Biology subjects

Igarashi, K.

Publications and source records attributed to Igarashi, K..

At least 19 recordsLinked to original sources

bioRxiv2026

Neonatal NMDA receptor blockade disrupts prefrontal cortical regulation of social affective behavior: implications for schizophrenia

Developmental N-methyl-D-aspartate receptor (NMDAr) hypofunction has been implicated in the pathophysiology of schizophrenia, including cognitive and emotional deficits. However, the neural circuit mechanisms linking developmental NMDAr hypofunction to social affective impairments remain poorly understood. Here, we investigated schizophrenia-related social affective dysfunction induced by neonatal exposure to the NMDAr antagonist MK-801 and examined the contribution of the medial prefrontal cortex (mPFC), a key hub for socio-cognitive function. Sprague-Dawley rat pups received subcutaneous injections of saline or MK-801 (MK-Low: 0.2 mg/kg; MK-High: 0.4 mg/kg) during the neonatal period. In adulthood, social affective behaviors were assessed using the Social Affective Preference (SAP) and Social Interaction (SI) tests. MK-801-treated rats, particularly the MK-High group, displayed impaired social affective responses, characterized by reduced preference for and investigation of distressed conspecifics. These impairments were ameliorated by chemogenetic inhibition of pyramidal cells in the mPFC, whereas activation of these neurons disrupted social affective behavior in naive rats. Histological analyses revealed reduced parvalbumin-positive interneuron (PVIN) density in the mPFC of MK-801-treated rats. Consistent with the involvement of PVIN dysfunction, selective activation of mPFC PVINs alleviated social affective deficits in MK-801-treated rats. These findings identify impaired PVIN-mediated inhibitory regulation within the mPFC as a circuit mechanism underlying social affective dysfunction following neonatal NMDAr blockade, providing insight into the pathophysiology of schizophrenia-related social impairments.

neuroscience↗

bioRxiv2026

Renal nutrient loss promotes metabolic health at the expense of increased vulnerability to acute kidney injury

Obesity is a major risk factor for interrelated cardiorenal metabolic diseases including type 2 diabetes, heart failure and chronic kidney disease (1-4). Although obesity develops when energy intake chronically exceeds energy expenditure, individuals vary markedly in the amount of adiposity and metabolic dysfunction that develop in response to comparable caloric excess. Controlled overfeeding studies demonstrate several-fold variation in weight gain between individuals (5), while susceptibility to metabolic dysfunction also differs substantially between populations (6), suggesting considerable variation in how excess nutrients are partitioned. Energy balance is conventionally considered in terms of intake and expenditure, yet energy-containing nutrients can also be eliminated from the body. The kidney is uniquely positioned to regulate this third component of energy balance by determining whether filtered metabolites are reabsorbed or excreted. The metabolic benefits of SGLT2 inhibition demonstrate that reducing renal nutrient reabsorption can favourably alter systemic metabolic function (7,8), but whether naturally occurring variation in renal nutrient conservation contributes to metabolic disease susceptibility remains unknown. Here, screening eleven genetically divergent mouse strains identified BXD34 mice as strikingly resistant to diet-induced obesity, ectopic lipid accumulation and insulin resistance despite increased caloric intake. Mechanistically, this protection was associated with widespread urinary nutrient loss accompanied by coordinated suppression of renal solute transport, but came at the cost of profound susceptibility to acute kidney injury. Together, these findings identify renal nutrient conservation as an underappreciated determinant of whole-body metabolism and reveal a renometabolic trade-off in which protection from obesity is achieved at the expense of renal resilience.

physiology↗

bioRxiv2026

Structural basis for loss of covalent flavinylation in the H158Y mutant of pyranose oxidase

Pyranose oxidase from Phanerochaete chrysosporium (PcPOx) is a flavoprotein that forms a covalent 8-N3-histidyl-FAD linkage at His158. Here, we determined the crystal structure of the PcPOx H158Y variant at 1.69 [A] resolution and investigated its FAD occupancy and catalytic activity. Tyr158 adopts a rotamer conformation incompatible with covalent flavinylation, placing its phenolic O atom 8.7 [A] away from the FAD C8 atom. This conformation is stabilized through a Tyr158-Lys79 hydrogen bond. The additional mutation K79A abolishes this hydrogen bond, potentially freeing the Tyr158 residue for other conformations, but does not restore covalent flavin attachment. The H158Y variant retains substantial FAD occupancy and tetrameric assembly but shows markedly reduced oxidase and dehydrogenase turnover rates (less than 13% of WT). These results provide a structural explanation for the failure of tyrosine substitution to support covalent flavinylation in PcPOx and offer insights into requirements for engineering alternative covalent flavin linkages.

