Biology subjects

Sumiyoshi, A.

Publications and source records attributed to Sumiyoshi, A..

5 recordsLinked to original sources

bioRxiv2026

Inosine Triphosphate Pyrophosphatase as a Candidate Associated with White Matter Abnormalities in Chronic Heart Failure

Background: White matter hyperintensities (WMHs) are common with normal brain aging and frequently observed also in chronic heart failure (CHF). However, the relationship between CHF and white matter abnormalities and the biological factors remain unclear. We investigated WMH and associated white matter microstructural changes, such as fractional anisotropy (FA), in CHF and explored candidate molecular factors. Methods: We conducted a longitudinal prospective observation including brain T2-FLAIR magnetic resonace imaging for 32 asymptomatic Stage B (mean age 63.3{+/-}10.5 years; 25% women) and 23 symptomatic Stage C CHF patients (mean age 67.3{+/-}7.1 years; 30% women). Plasma proteomics and Mendelian randomization (MR) were used to identify candidate proteins associated with both CHF and WMH. The association of candidate proteins was further investigated using complementary analyses in CHF rats, cultured cortical neurons, and community-based genetic data in UK Biobank. Results: Global WMH volume increased more in Stage C than Stage B patients, predominantly near the anterior periventricular white matter, despite comparable cardiac indices (4,717{+/-}5,335 mm3 vs. 2,116{+/-}3,134 mm3, P=0.027). SomaScan-based proteomic analysis of plasma samples from this patient cohort revealed that 44 proteins are significantly associated with both Stage C CHF and WMH progression (P<0.05). Of these 44 proteins, two-step Mendelian randomization analysis identified inosine triphosphate pyrophosphatase (ITPA) as the only candidate protein, further supported by an association between rare variants in ITPA and FA. In CHF rats, the anterior pericallosal cortex showed decreases in myelin basic protein density and FA and an increase in ITPA expression compared to sham rats. In cultured cortical neurons, recombinant ITPA exposure reduced total axonal length. Conclusions: Symptomatic CHF was associated with WMH and impaired white matter integrity. ITPA emerged as a candidate factor across human, animal, and cellular analyses. These findings provide a basis for investgating the biological pathways linking CHF and white matter injury.

neuroscience↗

bioRxiv2024

Activation mapping in multi-center rat sensory-evoked functional MRI datasets using a unified pipeline.

Functional Magnetic Resonance Imaging (fMRI) in rodents is pivotal for understanding the mechanisms underlying Blood Oxygen Level-Dependent (BOLD) signals and phenotyping animal models of disorders, amongst other applications. Despite its growing use, comparing rodent fMRI results across different research sites remains challenging due to variations in experimental protocols. Here, we aggregated and analyzed 22 sensory-evoked rat fMRI datasets from 12 imaging centers, totaling scans from 220 rats, to assess the consistency of results across diverse protocols. We applied a standardized preprocessing pipeline and evaluated the impact of different hemodynamic response function models on group and individual level activity patterns. Our analysis revealed inter-dataset variability attributed to differences in experimental design, anesthesia protocols, and imaging parameters. We identified robust activation clusters in all (22/22) datasets. The comparison between stock human models implemented in software and rat-specific models showed significant variations in the resulting statistical maps. Our findings emphasize the necessity for standardized protocols and collaborative efforts to improve the reproducibility and reliability of rodent fMRI studies. We provide open access to all datasets and analysis code to foster transparency and further research in the field.

neuroscience↗

bioRxiv2023

Structural alterations in the amygdala and impaired social incentive learning in a mouse model of a genetic variant associated with neurodevelopmental disorders

Copy number variants (CNVs) are robustly associated with psychiatric disorders and their dimensions and changes in brain structures and behavior. However, as CNVs contain many genes, the precise gene-phenotype relationship remains unclear. Although various volumetric alterations in the brains of 22q11.2 CNV carriers have been identified in humans and mouse models, it is unknown how the genes in the 22q11.2 region individually contribute to structural alterations and associated mental illnesses and their dimensions. Our previous studies have identified Tbx1, a T-box family transcription factor encoded in 22q11.2 CNV, as a driver gene for social interaction and communication, spatial and working memory, and cognitive flexibility. However, it remains unclear how TBX1 impacts the volumes of various brain regions and their functionally linked behavioral dimensions. In this study, we used volumetric magnetic resonance imaging analysis to comprehensively evaluate brain region volumes in congenic Tbx1 heterozygous mice. Our data show that the volumes of anterior and posterior portions of the amygdaloid complex and its surrounding cortical regions were reduced in Tbx1 heterozygous mice. Moreover, we examined the behavioral consequences of an altered volume of the amygdala. Tbx1 heterozygous mice were impaired for their ability to detect the incentive value of a social partner in a task that depends on the amygdala. Our findings identify the structural basis for a specific social dimension associated with loss-of-function variants of TBX1 and 22q11.2 CNV.

neuroscience↗

bioRxiv2023

Dentate neurogenesis mediates cognitive flexibility via modulation of the hippocampal longitudinal-axis network

Adult neurogenesis endows the hippocampus with unparalleled neural plasticity, essential for intricate cognitive functions. However, the manner in which sparse newborn neurons (NBNs) modulate neural activities and subsequently shape behavior remains enigmatic. Utilizing a newly engineered NBN-Tetanus Toxin mouse model, we non-invasively silenced NBNs and confirmed their crucial role in cognitive flexibility, as demonstrated through reversal learning in the Morris water maze and the Go/Nogo task in operant learning. Pairing task-based functional MRI (tb-fMRI) with operant learning revealed a dorsal hippocampal hyperactivation during Nogo task, implying that hippocampal hyperexcitability might underlie the observed behavioral deficits. Notably, resting-state fMRI (rs-fMRI) revealed enhanced functional connectivity between the dorsal and ventral dentate gyrus following NBN silencing. Further exploration of PV+ interneurons and mossy cells activities highlighted NBNs integral part in preserving the excitation/inhibition balance within the hippocampus. Our findings emphasize how the neural plasticity driven by NBNs extensively modulates the hippocampus, sculpting cognitive flexibility.

neuroscience↗

bioRxiv2021

Tbx1, a 22q11.2-encoded gene, is a link between alterations in fimbria myelination and cognitive speed in mice

Copy number variants (CNVs) have provided a reliable entry point to identify structural correlates of atypical cognitive development. Hemizygous deletion of human chromosome 22q11.2 is associated with impaired cognitive function; however, the mechanisms by which numerous genes encoded in this CNV contribute to cognitive deficits via diverse structural alterations in the brain remain unclear. This study aimed to determine the cellular basis of the link between alterations in brain structure and cognitive functions in a mouse model. The heterozygosity of Tbx1, a 22q11.2 gene, altered the composition of myelinated axons in the fimbria, reduced oligodendrocyte production capacity, and slowed the acquisition of spatial memory and cognitive flexibility. Our findings provide a cellular basis for specific cognitive dysfunctions that occur in patients with loss-of-function TBX1 variants and 22q11.2 hemizygous deletion. TeaserA risk gene for autism alters myelin composition in the hippocampal connection and slows cognitive speed.

neuroscience↗