Biology subjects

Ikegaya, Y.

Publications and source records attributed to Ikegaya, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Hearing hippocampal ripples: Event-faithful, reproducible sonification of multineuronal spiking with hierarchy-guided orchestration

Among the human senses, hearing is distinguished by its high frequency resolution and sensitivity to spatiotemporal patterns. Accordingly, sonification--the rendering of neural activity as sound for direct perception--has a long history in neuroscience. Although sonification can facilitate exploration of the temporal structure of population activity, dense spike trains are often difficult to track by ear. Here, I present HERO (Hierarchy-guided Event-faithful Reproducible Orchestration), a pipeline that assigns stable musical voices to recorded units while preserving spike onsets in a MIDI event representation. Each spike within a selected interval produces a single Note On message whose timing is determined by a global temporal dilation followed by bounded clock rounding. A separate analysis pathway uses multiscale correlations and block-bootstrap co-association to organize units into a hierarchy. This hierarchy guides instrument assignment, whereas each unit is assigned a fixed key, tuning offset, velocity, and stereo position. A derived SoundFont stores tuning and pan parameters independently for units that share a MIDI channel. Rate-dependent velocity and channel-volume settings are intended to reduce the dominance of frequently firing units. An online audio example illustrating the audibility of individual activity during large-scale firing is available at: https://www.youtube.com/watch?v=zOYGXcp727A. HERO provides a reproducible auditory representation of population activity that may help direct attention toward features warranting subsequent quantitative analysis.

neuroscience↗

bioRxiv2026

Ramelteon facilitates hippocampal ripple occurrence and amplitude in mice

The hippocampus is essential for memory consolidation, a process mediated by high-frequency oscillations known as ripples during non-rapid eye movement (NREM) sleep. Ramelteon, a selective MT1/MT2 receptor agonist, has been reported to possess cognitive-enhancing properties; however, its impact on the fine-scale dynamics of hippocampal ripples remains unclear. We performed chronic local field potential recordings from the dorsal hippocampus and prefrontal cortex in mice. Following the intraperitoneal administration of either vehicle or ramelteon, we evaluated sleep architecture and characterized ripple properties, including occurrence rate, amplitude, instantaneous frequency, and duration during NREM sleep. Ramelteon administration significantly increased NREM sleep occupancy. Notably, we found that ramelteon significantly enhanced both the occurrence rate and amplitude of hippocampal ripples compared to the control group. While a slight increase in intra-ripple frequency was observed, other structural features, such as ripple duration and asymmetry index, remained unaffected. Our findings demonstrate that ramelteon facilitates hippocampal ripple dynamics by increasing their occurrence and synchrony during NREM sleep. Given the critical role of ripples in memory consolidation, these neurophysiological changes may underlie the procognitive effects of ramelteon. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=55 SRC="FIGDIR/small/723673v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@77b58org.highwire.dtl.DTLVardef@132dbc1org.highwire.dtl.DTLVardef@1f98dc1org.highwire.dtl.DTLVardef@c9a3f2_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2026

Enzyme activity as an actionable axis for small-molecule precision oncology

Current precision oncology--molecular targeted therapies and immunotherapies--relies on genomic or expressed biomarkers, yet most cancer patients remain ineligible for these treatments. Here, we establish enzyme activity as an actionable and orthogonal axis for precision cancer medicine. Strategic activity-based screening of mouse organs and human clinical specimens with a panel of enzyme-reactive fluorescence probes identified {beta}-galactosidase 1 (GLB1) and {beta}-hexosaminidases (HEX) as broadly elevated tumor-selective biomarkers. Leveraging these activities, we developed 7-ethyl-10-hydroxycamptothecin (SN38)-based GLB1-and HEX-reactive prodrugs. These prodrugs exhibited dramatically reduced systemic toxicities and improved therapeutic windows, compared to a clinically used SN38-based prodrug, irinotecan (CPT-11). Both prodrugs demonstrated activity-dependent therapeutic efficacy, affording a dramatic reduction of tumor volumes across multiple in vivo models, including a subcutaneous patient-derived xenograft (PDX) of lung squamous cell carcinoma that lacked genetic alterations targeted by current precision medicine. Furthermore, this strategy is broadly applicable across various cytotoxic payloads, establishing a generalizable platform for small-molecule precision medicines. Our results define an enzyme-targeting paradigm for precision oncology, in which fluorescence probes serve as companion diagnostic tools to guide development and selection of appropriately targeted prodrugs, which are expected to provide safer and more efficacious treatment options for cancer patients with elevated enzyme activities.