biochemistry↗

bioRxiv2026

The significance of sukumo (composted indigo leaves) as a microbial source for traditional Japanese indigo dyeing

A critical process in traditional Japanese indigo dyeing is the microbial reduction of indigo within the dye suspension, which consists solely of sukumo (fermented indigo leaves), wood ash lye, and microbial nutrients such as wheat bran. Although sukumo has long been recognized as a potential microbial source, the microbial community dynamics during its production is still largely unexplored, and its contribution to dyeing performance via microbial supply remains poorly characterized. In this study, we investigated the significance of sukumo as a microbial source, in addition to its established role as a pigment source. We conducted a time-series analysis of microbial communities throughout the four-month fermentation process of sukumo, using weekly samples collected from two geographically distinct indigo dyeing studios. Microbial profiling revealed similar successional patterns between the two sites. Notably, in the later stages of fermentation, known indigo-reducing bacteria, such as the genus Oceanobacillus and the family Tissierellaceae, emerged at both locations. Laboratory-scale dyeing experiments using immature sukumo demonstrated that supplementation with a small amount of mature sukumo restored dyeing activity and increased the abundance of Oceanobacillus and Tissierellaceae. Furthermore, the addition of the indigo-reducing isolate Tissierellaceae strain TU-1 to the immature sukumo-based dye suspension led to a marked enhancement in dyeing performance. These findings highlight the critical role of sukumo as a microbial source in traditional indigo dyeing and suggest that prolonged fermentation is essential for nurturing functional indigo-reducing bacteria. This insight provides a foundation for improving dye suspension performance through targeted microbial community management.

microbiology↗

bioRxiv2026

Metabolic diversity of microorganisms toward atypical sugar enantiomers

Life on Earth has long been regarded as homochiral, relying almost exclusively on a single enantiomer of sugars--typically the D-form. However, recent discoveries challenge this paradigm, including the identification of L-glucose-catabolizing bacteria and microbial L-glucoside hydrolases. Despite these findings, the metabolic diversity of organisms toward a broader range of atypical sugar enantiomers and their ecological relevance remains largely unexplored. This study aimed to identify and isolate microorganisms capable of catabolizing atypical enantiomers of diverse sugars. We performed enrichment cultures with either the D- or L-forms of glucose, fructose, xylose, and sorbose, using soil and activated sludge as microbial sources. Microbial growth was observed under all tested conditions, with the dominant taxa varying depending on the sugars supplied. Six phylogenetically distinct bacterial isolates exhibited the ability to catabolize atypical sugar enantiomers, two of which exhibited growth on all tested sugars. These findings uncover a previously unrecognized diversity in microbial sugar metabolisms, providing new insights into the environmental dynamics of atypical sugar enantiomers and offering a novel perspective on the principle of biological homochirality. Furthermore, this work lays a foundation for the development of biomanufacturing processes using racemic sugar mixtures synthesized via abiotic chemical reactions.

microbiology↗

bioRxiv2025

Genome organizer SATB1 restrains the BACH1-cMAF axis that drives autoimmunity

The establishment of central tolerance in the thymus is governed by precise gene regulatory networks, but how disrupted chromatin architecture leads to autoimmunity is unclear. The genome organizer SATB1 is essential for T cell development and its loss triggers a severe autoimmune phenotype. Here, we identify a pathogenic transcriptional axis, involving BACH1 and cMAF, that is unleashed upon SATB1 deletion. Using integrated multi-omics in T cell-specific Satb1-knockout mice, we demonstrate that SATB1 constrains BACH1 chromatin occupancy. In its absence, BACH1 redistributes to promoter-proximal regions and SATB1-bound immune loci, where it facilitates the recruitment of the transcription factor cMAF. This BACH1-cMAF complex drives a pro-inflammatory transcriptional program in thymocytes, which seeds the periphery and results in a systemic autoimmune disease. Strikingly, genetic ablation of Bach1 in Satb1-deficient mice rescues the pathology, normalizes immunity and prevents mortality. Furthermore, genetic or pharmacological inhibition of cMAF ameliorates the disease. The pro-inflammatory signature in mutant T cells overlaps with T cells from Systemic Lupus Erythematosus (SLE) patients. Our findings reveal a BACH1-cMAF axis that is derepressed upon SATB1 loss and bridges disrupted thymic chromatin organization to peripheral autoimmunity, nominating new therapeutic targets.

