Biology subjects

Tsuji, N.

Publications and source records attributed to Tsuji, N..

4 recordsLinked to original sources

bioRxiv2025

Thalamo-insular pathway regulates tic generation via motor-limbic crosstalk

Tic disorders accompanied by premonitory urges are hallmark symptoms of Tourette syndrome (TS), yet the underlying neuronal mechanisms remain elusive. Here, we establish a mouse model of motor tics by unilateral striatal injection of a GABAA receptor antagonist. This model induces c-Fos activation in both motor and limbic structures, including the insular cortex (IC). Fiber photometry reveals tic-associated activity in IC as well as the primary motor cortex (M1). Viral tracing demonstrates that basal ganglia outputs from the substantia nigra pars reticulata are transmitted to IC via the intralaminar thalamic nuclei (ITN). Chemogenetic inhibition of IC or the thalamo-insular pathway suppresses tic-related cortical activity and alleviates tic-like behaviors. These findings identify IC as a key node in tic generation and highlight ITN as critical relay stations linking motor and limbic circuits. Aberrant thalamo-insular signaling thus contributes to the pathophysiology of tic disorders and represents a potential therapeutic target in TS. HighlightsO_LIc-Fos activation occurs in both motor and limbic structures in a mouse tic model C_LIO_LIBasal ganglia outputs are transmitted to insula via intralaminar thalamic nuclei C_LIO_LIChemogenetic inhibition of thalamo-insular pathway suppresses motor tics C_LIO_LIThalamo-insular inhibition diminishes tic-associated activity in primary motor cortex C_LI In briefAbnormal basal ganglia activity originating from the striatum drives dysfunction of the insular cortex via the intralaminar thalamic nuclei, leading to motor tics. Chemogenetic inhibition of this pathway suppresses tic-like behaviors, highlighting motor-limbic circuit pathology in tic disorders.

neuroscience↗

bioRxiv2023

Patchy and widespread distribution of bacterial translation arrest peptides associated with the protein localization machinery

Regulatory arrest peptides exert cellular functions via mechanisms involving regulated translational arrest. Monitoring substrates, a class of arrest peptides, feedback-regulate the expression of the Sec or YidC protein localization machinery. Previously, only a limited number of monitoring substrates were identified. In this study, we performed a bacterial domain-wide search, followed by in vivo and in vitro analyses, leading to a comprehensive identification of many novel Sec/YidC-related arrest peptides that showed patchy, but widespread, phylogenetic distribution throughout the bacterial domain. Identification of five novel arrest-inducing sequences suggests that bacteria have evolved various arrest-inducing mechanisms. We also identified many arrest peptides that share an R-A-P-P like sequence, suggesting that this sequence could serve as a common evolutionary seed that could overcome the species-specific structures of ribosomes, to evolve arrest peptides. Our comprehensive phylogenetic study revealed that arrest peptide is a prevalent mechanism for the gene regulation of the protein localization machinery.

molecular biology↗

bioRxiv2023

Short-term Topiramate treatment prevents radiation-induced cytotoxic edema in preclinical models of breast-cancer brain metastasis

BackgroundBrain edema is a common complication of brain metastases (BM) and associated treatment. The extent to which cytotoxic edema, the first step in the sequence that leads to ionic edema, vasogenic edema and brain swelling, contributes to radiation-induced brain edema during BM remains unknown. This study aimed to determine whether radiation-associated treatment of BM induces cytotoxic edema and the consequences of blocking the edema in pre-clinical models of breast cancer brain metastases (BCBM). MethodsUsing in vitro and in vivo models, we measured astrocytic swelling, trans-electric resistance (TEER) and aquaporin 4 (AQP4) expression following radiation. Genetic and pharmacological inhibition of AQP4 in astrocytes and cancer cells was used to assess the role of AQP4 in astrocytic swelling and brain water intake. An anti-epileptic drug that blocks AQP4 function (topiramate) was used to prevent cytotoxic edema in models of BM. ResultsRadiation-induced astrocytic swelling and transient upregulation of AQP4 within the first 24 hours following radiation. Topiramate decreased radiation-induced astrocytic swelling, loss of TEER in astrocytes in vitro, and acute short term treatment (but not continuous administration), prevented radiation-induced increase in brain water content without pro-tumorigenic effects in multiple pre-clinical models of BCBM. AQP4 was expressed in clinical BM and breast cancer cell lines, but AQP4 targeting had limited direct pro-tumorigenic or radioprotective effects in cancer cells that could impact its clinical translation. ConclusionsPatients with BM could find additional benefits from acute and temporary preventive treatment of radiation-induced cytotoxic edema using anti-epileptic drugs able to block AQP4 function. Key pointsO_LIRadiation induces cytotoxic edema via acute dysregulation of AQP4 in astrocytes in preclinical models of BM. C_LIO_LIPharmacologic blockage of AQP4 function prevents water intake, astrocytic swelling and restores TEER in vitro. C_LIO_LIPre-treatment with single-dose Topiramate prevents brain radiation-induced brain edema without direct tumor effects in pre-clinical models of BCBM. C_LI IMPORTANCE OF THE STUDYIn this study we describe a novel role for astrocytic swelling and cytotoxic edema in the progression of radiation-induced brain edema during BM treatment. While radiation-induced edema has been fully attributed to the disruption of the blood-brain barrier (BBB) and ensuing vasogenic effects, our results suggest that cytotoxic edema affecting astrocytes in the acute setting plays an important role in the progression of brain edema during BM standard of care. Current standard of care for brain edema involves pre-treatment with steroids and the use of bevacizumab only after clinically significant edema develops. Both interventions are presumed to target vasogenic edema. This study suggests that patients with BM could find additional benefits from acute and temporary preventive treatment of radiation-induced cytotoxic edema using an already FDA-approved anti-epileptic drug. Such early prevention strategy can be easily clinically implemented with the goal of minimizing treatment-related toxicities.

cancer biology↗

bioRxiv2021

BAM15 treats mouse sepsis and sepsis-AKI, linking circulating mitochondrial DNA and tubule reactive oxygen species

The pathogenesis of sepsis is complex and heterogeneous; hence, a precision medicine strategy may be required. Acute kidney injury (AKI) following sepsis portends higher mortality. Overproduction of mitochondrial reactive oxygen species (mtROS) is a potential mediator of sepsis and sepsis-induced AKI. BAM15 is a chemical uncoupler that dissipates the mitochondrial proton gradient without generating mtROS, and improves experimental renal ischemic injury. We injected BAM15 into mice at 0 or 6 hours after cecal ligation and puncture (CLP) treated with fluids and antibiotics. BAM15 reduced mortality, even when started at 6 hours, when mice were ill, and reduced kidney damage but did not affect other organs. Serial plasma and urinary levels of mitochondrial DNA (mtDNA) were increased following CLP, and decreased after BAM15 (at 0 and at 6 hours). In vitro BAM15 prevented mtROS overproduction and mtDNA release from septic kidney tubule cells; mtROS generation correlated with mtDNA release. BAM15 also promotes mitochondrial biogenesis signaling. We conclude that BAM15 is an effective preventive and therapeutic candidate in experimental sepsis, and that BAM15 and mtDNA are mechanistically linked via mtROS, which may form a drug-companion diagnostic pair to improve precision medicine approaches to diagnosing and treating clinical sepsis.

pharmacology and toxicology↗