bioRxiv Science⌕ Search

Biology subjects

Kawasaki, H.

Publications and source records attributed to Kawasaki, H..

At least 19 recordsLinked to original sources

A genome-wide catalog of sites where peripheral DNA methylation reflects the brain

Epigenetic studies of psychiatric and neurological disorders rely largely on peripheral tissues, yet where peripheral DNA methylation (DNAm) reflects the brain remains unclear. We generated a paired brain and peripheral DNAm dataset from 148 donors in three cohorts and combined it with five published cohorts for consensus brain-peripheral correlations. By cross-validation across cohorts, we defined brain epigenome shared sites (BrESS), more than 100,000 CpGs per tissue at which peripheral DNAm reproducibly predicts brain DNAm. BrESS lay at promoters active in both brain and periphery and in housekeeping genes, and most were not explained by genetic effects. BrESS did not contribute to the heritability of seven disorders, and CpGs from epigenome-wide association studies of these disorders were not enriched at BrESS. Peripheral DNAm reflects the brain mainly in a regulatory compartment shared across tissues, outside which disease signals largely lie, and BrESS separate peripheral signals attributable to the brain from others.

neuroscience↗

Protective effects of heat shock protein 70 induction against global warming by using oriental bezoar and ginseng

The interest in compounds that protect against heat stress-induced damage has been heightened due to world global warming. We found the protective effects of a Japanese natural drug named BG, containing oriental bezoar and ginseng, against heat stress in Drosophila. BG suppressed the heat-induced shortened lifespan and reduced fertility in Drosophila. Interestingly, the protective effects of BG against heat stress were abolished in heat shock protein 70 (HSP70) mutant flies. To see the protective effects in humans, we applied BG on the cytotoxicity in heat-stressed human hepatic cell line, HepG2. BG suppressed heat stress-induced cytotoxicity at 43{degrees}C, and increased HSP70 and heat shock factor 1 (HSF1) mRNA expression in HepG2 cells. These findings indicate that BG protects against heat stress-induced damage via the HSF1/HSP70 pathway and has potential as a therapeutic agent for heat stress-induced disorders, including heatstroke even in human.

pharmacology and toxicology↗

Hippocampal-cingulate dynamics in the human brain link reinforcement-learning and memory

Reinforcement learning (RL) models describe how reward computations shape our choices, but whether the same computations also shape memory in the human brain is unclear. To address this question, we combined multi-areal intracranial recordings with computational modeling of reward and memory in neurosurgical patients. Patients played a gambling task in which decisions yielded monetary rewards tied to trial-unique images, followed immediately by a recognition test for those images. Model-derived positive reward prediction errors (RPEs) predicted later memory for each image. During feedback, multivariate high-frequency activity revealed the spatiotemporal evolution of RPE representations across distributed prefrontal cortex. During subsequent recognition, however, only anterior cingulate cortex (ACC) transiently reinstated RPE representations, and successful recognition specifically associated with hippocampal reinstatement of these ACC representations. Hippocampal-cingulate theta synchrony scaled with RPE during recognition, alongside hippocampal theta decoding of upcoming memory choices. Thus, the RL computations that guide decision-making also shape memory through hippocampal-cingulate circuit dynamics in the human brain.

neuroscience↗

Network and hierarchical organization of intrinsic timescales in the human brain

Intrinsic neural timescales represent the characteristic duration over which information is maintained in neuronal circuits. Evidence suggests that neural timescales vary systematically across the cortical hierarchy, with shorter timescales in primary sensory areas and longer timescales in higher-order association regions. In previous studies, hierarchy has been defined categorically, anatomically, or from the principal gradient of resting-state fMRI functional connectivity derived using diffusion map embedding (DME). Here, we assign hierarchical position to individual human intracranial electroencephalography (iEEG) recording sites by projecting their MNI coordinates onto this embedding space, derived from Human Connectome Project resting-state fMRI data. We estimated neural timescales from resting-state iEEG recordings in adult neurosurgical patients (n=46, 25 female) by extracting the aperiodic component of the local field potential power spectrum using spectral parameterization. Timescales increased monotonically with hierarchical position and associated with two region of interest (ROI)-level measures of network topology derived from DME of participants iEEG functional connectivity: ROIs with stronger mean functional connectivity exhibited longer timescales, as did ROIs functioning as hubs, defined by proximity to the center of embedding space. Finally, timescales varied with sleep stage, with slowest values during NREM and fastest during wake and REM. The hierarchical gradient present during wake and N1 was no longer detected during REM, N2, and N3 sleep, driven by a selective increase in timescales at lower levels of the hierarchy. This work presents a novel metric of hierarchy that can be applied to iEEG data, establishes a direct link between neural timescales, cortical hierarchy, and network topology in human iEEG, and demonstrates that this hierarchical organization is dynamically modulated by brain state. Significance StatementThe brain processes information across multiple timescales simultaneously, with different cortical regions specialized for fast sensory processing or slow integration of context. We measured intrinsic neural timescales from human intracranial electrophysiological recordings and applied a novel method to locate each recording site along the cortical hierarchy. Timescales increased systematically from sensory to association areas, and were longest in network hubs, i.e., regions that are uniformly and widely connected to the rest of the brain. During sleep, this hierarchical organization was not detected, with sensory areas showing the largest increases in timescale. These findings advance our understanding of how the brains temporal organization is shaped by network architecture and modulated by brain state.

