time course of behavioral restoration.

neuroscience↗

bioRxiv2025

Discovery of The Clinical Candidate S-892216: A Second-Generation of SARS-CoV-2 3CL Protease Inhibitor for Treating COVID-19

The coronavirus disease 2019 (COVID-19) pandemic crisis has been mitigated by worldwide efforts to develop vaccines and therapeutic drugs. However, there remains concern regarding public health and an unmet need for therapeutic options. Herein, we report the discovery of S-892216, a second-generation SARS-CoV-2 3C-like protease (3CLpro) inhibitor, to treat COVID-19. S-892216 is a reversible covalent 3CLpro inhibitor with highly potent antiviral activity and an EC50 value of 2.48 nM against SARS-CoV-2 infected cells. Structure-based design of a covalent modifier for compound 1 revealed that introducing a nitrile warhead increased 3CLpro inhibition activity by 180-fold. Subsequent optimization efforts yielded S-892216, which combined a favorable pharmacokinetic profile and high off-target selectivity. S-892216 exhibited antiviral activity against diverse SARS-CoV-2 variants, with no cross-resistance to major mutations reducing antiviral activities of nirmatrelvir and ensitrelvir. In SARS-CoV-2-infected mice, S-892216 inhibited viral replication in the lungs similar to ensitrelvir, although at a 30-fold lower dose.

biochemistry↗

bioRxiv2024

Two Stabiliser loci in Antirrhinum suppress the transposition of Tam3 without compromising transposase production

Antirrhinum majus has been known to exhibit occasional instabilities that are manifested as variegations and morphological chimeras. Stabiliser (St) is a historical locus that stabilizes phenotypically unstable or mutable traits in Antirrhinum. Here, we characterized two St loci, the previously described Old Stabiliser (OSt) and New Stabiliser (NSt), in Antirrhinum that specifically suppress the transposition of the Class II DNA transposable element, Tam3. Both St loci involve derivatives of Tam3 with unique structures: OSt has a pseudo-Tam3 copy whose 5-terminal region has been rearranged compared to the cognate Tam3 element, and NSt consists of two intact copies of Tam3 in a head-to-head orientation. Neither locus interferes with the production of the intact Tam3 transposase (TPase) or the nuclear import of TPase. Both OSt and NSt produce specific sRNAs from their 5 terminal regions containing multiple TPase binding motifs. These specific sRNAs could repress Tam3 transposition by interacting with the TPase binding motifs within the Tam3 element or with the TPase itself.

genetics↗

bioRxiv2022

Multi-modal deep neural decoding of visual object representation in humans

Perception and categorization of objects in a visual scene are essential to grasp the surrounding situation. However, it is unclear how neural activities in spatially distributed brain regions, especially in terms of temporal dynamics, represent visual objects. To address this issue, we explored the spatial and temporal organization of visual object representations using concurrent functional magnetic resonance imaging (fMRI) and electroencephalography (EEG), combined with neural decoding using deep neural networks (DNNs). Visualization of the fMRI DNN revealed that visual categorization (faces or non-face objects) occurred in brain-wide cortical regions, including the ventral temporal cortex. Interestingly, the EEG DNN valued the earlier phase of neural responses for categorization and the later phase of neural responses for sub-categorization. Combination of the two DNNs improved the classification performance for both categorization and sub-categorization. These deep learning-based results demonstrate a categorization principle in which visual objects are represented in a spatially organized and coarse-to-fine manner.

neuroscience↗

bioRxiv2022

Discovery of S-217622, a Non-Covalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Despite the rapid global spread of COVID-19 vaccines, effective oral antiviral drugs are urgently needed. Here, we describe the discovery of S-217622, the first oral non-covalent, non-peptidic SARS-CoV-2 3CL protease inhibitor clinical candidate. S-217622 was discovered via virtual screening followed by biological screening of an in-house compound library, and optimization of the hit compound using a structure-based drug-design strategy. S-217622 exhibited antiviral activity in vitro against current outbreaking SARS-CoV-2 variants and showed favorable pharmacokinetic profiles in vivo for once-daily oral dosing. Furthermore, S-217622 dose-dependently inhibited intrapulmonary replication of SARS-CoV-2 in mice, indicating that this novel non-covalent inhibitor could be a potential oral agent for treating COVID-19.

biochemistry↗

bioRxiv2022

An excitatory-inhibitory fronto-cerebellar loop resolves the Stroop effect

The Stroop effect is a well-known behavioral phenomenon in humans that refers to robust interference between language and color information. Although this effect has long been studied, it remains unclear when the interference occurs and how it is resolved in the brain. By manipulating the verbality of stimulus perception and response generation, here we show that the Stroop effect occurs during perception of color-word stimuli and is resolved by a cross-hemispheric, excitatory-inhibitory functional loop involving the lateral prefrontal cortex and cerebellum. Humans performed a Stroop task and a control task in which the stimulus did not contain verbal information, and made a response either vocally or manually. The resolution of Stroop interference involved the lateral prefrontal cortex in the left hemisphere and the cerebellum in the right hemisphere, independently of whether the response was made vocally or manually. In contrast, such cross-hemispheric lateralization was absent during the non-verbal control task. Moreover, the prefrontal cortex amplified cerebellar activity, whereas the cerebellum suppressed prefrontal activity, and these effects were enhanced during interference resolution. These results suggest that this fronto-cerebellar loop involving language and cognitive systems regulates goal-relevant information to resolve the interference occurring during simultaneous perception of a word and color.

