Biology subjects

Morita, M.

Publications and source records attributed to Morita, M..

27 records · Page 2Linked to original sources

bioRxiv2023

Asymmetric spread of excitatory synaptic potentialin hippocampal neuronal dendrites revealed by voltage imaging

Processing of synaptic signals in somatodendritic compartments determines the neuronal computation. Although amplification of excitatory signals by local voltage-dependent cation channels has been extensively studied, its spatio-temporal dynamics in elaborate dendritic branches remains obscure because of technical limitation. Using fluorescent voltage imaging throughout dendritic arborizations in hippocampal pyramidal neurons, here we demonstrate a unique Cl--dependent remote computation mechanism equipped in distal branches. Local laser photolysis of caged-glutamate triggered excitatory postsynaptic potentials spreading along dendrites with gradual amplification toward the distal end whereas with attenuation toward the soma. Tour-de-force subcellular patch-clamp recordings from thin branches complemented with biophysical model simulation revealed that the asymmetric augmentation of excitation relies on the TTX-resistant Na+ channels and Cl--conductances accompanied with deeper dendritic resting potential. Taken together, the present study unveils cooperative voltage-dependent actions of cation and anion conductances for dendritic supralinear computation which can locally decode the spatio-temporal context of synaptic inputs.

neuroscience↗

bioRxiv2023

Emotional association enhances perceptual memory through amygdalo-cortical inputs during NREM sleep

Emotional arousal is thought to enhance the consolidation of associated memories by activating the basolateral amygdala (BLA) and its projections to memory-storing regions1-4. Although the importance of both rapid eye movement (REM) and non-REM (NREM) sleep-state specific BLA activity for emotional memory processing has been proposed5-9, how and when the BLA interacts with other brain regions to enhance memory consolidation remains unclear10. Here, by adding emotional information to a perceptual recognition task that relies on top-down inputs from frontal to sensory cortices, we demonstrated that the BLA not only associates emotional information with perceptual information, but also enhances the retention of associated perceptual memory through BLA-frontal projections. Electrophysiological recordings revealed that emotional association increases the reactivation of coordinated activity across the BLA-frontal-sensory region during NREM sleep, but not during REM sleep. Notably, this inter-regional coordinated reactivation during NREM sleep was entrained to the BLA high-frequency oscillations in the emotional condition, suggesting that the BLA triggers inter-regional interaction. Optogenetic silencing of BLA terminals in the frontal cortex during NREM sleep, but not REM sleep, disrupted the enhanced retention of the perceptual memory, but not the association itself or the emotional component of associative memory. Our results indicate that the inter-regional coordination through the BLA-cortical inputs during NREM sleep is causally required for memory enhancement by emotional arousal.

neuroscience↗

bioRxiv2022

Crosstalk between AQP4-dependent ATP/Adenosine release and dopamine neurotransmission in depressive behavior during cocaine withdrawal

Our previous study has demonstrated the AQP4-dependent ATP release and following elevation of extracellular adenosine in hippocampal slices during hypo-osmotic treatment. In the present study, we examined the crosstalk between AQP4-dependent adenosine elevation and dopaminergic neurotransmissions, especially focusing on the mouse depressive behavior during cocaine withdrawal. The depressive behavior was mitigated in AQP4 knockout mice, and was sensitive to adenosine A1 receptor antagonists. Thus, the influence of cocaine withdrawal on the adenosine or dopamine elevation in the slices from the striatum or medial prefrontal cortex, which is the focus of depression was analyzed by the originally-developed biosensor cells, which elevates intracellular Ca2+ in response to adenosine or dopamine. We have found that the evoked-dopamine release in the striatum is tonically suppressed via A1 receptor in a AQP4 dependent manner, and this suppression is augmented by the cocaine withdrawal. In contrast, the evoked dopamine elevation in the medial prefrontal cortex was suppressed by treating slices with adenosine or an A1 receptor antagonist, and the cocaine withdrawal abolished the suppression by A1 receptor antagonist alone in an AQP4-dependent manner. Since a GABAA or group II metabotropic glutamate receptor antagonist occluded the suppression by A1 receptor antagonist, it has been suggested that the glutamatergic and GABAergic terminals suppressing dopamine releases have A1 receptors, which the cocaine withdrawal down-regulates in a AQP4-dependent manner. These results indicate that astrocytes modulate dopaminergic neurotransmissions via A1 receptor in an AQP4-dependent manner, and suggest that cocaine causes depression by changing this modulation.

