Biology subjects

Usui, N.

Publications and source records attributed to Usui, N..

6 recordsLinked to original sources

bioRxiv2026

Region-specific cortico-striatal transcriptomic remodeling following early postnatal dopaminergic disturbance

Dopamine signaling plays critical roles in postnatal brain development, yet the molecular consequences of early dopaminergic disturbance remain incompletely understood. Here, we investigated transcriptomic alterations in the prefrontal cortex (PFC) and striatum (STR) of mice subjected to early postnatal dopaminergic disturbance by 6-hydroxydopamine (6-OHDA) treatment. Using bulk RNA sequencing (RNA-seq) and weighted gene co-expression network analysis (WGCNA), we identified 369 differentially expressed genes (DEGs) in the PFC, 493 DEGs in the STR, and 32 co-expression modules with region-specific expression patterns. Functional enrichment analyses showed that PFC DEGs were associated with cortical development, plasma membrane signaling, and transcriptional regulation, whereas STR DEGs were enriched for striatal development, locomotion, extracellular matrix organization, and amphetamine response. Co-expression network analysis further identified module-specific enrichments related to developmental, synaptic, metabolic, immune-related, and transcriptional programs. DEG sets from both regions also overlapped with genes implicated in attention-deficit/hyperactivity disorder (ADHD) and other neuropsychiatric disorders. Together, these findings reveal region-specific cortico-striatal transcriptomic remodeling following early postnatal dopaminergic disturbance and identify molecular programs that may link developmental dopaminergic perturbation to later behavioral phenotypes. HighlightsO_LIEarly dopaminergic disturbance reshapes cortico-striatal transcriptomes C_LIO_LIPFC changes were linked to developmental and transcriptional programs C_LIO_LISTR changes were linked to locomotion and extracellular matrix programs C_LIO_LINetwork analysis revealed region-specific developmental and synaptic programs C_LI

neuroscience↗

bioRxiv2025

N-Ethylmaleimide-Sensitive Factor Deletion in Dopamine D2 Receptor Cells and Associated Neuronal and Behavioural Changes in Mice

N-ethylmaleimide-sensitive factor (NSF) plays a crucial role in neurotransmitter release and membrane molecule trafficking by regulating membrane fusion. Dysfunction of NSF has been linked to neuropsychiatric disorders. Although the interaction of NSF with dopamine receptor 2 (D2R) and the resulting excitotoxicity from its reduction in vitro have been demonstrated, the role of NSF in D2R-expressing cells in vivo remains unclear. This study investigated the effects of NSF loss on the survival of D2R-expressing cells and on mouse behaviour. We generated D2R-specific NSF conditional knockout (Nsff/f;D2R-Cre) mice. Targeted deletion of NSF in D2R-expressing cells led to a significant decrease in D2R-expressing neurons, accompanied by increased apoptosis during postnatal development, reduced striatal volume, and substantially lowered dopamine levels in the striatum. Further evidence of dopaminergic dysfunction was shown by reduced dopamine transporter expression in the striatum and tyrosine hydroxylase expression in the striatum and substantia nigra. The Nsff/f;D2R-Cre mice exhibited attention deficit hyperactivity disorder (ADHD)-like behaviours, including hyperactivity and impulsivity. Notably, combined administration of methylphenidate and a D2R agonist effectively alleviated hyperactivity and impulsivity, indicating a potential synergistic approach for ADHD treatment. These findings highlight the critical role of NSF in the survival of D2R-expressing neurons and suggest that disruption of the NSF-D2R interaction may contribute to ADHD-like phenotypes. This study underscores the translational relevance of the Nsff/f;D2R-Cre model for ADHD and suggests that targeting D2R dysfunction, particularly in treatment-resistant cases, may represent a promising therapeutic strategy for ADHD.

neuroscience↗

bioRxiv2020

Zbtb16 regulates social cognitive behaviors and neocortical development.