cancer biology↗

bioRxiv2026

Ripples precede insight in the right human hippocampus

Insight is a sudden transition from uncertainty to awareness of a solution, often preceded by non-conscious processing. Despite the ubiquity of insights in human cognition, the neural mechanisms underlying this pre-conscious restructuring phase remain largely unknown. Recent theoretical frameworks suggest that the hippocampus, through its capacity for rapid associative retrieval and flexible recombination of stored representations, may facilitate the non-conscious exploration that precedes insight. Hippocampal ripples associated with memory replay and consolidation, represent a promising candidate mechanism for this process. We recorded intracranial local field potentials from depth electrodes in the hippocampus of ten patients with drug-resistant epilepsy while they performed non-verbal reasoning tasks. Participants indicated the moment of solution awareness via button press, enabling precise temporal alignment of neural activity to subjective insight. We observed a significant increase in ripple rate during a pre-response window. Critically, this effect was lateralized to the right hippocampus. These findings provide the first direct human electrophysiological evidence linking right-lateralized hippocampal ripples to the non-conscious phase of insight. We propose that right hippocampal ripples support rapid retrieval and flexible recombination of representations, potentially triggering cortical processes that culminate in conscious solution awareness.

neuroscience↗

bioRxiv2025

Nonlinear hippocampal coding of the pair-bonded partner in prairie voles

Neural representation of specific opposite-sex partners remains largely unexplored. Using monogamous prairie voles, we demonstrated that partner preference required the ventral hippocampus, in which 3-4 Hz oscillations were enhanced following partner interaction. We identified ventral hippocampal neurons responding selectively to the pair-bonded partner and stranger, which encoded identity-related information in a nonlinear manner, shedding light upon how mammalian brains create distinct neural representations of romantic opposite-sex partners.

neuroscience↗

bioRxiv2025

Theanine boosts frontal theta and hippocampal beta and gamma oscillations for familiarity in object recognition

Theanine, a non-proteinogenic amino acid derivative from green tea leaves, enhances object recognition memory in rats through facilitated neurogenesis. In this sense, the cellular mechanism for the theanine-enhanced object recognition memory has been elucidated to some extent, but physiological evidence still remains unclear. To tackle this issue, we chronically fed mice with theanine (or tap water) for three weeks, implanted electrodes into the hippocampus and frontal cortex, both of which are responsible for object recognition memory. We then recorded the local field potentials from the two regions during the novel object recognition task, evaluated the task performance, and broke down the neural signals in the hippocampus and frontal cortex into delta, theta, beta, low gamma, and high gamma frequency bands. The discrimination ratio of theanine-treated mice was higher than that of vehicle-treated mice. We also found that theta oscillations in the frontal cortex and beta and low gamma oscillations in the hippocampus in theanine-treated mice were simultaneously enhanced for familiar objects. These results shed light on the new physiological underpinnings of object recognition memory enhanced by exogenous substances.

pharmacology and toxicology↗

bioRxiv2025

Age-Dependent, Odorant-Specific Changes in Olfactory Sensitivity in an Alzheimer's Disease Mouse Model

BackgroundOlfactory impairment often precedes cognitive decline in Alzheimers disease (AD). Recent studies suggest odor specificity in olfactory deficits during early AD stages, making olfactory tests a promising tool for early diagnosis. However, the mechanisms underlying olfactory impairment remain unclear, complicating the identification of optimal odorants for diagnostic purposes. ObjectiveIn this study, we assessed olfactory sensitivity in a knock-in mouse model of Alzheimers disease (AppNL-G-F mice) that recapitulates key features of human AD pathology. MethodsTo evaluate odor detection thresholds, we employed an olfactory assay that leverages innate behavior without requiring associative learning. Six odorants representing distinct functional groups were tested in wild-type (WT) and AppNL-G-F mice at 2 and 4 months of age. ResultsAppNL-G-F mice exhibited odorant-specific hyposmia at 4 months of age, coinciding with amyloid deposition in cortical and subcortical regions but preceding measurable cognitive deficits. Unexpectedly, at an earlier stage (2 months), these mice showed odorant-specific hyperosmia to ester odorants, which transitioned to hyposmia by 4 months, indicating dynamic, age-dependent alterations in olfactory sensitivity as AD pathology progresses. ConclusionsOur findings demonstrate that odorant-specific olfactory testing could serve as a promising diagnostic tool for early-stage AD, providing insights into the mechanisms underlying olfactory dysfunction in neurodegenerative diseases.