molecular biology↗

bioRxiv2025

The nuclear role of methionine adenosyltransferase 2A in immunoglobulin class switch recombination

Methionine adenosyltransferase synthesizes S-adenosylmethionine (SAM), the universal methyl donor. Its ubiquitous isozyme MAT2 is present in the nucleus and regulates gene expression through histone methylation. However, the physiological significance of its nuclear enzymatic activity remains unclear. Here, we investigate the role of nuclear MAT2 in antibody class switch recombination (CSR), a crucial process in adaptive immunity. We established murine B-cell lines expressing either wild-type (WT) or catalytically-inactive (D134A) MAT2A subunits, targeted to the nucleus with nuclear localization signal (NLS). Inhibition of nuclear MAT2 enzymatic activity by expressing NLS-MAT2A(D134A) significantly suppressed CSR from IgM to IgA and reduced intracellular SAM levels. Chromatin immunoprecipitation revealed that MAT2A localized to the IgA switch region. Interestingly, while the expression of germline transcripts was enhanced, the expression of activation-induced cytidine deaminase (AID), an essential enzyme for CSR, was downregulated in NLS-MAT2A(D134A) cells. Our findings demonstrate that the enzymatic activity of MAT2 in the nucleus is indispensable for CSR, likely by ensuring proper AID expression subsequent to germline transcription, thus revealing a critical link between nuclear SAM metabolism and adaptive immunity.

biochemistry↗

bioRxiv2025

Human fibrosarcoma cells selected for very-high doxorubicin resistance, acquire trabectedin and eribulin cross-resistance, remain sensitive to recombinant methioninase, and have increased c-MYC expression

Doxorubicin is first-line chemotherapy for soft tissue sarcoma; however, the development of drug resistance limits its efficacy. The purpose of the present study was to select very-high doxorubicin-resistant (VHDR) HT1080 fibrosarcoma cells, determine cross-resistance to second-line chemotherapy drugs, determine maintenance of sensitivity to recombinant methioninase (r-METase) alone and in combination with doxorubicin, and measure the level of c-MYC expression. VHDR-HT1080 cells were generated by cultivating HT-1080 cells in a series of step-wise progressively higher concentrations of doxorubicin, ranging from 8 nM to 15 {micro}M, an 1875-fold increase, over a five-month period. The WST-8 reagent was used to assess cell viability. Four groups of in vitro drug-sensitivity tests were conducted, which involved both parental HT1080 and VHDR-HT1080 cells: 1) doxorubicin alone; 2) rMETase alone; 3) a combination of doxorubicin and rMETase; and 4) untreated control. The cross-resistance of VHDR-HT1080 cells to eribulin, trabectedin, gemcitabine and docetaxel was determined. The c-MYC levels in HT1080 and VHDR-HT1080 cells were measured using Western blotting. Doxorubicin had an IC50 of 3.3 {micro}M against HT1080 cells and 38.2 {micro}M against VHDR-HT1080 cells an 11.6-fold increase. The rMETase IC50 value for HT1080 was 0.75 U/ml and 0.59 U/ml for VHDR-HT1080. rMETase sensitized VHDR-HT1080 cells to doxorubicin. VHDR-HT1080 cells were cross-resistant to trabectedin 8.9-fold and cross-resistant to eribulin 1.87-fold compared to parental HT1080 cells. c-MYC expression was 8.4 times higher in VHDR-HT1080 cells compared to HT-1080 cells. The present results suggest rMETase may be used as a future clinical strategy to overcome super-doxorubicin resistance in soft tissue sarcoma.

cancer biology↗

bioRxiv2025

Metabolic cell death of labile iron deficiency as a vulnerability of head and neck squamous cancer cells evaded by BACH1

Head and neck squamous cell carcinoma (HNSCC) remains difficult to treat due to the lack of molecularly targeted drugs with high anti-tumor efficacy and safety. To investigate the involvement of the transcription factor BACH1, which is known to promote the metastasis of various cancers, in the malignant properties of HNSCC cells, we examined the effects of BACH1 depletion with short interfering RNAs in human HNSCC cell lines. We found that knockdown of BACH1 induced cell death due to depletion of intracellular labile iron which is not tightly bound to protein. Mitochodrial electron transfer chain activity was severely reduced but efficiently resuced with supplementation of iron in the medium. By combining chromatin immunoprecipitation-sequence and RNA-sequence analyses, we found that BACH1 represses ferritin genes in HNSCC cells. BACH1 knockdown was found to enhance the effect of tipifarnib, a selective inhibitor of farnesyltransferase required for HRAS activation, resulting in efficient inhibition of proliferation of HNSCC cell lines in vitro. These results indicate that BACH1 is essential for maintaining the amount of labile iron in HNSCC cells to evade metabolic cell death of iron deficiency and to proliferate. BACH1 can be a target for conferring Tipifarnib sensitivity to HNSCC cells.