neuroscience↗

Early reactivation of medial temporal lobe neurons during emergence from propofol anesthesia in neurosurgical patients

Although much is known about the molecular and cellular effects of general anesthetics, the neural mechanisms underlying loss and recovery of consciousness during anesthesia remain elusive. We provide the first report of human single neuron activity recorded throughout emergence from general anesthesia. Following cessation of propofol infusion, emergence was assessed as motor response to verbal command (RC). In most cells, firing rates increased during the course of emergence. Analysis of pooled firing rate changes indicated a shift towards criticality during emergence and attractor states during and immediately following anesthesia and immediately after RC. Changes in activity in some regions occurred prior to overt RC, with shortest latencies in the hippocampus, parahippocampal gyrus, and amygdala, followed by cingulate and then insular cortex. This work reveals that brain activity in medial temporal regions may presage restoration of responsiveness in humans following general anesthesia.

neuroscience↗

Transcranial magnetic stimulation to the dorsolateral prefrontal cortex modulates single-neuron activity in humans

Transcranial magnetic stimulation (TMS) to the dorsolateral prefrontal cortex (dlPFC) is an FDA-cleared treatment for depression, yet how cortical stimulation influences single neurons in deep brain circuits remains unknown. Using intracranial microelectrode recordings in four neurosurgical patients, we resolved single-neuron spikes as early as 8 ms from 185 single neurons after single-pulse left dlPFC TMS. TMS elicited time-locked firing responses in 46% of neurons across deep cortical and subcortical structures bilaterally. TMS facilitated putative interneuron spiking in striato-thalamic regions from [~]8 ms, peaking at [~]80-100 ms, and lasting to [~]1000 ms, while suppressing putative pyramidal cell spiking with a delayed and slower time course. Trial-by-trial single-neuron modulations were positively correlated with cortico-striato-thalamic network activity and anti-correlated with limbic network activity. These findings reveal that dlPFC TMS facilitates inhibitory firing in executive control networks while suppressing limbic excitatory drive, providing a cellular mechanism for how cortical stimulation modulates distributed brain networks.

neuroscience↗

Improved adenine-HPLC method for quantifying yeast based on cellular DNA content

Accurate quantification of fungi is important for a myriad of applications but remains challenging. Previously, we demonstrated that an approach called the adenine-HPLC method can quantify bacteria, including those with aggregating properties that are difficult to quantify using conventional methods, by measuring cellular adenine derived from DNA and converting the adenine amount to genome copy number, without being influenced by cell morphology. However, in this study, when this adenine-HPLC method was applied to the quantification of budding yeast as a model fungus, accurate measurement proved impossible. This limitation was attributed to adenine release from other adenine-containing biomolecules, such as RNA and ATP, and we therefore developed a method that suppresses adenine release from these molecules. This method involves reducing the temperature of the acid treatment and prewashing the cells before acid treatment. In addition, we incorporated a process that corrects for the naturally occurring free adenine level as background during total adenine measurement. The improved adenine-HPLC method based on these modifications enables accurate quantification of budding yeast using genomic DNA content in whole cells as the quantification unit.

microbiology↗

High-Frequency Spinal Cord Stimulation Reorganizes Cortical Cross-Frequency Coupling in a Region- and Time-Dependent Manner