pathology↗

bioRxiv2025

Enhanced Tactile Coding in Rat Neocortex Under Darkness

Sensory systems are known for their adaptability, responding dynamically to changes in environmental conditions. A key example of this adaptability is the enhancement of tactile perception in the absence of visual input. Despite behavioral studies showing visual deprivation can improve tactile discrimination, the underlying neural mechanisms, particularly how tactile neural representations are reorganized during visual deprivation, remain unclear. In this study, we explore how the absence of visual input alters tactile neural encoding in the rat somatosensory cortex (S1). Rats were trained on a custom-designed treadmill with distinct tactile textures (rough and smooth), and local field potentials (LFPs) were recorded from S1 under light and dark conditions. Machine learning techniques, specifically a convolutional neural network, were used to decode the high-dimensional LFP signals. We found that the neural representations of tactile stimuli became more distinct in the dark, indicating a reorganization of sensory processing in S1 when visual input was removed. Notably, conventional amplitude-based analyses failed to capture these changes, highlighting the power of deep learning in uncovering subtle neural patterns. These findings offer new insights into how the brain rapidly adapts tactile processing in response to the loss of visual input, with implications for multisensory integration.

neuroscience↗

bioRxiv2024

Dopamine-induced Relaxation of Connectivity Diversifies Burst Patterns in Cultured Hippocampal Networks

The intricate interplay of neurotransmitters orchestrates a symphony of neural activity in the hippocampus, with dopamine emerging as a key conductor in this complex ensemble. Despite numerous studies uncovering the cellular mechanisms of dopamine, its influence on hippocampal neural networks remains elusive. Combining in vitro electrophysiological recordings of rat embryonic hippocampal neurons, pharmacological interventions, and computational analyses of spike trains, we found that dopamine induces a relaxation in network connectivity, characterised by a reduction in spike coherence. This relaxation expands the repertoire of burst dynamics within these hippocampal networks, a phenomenon notably absent under the administration of dopamine antagonists. Our study provides a thorough understanding of the roles of dopamine signalling in shaping functional networks of hippocampal neurons.

neuroscience↗

bioRxiv2024

Diffusion model-based image generation from rat brain activity

Brain-computer interface (BCI) technology has gained recognition in various fields, including clinical applications, assistive technology, and human-computer interaction research. BCI enables communication, control, and monitoring of the affective/cognitive states of users. Recently, BCI has also found applications in the artistic field, enabling real-time art composition using brain activity signals, and engaging performers, spectators, or an entire audience with brain activity-based artistic environments. Existing techniques use specific features of brain activity, such as the P300 wave and SSVEPs, to control drawing tools, rather than directly reflecting brain activity in the output image. In this study, we present a novel approach that uses a latent diffusion model, a type of deep neural network, to generate images directly from continuous brain activity. We demonstrate this technology using local field potentials from the neocortex of freely moving rats. This system continuously converted the recorded brain activity into images. Our end-to-end method for generating images from brain activity opens up new possibilities for creative expression and experimentation.

neuroscience↗

bioRxiv2024

Distributed encoding of hippocampal information in mossy cells

In neural information processing, the nervous system transmits neuronal activity across layers of neural circuits, occasionally passing through small layers composed only of sparse neurons. Hippocampal hilar mossy cells (MCs) constitute such a typical bottleneck layer. In vivo/vitro patch-clamp recordings revealed that MCs were reliably depolarized in response to sharp-wave ripples (SWRs), synchronous neuronal events transmitted from the CA3 region to the dentate gyrus via the MC layer. Machine-learning algorithms predicted the waveforms of SWRs in the CA3 region, based on the MC depolarization waveforms, suggesting that CA3 neural information is indeed transmitted to the MC layer. However, the prediction accuracy varied; i.e., a particular MC showed a more robust association with a particular SWR cluster, and the SWR cluster associated with one MC rarely overlapped with the SWR clusters associated with other MCs. Thus, CA3 network activity is distributed across MC ensembles with pseudo-orthogonal neural representations, allowing the small MC layer to effectively compress hippocampal information.

neuroscience↗

bioRxiv2023

Effects of novelty and temporal distance on post-experience reactivation of hippocampal place cells encoding multiple environments