cancer biology↗

bioRxiv2025

Low-Background Cancer Imaging With a Bioorthogonal Fluorescence Probe and Engineered Reporter Enzyme Bearing a Targeting Moiety

Combinatorial use of an antibody-reporter enzyme conjugate and a fluorescence probe activated by the enzyme is a powerful strategy for fluorescence-guided cancer surgery. However, conventional probes for typical reporter enzymes are insufficiently bioorthogonal, resulting in high background signals in non-target tissues. We screened a library of HMRef (rhodol derivative)-based fluorescence probes bearing various sugar moieties, and discovered that HMRef-{beta}-D-fucose is bioorthogonal in mammalian systems, but is activated by a metagenomic glycosidase, Td2F2. Directed evolution generated a mutant with a kcat/Km value for HMRef-{beta}-D-fucose of 3.3 x 105/M/sec, 7.3 times higher than that of wild-type Td2F2 and comparable to that of {beta}-galactosidase (LacZ) with a corresponding probe. Theoretical calculation suggested that E296G mutation in Td2F2 causes structural changes that facilitate the probes access to the enzymes active site. In a proof-of-concept study, cancer cells were visualized with a minimal background in the mesentery of a mouse model of peritoneally disseminated human-ovarian-cancer-derived SKOV-3 cells, which endogenously express HER2, by using HMRef-{beta}-D-fucose together with engineered Td2F2 conjugated/fused to a HER2-binding antibody/nanobody.

bioengineering↗

bioRxiv2025

Protein-ligand affinity prediction via Jensen-Shannon divergence of molecular dynamics simulation trajectories

Predicting the binding affinity between proteins and ligands is a critical task in drug discovery. Although various computational methods have been proposed to estimate ligand target affinity, the method of Yasuda et al. (2022) ranks affinities based on the dynamic behavior obtained from molecular dynamics (MD) simulations without requiring structural similarity among ligand substituents. Thus, its applicability is broader than that of relative binding free energy calculations. However, their approach suffers from high computational costs due to the extensive simulation time and the deep learning computations needed for each ligand pair. Moreover, in the absence of experimental {Delta}G values (oracle), the sign of the correlation can be misinterpreted. In this study, we present improvements to Yasuda et al.s method. Our contributions are threefold: (1) By introducing the Jensen-Shannon (JS) divergence, we eliminate the need for deep learning-based similarity estimation, thereby significantly reducing computation time; (2) We demonstrate that production run simulation times can be halved while maintaining comparable accuracy; and (3) We propose a method to predict the sign of the correlation between the first principal component (PC1) and {Delta}G by using coarse {Delta}G estimations obtained via AutoDock Vina.

bioinformatics↗

bioRxiv2024

Isolation of bacteria that catabolize abiotically synthesized tetroses via the formose reaction

Sugars synthesized through abiotic processes, specifically the formose reaction, are promising candidates for next-generation feedstocks for biomanufacturing due to their significantly higher productivity compared to cultivated crops. One of the significant challenges associated with the utilization of abiotically synthesized sugars via the formose reaction is the presence of unusual sugars, which are not metabolized by typical microorganisms. This study aimed to identify microorganisms capable of catabolizing tetroses, which are among the unusual sugars present in the abiotically synthesized sugars. Four model bacteria commonly used in biomanufacturing, including Escherichia coli, were unable to catabolize tetroses and their growth was completely inhibited by 2 to 4 g/L of D-erythrose or 0.5 to 1 g/L of L-erythrulose. We successfully isolated eight phylogenetically diverse bacterial strains from river sediments, capable of utilizing D-erythrose and L-erythrulose as the sole carbon sources. These isolates exhibited higher tolerances to tetroses compared to the model bacteria. The isolates exhibited the ability to grow in high concentrations of the abiotically synthesized sugars, which inhibit the growth of typical microorganisms, and to consume tetroses contained therein. Further investigation into the molecular mechanisms of tetrose metabolisms in the isolates will facilitate the development of biomanufacturing processes utilizing the abiotically synthesized sugars.