Recent genetic studies have underscored the pleiotropic effects of single genes to multiple cognitive disorders. Mutations of ZBTB16 are associated with autism spectrum disorder (ASD) and schizophrenia (SCZ), but how the function of ZBTB16 is related to ASD or SCZ remains unknown. Here we show the deletion of Zbtb16 in mice leads to both ASD- and SCZ-like behaviors such as social impairment, repetitive behaviors, risk-taking behaviors, and cognitive impairment. To elucidate the mechanism underlying the behavioral phenotypes, we carried out histological studies and observed impairments in thinning of neocortical layer 6 (L6) and a reduction of TBR1+ neurons in the prefrontal cortex (PFC) of Zbtb16 KO mice. Furthermore, we found increased dendritic spines and microglia as well as developmental defects in oligodendrocytes and neocortical myelination in the PFC of Zbtb16 KO mice. Using a genomics approach, we identified the Zbtb16-transcriptome that includes genes involved in both ASD and SCZ pathophysiology and neocortical maturation such as neurogenesis and myelination. Co-expression networks further identified Zbtb16-correlated modules that are unique to ASD or SCZ respectively. Our study provides insight into the differential role of ZBTB16 in ASD and SCZ.

neuroscience↗

bioRxiv2020

Cell-type and cytosine context-specific evolution of DNA methylation in the human brain

Cell-type specific epigenetic modifications are critical for brain development and neuropsychiatric diseases. Here we elucidate evolutionary origins of neuron- and oligodendrocyte-specific DNA methylation in human prefrontal cortex, and demonstrate dynamic and distinctive changes of CG and CH methylation. We show that the human brain has experienced pronounced reduction of CG methylation during evolution, which significantly contributed to cell-type specific active regulatory regions. On the other hand, a substantial increase of CH methylation occurred during human brain evolution, associated with fine-tuning expression in development and neuronal subtypes. The majority of differential CG methylation between neurons and oligodendrocytes originated before the divergence of hominoids and catarrhine monkeys, and carries strong signal for genetic risk for schizophrenia. Remarkably, a substantial portion of differential CG methylation between neurons and oligodendrocytes emerged in the human lineage and harbors additional genetic risk for schizophrenia, implicating epigenetic evolution of human cortex in increased vulnerability to neuropsychiatric diseases.

genomics↗

bioRxiv2019

Cell-type specific epigenetic links to schizophrenia risk in brain

The importance of cell-type specific epigenetic variation of non-coding regions in neuropsychiatric disorders is increasingly appreciated, yet data from disease brains are conspicuously lacking. We generated cell-type specific whole-genome methylomes (N=95) and transcriptomes (N=89) from neurons and oligodendrocytes from brains of schizophrenia and matched controls. The methylomes of these two cell-types are highly distinct, with the majority of differential DNA methylation occurring in non-coding regions. DNA methylation difference between control and schizophrenia brains is subtle compared to cell-type difference, yet robust against permuted data and validated in targeted deep-sequencing analyses. Differential DNA methylation between control and schizophrenia tends to occur in cell-type differentially methylated sites, highlighting the significance of cell-type specific epigenetic dysregulation in a complex neuropsychiatric disorder. Our resource provides novel and comprehensive methylome and transcriptome data from distinct cell populations from schizophrenia brains, further revealing reduced cell-type epigenetic distinction in schizophrenia.

genomics↗

bioRxiv2019

Accelerated evolution of oligodendrocytes in human brain

Recent discussions of human brain evolution have largely focused on increased neuron numbers and changes in their connectivity and expression. However, it is increasingly appreciated that oligodendrocytes play important roles in cognitive function and disease. Whether both cell-types follow similar or distinctive evolutionary trajectories is not known. We examined the transcriptomes of neurons and oligodendrocytes in the frontal cortex of humans, chimpanzees, and rhesus macaques. We identified human-specific trajectories of gene expression in neurons and oligodendrocytes and show that both cell-types exhibit human-specific upregulation. Moreover, oligodendrocytes have undergone accelerated gene expression evolution in the human lineage compared to neurons. The signature of acceleration is enriched for cell type-specific expression alterations in schizophrenia. These results underscore the importance of oligodendrocytes in human brain evolution.

evolutionary biology↗