The hippocampus plays a crucial role in consolidating episodic memories from diverse experiences that encompass spatial, temporal, and novel information. This study analyzed the spike patterns of hippocampal place cells in the CA3 and CA1 areas of rats that sequentially foraged in five rooms, including familiar and novel rooms, followed by a rest period. Across multiple rooms, the generation of place fields by CA1 place cells was coordinated with other place cells. In the subsequent rest period, CA3 place cells that encoded novel environments exhibited stronger and more coordinated reactivation during sharp wave ripples (SWRs) than CA1 place cells. In contrast, CA1 place cells that encoded more recent environments exhibited stronger SWR-associated reactivation, independent of spikes of other cells, with weaker influences from novelty compared to CA3 place cells. These results suggest that post-experience SWR-associated reactivation of CA3 and CA1 neurons primarily processes novelty-related and temporal distance-related aspects of memory, respectively.

neuroscience↗

bioRxiv2023

Hippocampal sharp-wave ripples correlate with naturally occurring self-generated thoughts in humans

Core features of human cognition, for example, the experience of mind wandering, highlight the importance of the capacity to focus on information separate from the here and now. However, the brain mechanisms that underpin these self-generated states remain unclear. An emerging hypothesis is that self-generated states depend on the process of memory replay, which, in animals, is linked to sharp-wave ripples (SWRs) originating in the hippocampus. SWRs are transient high-frequency oscillations that exhibit circadian fluctuations and, in the laboratory, are important for memory and planning. Local field potentials were recorded from the hippocampus of 11 patients with epilepsy for up to 15 days, and experience sampling was used to describe their association with ongoing thought patterns. SWRs were correlated with patterns of vivid, intrusive ongoing thoughts unrelated to the task being performed, establishing their contribution to the ongoing thoughts that humans experience in daily life.

neuroscience↗

bioRxiv2023

Slow gamma oscillations in the mouse olfactory bulb are correlated with sniffing in the dark period

Neural activity in the olfactory bulb is reflected in local field potentials (LFPs). Functionally, LFPs in the olfactory bulb are categorized into different frequency bands: 1-4 Hz, 6-12 Hz, 25-50 Hz, and 65-130 Hz, which respectively correspond to respiration, sniffing, slow gamma, and fast gamma oscillations. While gamma oscillations in the olfactory bulb are modulated by respiration and sniffing, it remains unknown how and whether the modulation of LFP oscillations is affected by the time of day. To address this question, we recorded LFPs in the olfactory bulb, hippocampus, and neocortex of unrestrained mice for up to 3 d. For each recording site, we calculated the correlation coefficients of normalized LFP powers between pairs of frequency bands in the three regions during the dark and light periods. We then compared these correlations with those generated by surrogate data to investigate whether the correlation was statistically significant. We found that the correlation between sniffing and slow gamma oscillations was higher in the dark period than in the light period. Our finding has the potential to shed light on the coding scheme of olfactory information that is dependent on the light/dark cycle.

neuroscience↗

bioRxiv2023

Hippocampal neural fluctuation between memory encoding and retrieval states during a working memory task in humans

BackgroundWorking memory (WM) is essential for everyday life, yet its neural mechanism remains unclear. Although the hippocampus plays a critical role in memory consolidation and retrieval, its role in WM tasks has yet to be fully elucidated. We hypothesized that multiunit activities in the hippocampus alter their representations depending on the memory load and phase of a WM task, particularly in relation to sharp-wave ripple complexes (SWRs), which are known as various cognitive biomarkers. MethodsWe used an open dataset of intracranial electroencephalogram (iEEG) data and multiunit activity recorded from the medial temporal lobe (MTL) of nine patients with epilepsy. The MTL includes the hippocampus, entorhinal cortex, and amygdala. During the recording, all subjects performed an eight-second Sternberg test, in which they memorized sets of four, six, or eight letters (encoding phase), waited for three seconds (maintenance phase), and recalled whether a probe letter was included (Match IN task) or not (Mismatch OUT task) (retrieval phase). We used Gaussian-process factor analysis to visualize the neural trajectories of multiunit activity in MTL regions during the task. We also detected SWRs from the iEEG data in the hippocampus. FindingsWe found that the trajectory distance between phases of the Sternberg task was larger in the hippocampus compared to the entorhinal cortex and amygdala. Additionally, the trajectory distance between the encoding and retrieval phases was memory load dependent. Moreover, a transient trajectory increase was detected during SWRs. Finally, the trajectory direction of the hippocampus fluctuated between the encoding and retrieval states, and the balance of the fluctuation was shifted to the retrieval state during SWR periods. InterpretationOur results demonstrate the involvement of the hippocampus during a WM task. Furthermore, it is suggested that SWR in the retrieval phase plays a role in memory retrieval for a WM task. Our results provide new insight into the two-stage model of memory formation.