microbiology↗

bioRxiv2024

Identifying simultaneous inhibition of riboflavin metabolism and MEK as a novel therapeutic strategy for pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) remains a formidable challenge with a survival rate of approximately 10%, largely due to the lack of diagnostic and therapeutic options. To identify novel therapeutic targets for PDAC, we previously developed a Drosophila melanogaster model, the 4-hit fly, which mimics the alterations in KRAS, TP53, CDKN2A, and SMAD4 genes observed in PDAC. Through whole-body genetic screening using the 4-hit model, we identified riboflavin (RF) metabolism as a novel potential therapeutic target for PDAC. Additionally, transcript levels of four out of five genes that are involved in RF metabolism were elevated in human PDAC compared to non-tumor tissues. Roseoflavin (RoF), an antimetabolite of RF, resulted in a variety range of metabolic changes, decreased mitochondrial respiratory chain activity, and suppressed proliferation in cultured PDAC cells. Furthermore, the combination of RoF with the MEK inhibitor drug trametinib significantly suppressed the growth of human PDAC xenografts compared to either treatment alone. These findings underscore that dual targeting of RF metabolism and MEK represents a novel therapeutic strategy for PDAC.

cancer biology↗

bioRxiv2024

Random forest machine learning algorithm classifies white- and brown-rot fungi according to the number of Carbohydrate-Active enZyme genes

Wood-rotting fungi play an important role in the global carbon cycle because they are only known organisms that digest wood, the largest carbon stock in nature. In the present study, we used linear discriminant analysis and random forest (RF) machine learning algorithms to predict white- or brown-rot decay modes from the numbers of genes encoding Carbohydrate-Active enZymes (CAZymes) with over 98% accuracy. Unlike other algorithms, RF identified specific genes involved in cellulose and lignin degradation, including auxiliary activities (AA) family 9 lytic polysaccharide monooxygenases, glycoside hydrolase family 7 cellobiohydrolases, and AA family 2 peroxidases, as critical factors. This study sheds light on the complex interplay between genetic information and decay modes and underscores the potential of RF for comparative genomics studies of wood-rotting fungi. ImportanceWood-rotting fungi are categorized as either white- or brown-rot modes based on the coloration of decomposed wood. The process of classification can be influenced by human biases. The random forest machine learning algorithm effectively distinguishes between white- and brown-rot fungi based on the presence of Carbohydrate-Active enZyme genes. These findings not only aid in the classification of wood-rotting fungi but also facilitate the identification of the enzymes responsible for degrading woody biomass.

bioinformatics↗

bioRxiv2024

Cysteine restriction induces ferroptosis depending on the polyamine biosynthetic pathway in hepatic cancer cells

Background and AimsMetabolic activities are also known to affect responses and disease processes of the liver which is a central organ for organismal metabolism. Liver diseases such as intestinal failure associated liver disease (IFALD) and hepatocellular carcinoma are known to be affected by nutrition contents, but the mechanisms behind them remain unclear. In this study, we aimed to reveal the relationship between the concentration of sulfur-containing amino acids and hepatocellular response, and further investigated the mechanism focusing on methionine adenosyltransferase (MAT), which plays the central role in methionine metabolism by synthesizing S-adenosylmethionine (SAM). MethodsMouse hepatoma Hepa1 cells were cultured in media with reduced amounts of cysteine, methionine, or both. Cell death was monitored using propidium iodide (PI) and annexin V staining followed by flow cytometry. Inhibitors of ferroptosis (Fer-1), autophagy (GSK872), SAM synthesis (cycloleucine), or polyamine synthesis (sardomozide and DFMO) were used. ResultsCysteine restriction induced marked cell death, whereas simultaneous restriction of cysteine and methionine fully suppressed the cell death. Cysteine restriction-induced cell death was suppressed with Fer-1 and GSK872, suggesting the involvement of ferroptosis in this process. Cysteine restriction-induced cell death was also suppressed by knockdown of MAT2A or its inhibitor cycloleucine. Furthermore, inhibitors of several enzymes in the polyamine biosynthetic pathway also suppressed the cell death. In contrast, primary culture of mouse hepatocytes did not show cell death upon cysteine restriction. ConclusionsThese results suggest that SAM-polyamine metabolism is a critical modulator of ferroptosis of hepatic cancer cells. Since normal liver cells were more resistant to ferroptosis than cancer cells, cysteine restriction may be exploited in treating hepatic cancer by inducing ferroptosis specifically in cancer cells without affecting normal cells in the liver. Graphical abstrct O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=61 SRC="FIGDIR/small/582667v1_ufig1.gif" ALT="Figure 1"> View larger version (13K): org.highwire.dtl.DTLVardef@bcb32borg.highwire.dtl.DTLVardef@96d39corg.highwire.dtl.DTLVardef@1eaa25org.highwire.dtl.DTLVardef@1346f82_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