neuroscience↗

bioRxiv2021

Perceptual uncertainty alternates top-down and bottom-up fronto-temporal network signaling during response inhibition

Response inhibition is a primary executive control function that allows the withholding of inappropriate responses, and requires appropriate perception of the external environment to achieve a behavioral goal. It remains unclear, however, how response inhibition is achieved when goal-relevant information involves perceptual uncertainty. Twenty-six human participants of both sexes performed a go/no-go task where visually presented random-dot motion stimuli involved perceptual uncertainties. The right inferior frontal cortex (rIFC) was involved in response inhibition, and the middle temporal (MT) region showed greater activity when dot motions involved less uncertainty. A neocortical temporal region in the superior temporal sulcus (STS) specifically showed greater activity during response inhibition in more perceptually certain trials. In this STS region, activity was greater when response inhibition was successful than when it failed. Directional effective connectivity analysis revealed that in more coherent trials, the MT and STS regions showed enhanced connectivity to the rIFC, whereas in less coherent trials, the signal direction was reversed. These results suggest that a reversible fronto-temporal functional network guides response inhibition under perceptual uncertainty, and in this network, perceptual information in the MT is converted to control information in the rIFC via STS, enabling achievement of response inhibition. Significance statementResponse inhibition refers to withholding inappropriate behavior and is an important for achieving goals. Often, however, decision must be made based on limited environmental evidence. We showed that successful response inhibition is guided by a neocortical temporal region that plays a hub role in converting perceived information coded in a posterior temporal region to control information coded in the prefrontal cortex. Interestingly, when a perceived stimulus becomes more uncertain, the prefrontal cortex supplements stimulus encoding in the temporal regions. Our results highlight fronto-temporal mechanisms of response inhibition in which conversion of stimulus-control information is regulated based on the uncertainty of environmental evidence.

neuroscience↗

bioRxiv2021

Executive control by fronto-parietal activity explains counterintuitive decision behavior in complex value-based decision-making

In real life, humans make decisions by taking into account multiple independent factors, such as delay and probability. Cognitive psychology suggests that cognitive control mechanisms play a key role when facing such complex task conditions. However, in value-based decision-making, it still remains unclear to what extent cognitive control mechanisms become essential when the task condition is complex. In this study, we investigated decision-making behaviors and underlying neural mechanisms using a multifactor gambling task where participants simultaneously considered probability and delay. Decision-making behavior in the multifactor task was modulated by both probability and delay. The behavioral effect of probability was stronger than delay, consistent with previous studies. Furthermore, in a subset of conditions that recruited fronto-parietal activations, reaction times were paradoxically elongated despite lower probabilistic uncertainty. Notably, such a reaction time elongation did not occur in control tasks involving single factors. Meta-analysis of brain activations suggested an association between the paradoxical increase of reaction time and strategy switching. Together, these results suggest a novel aspect of complex value-based decision-makings that is strongly influenced by fronto-parietal cognitive control. Highlights* A value-based decision task with concurrent delay and probabilistic uncertainty * Stronger behavioral effect of probability than delay * Paradoxically long reaction time despite low probabilistic uncertainty * The task activated fronto-parietal cognitive control network * Reaction time elongation coincided with activation similar to strategy switching

neuroscience↗

bioRxiv2020

Flexible decision under ambiguous cues reverses neural signaling from occipitotemporal to prefrontal cortex

Adaptation to changing environments involves the appropriate extraction of environmental information to achieve a behavioral goal. It remains unclear how behavioral flexibility is guided under situations where the relevant behavior is ambiguous. Using functional brain mapping of machine-learning decoders and directional functional connectivity, we show that brain-wide reversible neural signaling underpins task encoding and behavioral flexibility in ambiguously changing environments. When relevant behavior is cued ambiguously during behavioral shifting, neural coding is attenuated in distributed cortical regions, but top-down signals from the prefrontal cortex complement the coding. When behavioral shifting is cued more explicitly, modality-specialized occipitotemporal regions implement distinct neural coding about relevant behavior, and bottom-up signals from the occipitotemporal region to the prefrontal cortex supplement the behavioral shift. These results suggest that our adaptation to an ever-changing world is orchestrated by the alternation of top-down and bottom-up signaling in the fronto-occipitotemporal circuit depending on the availability of environmental information.

neuroscience↗