neuroscience↗

bioRxiv2022

ACSF2: A MEDIUM-CHAIN ACYL-CoA SYNTHETASE WITH A POTENTIAL ROLE IN NEURONAL DIFFERENTIATION

By activating fatty acids to their CoA derivatives, acyl-CoA synthetases (ACS) play an essential role in fatty acid metabolism. We previously identified ACSF2 as an ACS that was phylogenetically distinct from known families of short-chain, medium-chain, long-chain, very long-chain, and bubblegum ACSs. Functionally, ACSF2 preferentially activated medium-chain fatty acids. In this work, we provide further characterization of this unique ACS. ACSF2 mRNA expression was found in most tissues, although immunohistochemical analysis revealed differences in protein expression between various cell types in each tissue. Endogenous ACSF2 was found in the Golgi region in Neuro2a and P19 cells, and disruption of the Golgi in Neuro2a cells with nocodazole disrupted ACSF2 localization. In contrast, MA-10, HepG2, and skin fibroblasts had a mitochondrial ACSF2 localization. ACSF2 activated saturated fatty acids containing 6 to 10 carbons when overexpressed in COS-1 cells. The Kmapp for C10:0 was 24.4 M and Vmaxapp was 385 nmol/20min/mg COS cell protein. Knockdown by RNA interference revealed that ACSF2 was responsible for most of the medium-chain ACS activity in Neuro2a cells. A lysine residue critical for activity in bacterial short-chain ACSs was found in ACSF2, and mutation of this residue to alanine abolished enzyme activity. Neurite outgrowth results when Neuro2a cells are induced to differentiate with retinoic acid, and ACSF2 migrated to nodes and points of neurite-neurite contact along with the presynaptic marker, synaptophysin. ACSF2-deficient Neuro2a cells showed significantly blunted neurite outgrowth in response to retinoic acid. These results suggest that this medium-chain ACS may play an important role in neuronal development.

biochemistry↗

bioRxiv2021

Genomic characteristics of recently recognized Vibrio cholerae El Tor lineages associated with cholera in Bangladesh, 1991-2017

Comparative genomic analysis of Vibrio cholerae El Tor associated with endemic cholera in Asia revealed two distinct lineages, one dominant in Bangladesh and the other in India. An in depth whole genome study of V. cholerae El Tor clinical strains isolated during endemic cholera in Bangladesh (1991 - 2017) included reference genome sequence data obtained online. Core genome phylogeny established using single nucleotide polymorphisms (SNPs) showed V. cholerae El Tor strains comprised two lineages, BD-1 and BD-2, which, according to Bayesian phylodynamic analysis, originated from paraphyletic group BD-0 around 1981. BD-1 and BD-2 lineages overlapped temporally but were negatively associated as causative agents of cholera 2004-2017. Genome wide association study (GWAS) revealed 140 SNPs and 31 indels, resulting in gene alleles unique to BD-1 and BD-2. Regression analysis of root to tip distance and year of isolation indicated early BD-0 strains at the base, whereas BD-1 and BD-2 subsequently emerged and progressed by accumulating SNPs. Pangenome analysis provided evidence of gene acquisition by both BD-1 and BD-2, of which six crucial proteins of known function were predominant in BD-2. BD-1 and BD-2 diverged and have distinctively different genomic traits, namely heterogeneity in VSP-2, VPI-1, mobile elements, toxin encoding elements, and total gene abundance. In addition, the observed phage-inducible chromosomal island-like element (PLE1), and SXT ICE elements (ICETET) in BD-2 presumably provided a fitness advantage for the lineage to outcompete BD-1 as the etiological agent of the endemic cholera in Bangladesh, with implications for global cholera epidemiology. ImportanceCholera is a global disease with specific reference to the Bay of Bengal Ganges Delta where Vibrio cholerae O1 El Tor, causative agent of the disease showed two circulating lineages, one dominant in Bangladesh and the other in India. Results of in-depth genomic study of V. cholerae associated with endemic cholera during the past 27 years (1991 - 2017) indicate emergence and succession of the two lineages, BD-1 and BD-2, arising from a common ancestral paraphylatic group, BD-0, comprising the early strains and short-term evolution of the bacterium in Bangladesh. Among the two V. cholerae lineages, BD-2 supersedes BD-1 and is predominant in the most recent endemic cholera in Bangladesh. The BD-2 lineage contained significantly more SNPs and indels, and showed richness in gene abundance, including antimicrobial resistance genes, gene cassettes, and PLE to fight against bacteriophage infection, acquired over time. These findings have important epidemic implications at a global scale.

genomics↗

bioRxiv2021

Serum hormone levels in infertile women between conceived with and without hormone replacement therapy: Safety of estradiol and progesterone replacement therapy in frozen-thawed embryo transfer cycles for breast cancer survivors.