Pain management strategies have progressed beyond traditional pharmacologic and physical interventions, integrating advanced neuromodulation techniques such as deep brain stimulation, peripheral nerve stimulation, and high-frequency spinal cord stimulation (hSCS). Despite its clinical efficacy, the supraspinal mechanisms underlying hSCS remain poorly understood. Prior work in sheep demonstrated that hSCS modulates gamma ({gamma}) band (70-150 Hz) activity in the primary somatosensory and association cortices, implicating cortical involvement in pain modulation. Given, the interaction between low and high oscillations, we hypothesized that hSCS modulates {gamma} activity in a region- and time-dependent manner through specific coupling with theta ({square}) rhythms (4-8 Hz). Using 96-channel subdural electrocorticography (ECoG), we computed {square}-{gamma} phase-amplitude coupling (PAC) and the corresponding modulation index (MI) to quantify the effects of hSCS. While the preferred {square}phase of {gamma} activity remained consistent across conditions and regions, MI increased significantly post-stimulation--most prominently in the association cortex, where robust -{gamma} phase locking was observed. In contrast, the somatosensory cortex exhibited weaker and more variable locking. Temporally, both cortices demonstrated an early, rapid increase in MI post-hSCS, accompanied by a shift (association) and attenuation (somatosensory) of the secondary peak. These findings reveal distinct regional and temporal dynamics in PAC following hSCS and suggest complementary roles of somatosensory and association cortices in processing neuromodulatory input. hSCS appears to reorganize cortical cross-frequency interactions, supporting its role in reorganizing functional network dynamics relevant to sensory processing and the subjective pain experience.

neuroscience↗

Species-specific imprinting of Adam23 and its implications for gyrencephalic brain development

Genomic imprinting is a parent-of-origin-specific epigenetic mechanism with essential roles in placental development and fetal growth in mice, but its contribution to brain function and evolution remains unclear. Here, we investigated genomic imprinting in the ferret, a gyrencephalic mammal whose cortical architecture closely resembles that of humans rather than mice. Guided by human imprinting datasets, we screened 65 candidate genes in ferret brain and identified paternal expression of Adam23, maternal expression of Atp10a, and biallelic expression of genes including Pxdc1, Wrb and Ube3a. Adam23 showed paternal expression in ferret cortex, particularly in the occipital region, whereas it was biallelically expressed in mouse brain. In human SH-SY5Y cells, ADAM23 was biallelic in undifferentiated cells but shifted toward monoallelic expression upon neuronal differentiation. CpG analysis of upstream islands indicated that Adam23 imprinting in ferrets is independent of promoter methylation, suggesting a non-canonical mechanism. Functional assays in Neuro-2aTG cells showed that Adam23 knockdown enhances neurite outgrowth, whereas overexpression promotes cell proliferation. These findings identify Adam23 as a non-canonical imprinted gene whose dosage influences stem cell dynamics and neurite development, linking imprinting to the evolution of gyrencephalic cortical structures and highlighting the ferret as a valuable model for imprinting studies in higher-order brain function.

microbiology↗

Brain-wide single-neuron bases of working memory for sounds in humans

In order to understand the constantly changing acoustic world our brains must maintain elements of auditory scenes in memory. The neural mechanisms for this fundamental process remain unclear. Here, we report human intracranial recordings of 1269 single neurons while participants performed a non-verbal auditory working memory task that required adjustment of a tone frequency to match a target. We found neurons within hippocampus, insula and cingulate cortex, for which firing rates were modulated at different phases of the task, particularly during maintenance and adjustment. For the majority of the neurons modulated during maintenance there was a striking suppression of activity rather than increased activity. Across the entire neuronal population, state-space analysis demonstrated attractor-like states corresponding to different task phases. Behaviorally, more neurons were modulated at the beginning of the maintenance phase in trials when participants performed better. State-space analysis was consistent with greater attractor-like activity during the adjustment phase supporting better performance. These data support the existence of a widely distributed neural code for auditory working memory that determines related behavior based on attractor-like states.

neuroscience↗

Astrocytes in white matter respond to tensile cues during cortical folding: a numerical study

Our understanding of the process of formation of gyri (ridges) and sulci (furrows) in the cerebrum during development is moving beyond the role of neurons. Glial cells such as astrocytes, which are the most common cell type in the brain, are especially prominent under the gyri and have been shown to be essential for gyrification in ferrets. Their dysfunction has been linked to a host of neurodevelopmental diseases and disorders in humans, leading to abnormal folding patterns, hence, it is crucial to understand their role in the mechanics of folding. In this work, we propose two hypotheses of how astrocytes affect cortical folding. Our previous study demonstrated that astrocytes proliferate in the white matter (subcortex), and that inhibiting this process impairs gyrification. This leads to the pushing hypothesis, where astrocytes push up the cortex outwards, leading to formation of folds. On the other hand, ex vivo studies demonstrate areas of the cortex and subcortex that experience tension, due to the differential growth between materials in the brain tissue. This leads to the pulling hypothesis, where astrocytes experience tension from the surrounding tissue, leading to their proliferation, distribution of tensile stresses, and initiation of growth in those regions. Using the theory of finite growth, we implement these hypotheses via morphogenetic growth (pushing) and stress-driven (pulling) growth criteria. We find that morphological trends during development between the pushing and pulling effects are not dissimilar, with a comparable gyrification index. The stress distributions from both models also show common features, but the pulling effect shows tension in the subcortex, which matches trends observed in experiments. Therefore, it is more likely that the astrocytes affect gyrification by proliferating as a response to tensile cues and decrease the tension they experience, leading to deeper folds, rather than astrocytes independently proliferating under a gyri and then pushing the cortex up.