TANK binding kinase 1 promotes BACH1 degradation through both phosphorylation-dependent and -independent mechanisms without relying on heme and FBXO22

BTB and CNC homology 1 (BACH1) represses the expression of genes involved in the metabolism of iron, heme and reactive oxygen species. While BACH1 is rapidly degraded when it is bound to heme, it remains unclear how BACH1 degradation is regulated under other conditions. We found that FBXO22, a ubiquitin ligase previously reported to promote BACH1 degradation, polyubiquitinated BACH1 only in the presence of heme in a highly purified reconstitution assay. In parallel to this regulatory mechanism, TANK binding kinase 1 (TBK1), a protein kinase that activates innate immune response and regulates iron metabolism via ferritinophagy, was found to promote BACH1 degradation when overexpressed in 293T cells. While TBK1 phosphorylated BACH1 at multiple serine and threonine residues, BACH1 degradation was observed with not only the wild-type TBK1 but also catalytically impaired TBK1. The BACH1 degradation in response to catalytically impaired TBK1 was not dependent on FBXO22 but involved both autophagy-lysosome and ubiquitin-proteasome pathways judging from its suppression by using inhibitors of lysosome and proteasome. Chemical inhibition of TBK1 in hepatoma Hepa1 cells showed that TBK1 was not required for the heme-induced BACH1 degradation. Its inhibition in Namalwa B lymphoma cells increased endogenous BACH1 protein. These results suggest that TBK1 promotes BACH1 degradation in parallel to the FBXO22- and heme-dependent pathway, placing BACH1 as a downstream effector of TBK1 in iron metabolism or innate immune response.

biochemistry↗

bioRxiv2023

Organelle landscape analysis using a multi-parametric particle-based method

Organelles have unique structures and molecular compositions for their functions and have been classified accordingly. However, many organelles are heterogeneous and in the process of maturation and differentiation. Because traditional methods have a limited number of parameters and spatial resolution, they struggle to capture the heterogeneous landscapes of organelles. Here, we present a method for multi-parametric particle-based analysis of organelles. After disrupting cells, fluorescence microscopy images of organelle particles labeled with six to eight different organelle markers were obtained, and their multi-dimensional data were represented in intuitive two-dimensional UMAP (uniform manifold approximation and projection) spaces. This method enabled visualization of landscapes of seven major organelles as well as the transitional states of endocytic organelles directed to the recycling and degradation pathways. Furthermore, endoplasmic reticulum-mitochondria contact sites were detected in these maps. Our proposed method successfully detects a wide array of organelles simultaneously, enabling the analysis of heterogeneous organelle landscapes.

cell biology↗

bioRxiv2022

Acquirement of the autonomic nervous system modulation evaluated by heart rate variability in medaka (Oryzias latipes)

Small teleosts have recently been established as models of human diseases. However, measuring heart rate by electrocardiography is highly invasive for small fish. The physiological nature and function of vertebrate autonomic nervous system (ANS) modulation of the heart has traditionally been investigated in larvae with an incompletely developed ANS or in anesthetized adults, whose ANS activity may possibly be disturbed under anesthesia. Here, we defined the frequency characteristics of heart rate variability (HRV) modulated by the ANS from observations of heart movement in high-speed movie images and changes in ANS regulation under environmental stimulation in unanesthetized adult medaka (Oryzias latipes), a small teleost. The HRV was significantly reduced by atropine (1 mM) in the 0.25 - 0.65 Hz and by propranolol (100 M) at 0.65-1.25 Hz range, suggesting that HRV in adult medaka is modulated by both the parasympathetic and sympathetic nervous systems within these frequency ranges. Such modulations of HRV by the ANS were remarkably suppressed in anesthetized adult medaka. Continuous exposure to light suppressed HRV only in the 0.25 - 0.65 Hz range, indicating parasympathetic withdrawal. The power of HRV increased along developmental processes. These results suggest that ANS modulation of the heart in adult medaka is frequency-dependent phenomenon, and that the impact of long-term environmental stimuli on ANS activities can be precisely evaluated in unanesthetized adult fish using this method.

physiology↗