neuroscience↗

bioRxiv2023

Intestelligence: A pharmacological neural network using intestine data

A neural network is a machine learning algorithm that can learn and make predictions by adjusting the strength of the connections between nodes. The sigmoid function is commonly used as an activation function in these nodes. This study explores the potential applicability of biological materials in the development of alternative activation functions. Inspired by the fact that acetylcholine induces intestinal contractions that follow a sigmoid function, we used pharmacological data obtained from guinea pig ilea in a layered neural network for image classification tasks. We found that the intestinal data-based neural network with the same structure as a conventional three-layer perceptron achieved an impressive classification accuracy of 85.7% {+/-} 0.6% based on the MNIST handwritten digit dataset (chance = 10%). Additionally, the neural network was trained to determine whether objects in photographs collected from the internet were digestible, achieving an accuracy of 88.5% {+/-} 0.9% (chance = 50%). Our approach highlights the potential applicability of intestine data in neural computations based on pharmacological mechanisms.

bioengineering↗

bioRxiv2023

Postnatal maturation of in vivo membrane potentialdynamics during hippocampal ripples

Sharp-wave ripples (SWRs) are transient high-frequency oscillations of local field potentials (LFPs) in the hippocampus and play a critical role in memory consolidation. During SWRs, CA1 pyramidal cells exhibit rapid spike sequences that often replay the sequential activity that occurred during behavior. This temporally organized firing activity gradually emerges during two weeks after the eye opening; however, it remains unclear how the organized spikes during SWRs mature at the intracellular membrane potential (Vm) level. Here, we recorded the Vm of CA1 pyramidal cells simultaneously with hippocampal LFPs from immature mice after the developmental emergence of SWRs. On postnatal days 16-17, Vm dynamics around SWRs were premature, characterized by prolonged depolarizations without either pre- or post-SWR hyperpolarization. The biphasic hyperpolarizations, which are a typical feature of adult SWR-relevant Vm, formed by approximately postnatal day 30. This Vm maturation was associated with an increase in SWR-associated inhibitory inputs to pyramidal cells. Thus, the development of SWR-relevant inhibition restricts the temporal windows for spikes of pyramidal cells and allows CA1 pyramidal cells to organize their spike sequences during SWRs. Significance statementSharp-wave ripples (SWRs) are prominent hippocampal oscillations and play a critical role in memory consolidation. During SWRs, hippocampal neurons synchronously emit spikes with organized temporal patterns. This temporal structure of spikes during SWRs develops during the third and fourth postnatal weeks, but the underlying mechanisms are not well-understood. Here, we recorded in vivo membrane potentials from hippocampal neurons in premature mice and suggest that the maturation of SWR-associated inhibition enables hippocampal neurons to produce precisely controlled spike times during SWRs.

neuroscience↗

bioRxiv2021

Prefrontal-amygdalar oscillations related to social interaction behavior in mice

The medial prefrontal cortex and amygdala are involved in the regulation of social behavior and associated with psychiatric diseases but their detailed neurophysiological mechanisms at a network level remain unclear. We recorded local field potentials (LFPs) from the dorsal medial PFC (dmPFC) and basolateral amygdala (BLA) while mice engaged on social behavior. We found that in wild-type mice, both the dmPFC and BLA increased 4-7 Hz oscillation power and decreased 30-60 Hz power when they needed to attend to another target mouse. In mouse models with reduced social interactions, dmPFC 4-7 Hz power further increased especially when they exhibited social avoidance behavior. In contrast, dmPFC and BLA decreased 4-7 Hz power when wild-type mice socially approached a target mouse. Frequency-specific optogenetic manipulations of replicating social approach-related LFP patterns restored social interaction behavior in socially deficient mice. These results demonstrate a neurophysiological substrate of the prefrontal cortex and amygdala related to social behavior and provide a unified pathophysiological understanding of neuronal population dynamics underlying social behavioral deficits.

neuroscience↗