bioengineering↗

Geographic Genetic Variation in the Introduced Insect Hyphantria cunea Drury in Japan Revealed by RAPD Analysis

The fall webworm Hyphantria cunea Drury (Lepidoptera: Arctiidae) is an invasive pest in Japan that has expanded its range since its accidental introduction in 1945. To investigate the genetic structure and potential source of a northern population recently established in Hirosaki (Aomori Prefecture), we analyzed five geographic populations using the random amplified polymorphic DNA (RAPD) method. Two primers revealed 18 polymorphic bands among 155 individuals collected across five prefectures. Cluster analysis based on Neis genetic distances grouped the populations into two major clusters corresponding to the Pacific coast and Sea of Japan coast, with the Hirosaki population showing close affinity to the Pacific coast group. These results suggest possible evolutionary divergence and local adaptation following invasion, and they highlight the utility of RAPD markers in assessing geographic genetic variation in introduced insect populations.

evolutionary biology↗

Effects of Cannabidiol to circadian period, sleep, life span, close-proximity rhythm, egg reproduction and motor function in Drosophila melanogaster

Cannabidiol (CBD), a non-psychoactive cannabinoid, has been studied for its various health-promoting effects recently. This study investigates the effects of dietary CBD to the circadian clock of Drosophila melanogaster as a model animal and its many physiological effect to flies. We showed that CBD extended the period of locomotor activity in a dose-dependent manner, suggesting its influence on the circadian clock. Additionally, CBD improved sleep quality and extended lifespan under starvation conditions. The study also revealed enhanced rhythmicity in Close Proximity (CP) rhythm and increased eggs reproduction with dietary CBD supplementation. Furthermor, CBD attenuates age-related motor dysfunction in wild-type and Parkinsons disease (PD) model in Drosophila. These findings strongly suggest that appropriate amount of CBD affects the circadian rhythms, sleep, life span, CP rhythm, egg reproduction and motor function of Drosophila melanogaster, and providing a basic data for exploring its potential applications in managing circadian-related disorders in other animals.

physiology↗

Reading specific memories from human neurons before and after sleep

The ability to retrieve a single episode encountered just once is a hallmark of human intelligence and episodic memory[1]. Yet, decoding a specific memory from neuronal activity in the human brain remains a formidable challenge. Here, we develop a transformer neural network model[2, 3] trained on neuronal spikes from intracranial microelectrodes recorded during a single viewing of an audiovisual episode. Combining spikes throughout the brain via cross-channel attention[4], capable of discovering neural patterns spread across brain regions and timescales, individual participant models predict vocalization of specific concepts such as persons or places during out-of-distribution memory recall. Brain regions differentially contribute to memory decoding before and after sleep. Models trained using only medial temporal lobe (MTL) spikes significantly decode concepts before but not after sleep, while models trained using only frontal cortex (FC) spikes decode concepts after but not before sleep, with better FC decoding relating to increased non-REM sleep. These findings suggest a system-wide distribution of information across neural populations that transforms over wake/sleep cycles[5]. Such decoding of internally generated memories suggests a path towards brain-computer interfaces to treat episodic memory disorders through enhancement or muting of specific memories.