ObjectiveRecent advances in cancer treatment and reproductive medicine have made the post-treatment quality of life an important concern for cancer survivors. We aimed to evaluate the safety of sex hormone (estradiol and progesterone) replacement therapy (HRT) in women who conceived by assisted reproductive technology (ART) with hormone receptor-positive breast cancer. MethodsWe measured serum E2 and P4 levels at 4-10 weeks of gestation in women who conceived naturally or after timed intercourse or intrauterine insemination for infertility without HRT for luteal support (non-HR group; n=135). We conducted a retrospective comparison of the values from the non-HR group with those of women who conceived by ART with HRT for infertility (HR group; n=75). ResultsSerum E2 levels were significantly higher in the non-HR group than in the HR group at 5, 6, and 8 weeks of gestation. Similarly, serum P4 levels were significantly higher in the non-HR group than in the HR group at 4, 5, and 6 weeks of gestation. ConclusionsThis study suggests that in cancer reproductive medicine for hormone-dependent breast cancer survivors, HRT administered during the first trimester of a pregnancy after primary disease treatment may not increase the sex hormone levels to levels above those seen in spontaneous pregnancy.

cancer biology↗

bioRxiv2020

APC mutant cells exploit compensatory chromosome alterations to restore tumour cell fitness

Cancer cells tolerate copy number alterations (CNAs) of genomic regions that are lethal to non-cancer cells. Certain CNAs are preferentially associated with specific cancer types and lineages, but the mechanisms underlying the emergence and selection of specific CNAs remain unclear. Adenomatous polyposis coli (APC) mutations induce mitotic errors, but their impact on tumor evolution remains elusive. We investigated APC function in cultured cells and tumors and found that its loss led to {beta}-catenin accumulation at centrosomes, suppressing its maturation through inhibition of key centrosome regulators, including Aurora kinase A (AURKA) that promotes tumor growth. These defects collectively reduced cellular fitness, leading to impaired mitotic fidelity and delayed cell cycle progression. However, in APC-mutant tumors, AURKA activity was maintained, at least in part, through the amplification of chromosomes harboring AURKA and its activator genes, yet this alone was insufficient to fully restore proliferation: aberrant chromosomal reorganization also emerged and contributed to the adaptive fitness of APC-mutant cells. Such a process of adaptive CNA selection provides a framework for understanding how specific CNAs are selected to counteract disadvantages imposed by genetic alterations during tumor progression, providing one key insight into how specific CNAs are selected in this context.

cell biology↗

bioRxiv2018

Development and validation of serological markers for detecting recent exposure to Plasmodium vivax infection

In order to accelerate towards malaria elimination, improved targeting of limited resources is essential. A major gap in our elimination toolkit for Plasmodium vivax malaria is the identification of individuals carrying arrested liver stages, called hypnozoites. These clinically silent but frequently relapsing hypnozoites are key to P. vivax persistence. Whilst hypnozoites cannot be directly detected, individuals who have had recent exposure to P. vivax and have not been treated are likely to harbor these parasites. By measuring IgG antibody responses to over 300 P. vivax proteins, a panel of serological markers capable of detecting exposure to P. vivax infections in the prior 9-month period was identified and validated. Using antibody responses to 8 P. vivax proteins, 80% sensitivity and specificity for detecting recent infections were achieved in three independent studies conducted in Thailand, Brazil and the Solomon Islands. As these individuals have a high likelihood of harboring hypnozoites, the suite of these 8 antibody responses can serve as biomarkers for the identification of individuals who should be targeted for treatment with liver-stage drugs such as primaquine and tafenoquine in mass drug administration programs aimed at controlling and eliminating P. vivax malaria.\n\nOne Sentence SummaryThe manuscript describes identification and validation of a novel panel of P. vivax proteins that can be used to detect recent exposure to P. vivax infections within the prior 9 months.

microbiology↗

bioRxiv2017

Translational and HIF1α-dependent metabolic reprograming underpin oncometabolomeplasticity and synergy between oncogenic kinase inhibitors and biguanides.

There is heightened interest to devise therapies that target the oncometabolome. We show that kinase inhibitors (KIs) and biguanides synergistically target melanoma, leukemia, and breast, colon and renal cancer cells, but not non-transformed cells. Metabolic profiling confirmed opposing effects of KIs and biguanides on glycolysis, but this was insufficient to explain the observed synergy between the drugs. Rather, we define a critical role for the synthesis of non-essential amino acids (NEAA) aspartate, asparagine and serine as well as reductive glutamine metabolism, in determining the sensitivity of cancer cells to KI - biguanide combinations. The mTORC1/4E-BP axis regulates aspartate, asparagine and serine synthesis by modulating translation of mRNAs encoding PC, ASNS, PHGDH and PSAT1. Ablation of 4E-BP1 and 2 results in a dramatic increase in serine, aspartate and asparagine levels and a substantial decrease in sensitivity of breast cancer and melanoma cells to KI - biguanide combinations. In turn, efficacy of KI - biguanide combinations is impeded by HIF1 and sustained reductive glutamine metabolism. These findings identify hitherto unappreciated translational reprograming of NEAA synthesis and HIF1-dependent stimulation of reductive glutamine metabolism as critical metabolic vulnerabilities of cancer that underpin synergy between KIs and biguanides.

cancer biology↗