neuroscience↗

Dexmedetomidine produces more sleep-like brain activity compared to propofol

IntroductionDexmedetomidine is a selective 2-adrenergic agonist used as an anesthesia adjunct to produce a state of sleep-like sedation. However, how brain activity compares quantitatively during dexmedetomidine anesthesia to that during natural sleep, and thus just how "sleep-like" dexmedetomidine anesthesia is, remains unclear. Previously, we showed that the general anesthetic propofol is associated with changes in connectivity and cortical network structure comparable to those observed during sleep. Here, we compare the effects on brain activity of dexmedetomidine, propofol, and sleep quantitatively using intracranial encephalographic (iEEG) recordings in human research participants. MethodsiEEG recordings were obtained in 34 epilepsy patients being evaluated for potential seizure resection surgery. Band power and functional connectivity (alpha weighted phase lag index, gamma envelope correlations) and network entropy were measured in recordings during task-free ("resting state") periods just prior to surgery during anesthesia with either dexmedetomidine or propofol, and during overnight sleep. Anesthesia stage (wake, sedated, unresponsive) was determined using the Observers Assessment of Arousal and Sedation. Sleep was staged using standard polysomnography. ResultsAs expected, significant differences in delta power were observed during dexmedetomidine and propofol as well as during sleep. However, the magnitude of changes in delta power were smaller and regionally heterogeneous for propofol compared to dexmedetomidine and sleep. Functional connectivity changes were comparable between dexmedetomidine, propofol, and natural sleep. Significant changes in network entropy were observed for dexmedetomidine, propofol, and sleep, but changes were larger for propofol compared to dexmedetomidine and sleep. Quantitative comparisons between changes in delta power and network entropy suggest that unresponsiveness under dexmedetomidine produces a similar brain state to that observed during N2 sleep. ConclusionsWhile delta power, functional connectivity, and network entropy all showed changes during propofol, dexmedetomidine, and sleep, the magnitudes of these changes suggest that dexmedetomidine is more similar than propofol to sleep, specifically to N2 sleep.

neuroscience↗

Glial Contribution to the Pathogenesis of Post-Operative Delirium Revealed by Multi-omic Analysis of Brain Tissue from Neurosurgery Patients

Post-operative delirium (POD) is a common complication after surgery especially in elderly patients, characterized by acute disturbances in consciousness and cognition, which negatively impacts long-term outcomes. Effective treatments remain elusive due to the unclear pathophysiology of POD. To address the knowledge gap, we investigated DNA methylation profiles and gene expression changes in brain cells from POD and non-POD patients who underwent brain resection surgery for medication refractory epilepsy. DNA methylation analysis revealed alteration in epigenetic status of immune and inflammation-related genes. Single-nucleus RNA sequencing (snRNAseq) identified POD-specific glial cell alterations, particularly in microglia, where neuroinflammation was strongly enhanced, consistent with epigenetic findings. Astrocytes exhibited changes in synapse-related functions and migration. Furthermore, downstream analysis indicated similarities between POD-associated glial cell states and pathologies such as encephalitis and dementia. Overall, this study--the first multi-omics analysis of brain tissue from POD patients--provides direct evidence of glial cell contributions to POD pathogenesis, and highlights potential therapeutic targets.

neuroscience↗

Human insula neurons respond to simple sounds during passive listening

The insula is critical for integrating sensory information from the body with that arising from the environment. Although previous studies suggest that posterior insula is sensitive to sounds, auditory response properties of insula neurons have not previously been reported. Here, we provide the first report of a population of human single neuron data from the insula and provide comparative data from the primary auditory cortex, recorded intracranially from human participants during passive listening. In each condition, more than 330 single neurons were recorded in 11 participants. Almost a third of neurons in posterior insula and a smaller subset in anterior insula responded to simple tones and clicks. Responsive neurons were distributed throughout posterior and anterior insula and showed preferred frequency tuning. Onset latencies in the insula were similar to those in the primary auditory cortex but response durations were significantly shorter. Overall, these data highlight that insula neurons respond to auditory stimuli even in non-behaviorally relevant contexts and suggest an important contribution of audition to the postulated integrative functions of insular cortex.

neuroscience↗

Electric-field induced sleep promotion and lifespan extension in Gaucher's disease model flies: Association with improving ER stress and autophagy

Gauchers disease (GD), one kind of genetic disease, is characterized by a mutation in metabolic enzyme, glucocerebrosidase (GBA), leading to accumulation of its substrate, glucosylceramide in tissues. We previously discovered that the minos-inserted mutation of the GBA gene in fruit flies, Drosophila melanogaster, reproduced human GD characteristics and can be used as a promising model for molecular mechanisms study. Recently, we reported that extremely low-frequency electric fields (ELF-EFs) promoted sleep and extended the lifespan of normal flies. In this study, GD model flies were exposed to ELF-EFs, and sleep parameters, gene expressions, and longevity were evaluated. The amount of sleep and lifespan increased after EF exposure. Simultaneously, the expression of the endoplasmic reticulum (ER) stress-related gene, PERK and the autophagy-related gene, p62 was elevated. The data suggest that the healthy effects of EFs on GD flies are associated with improved adaptation to cellular stress.

physiology↗