Molecular Brain最新文献

{"title":"Region-specific activation in the accumbens nucleus by itch with modified scratch efficacy in mice - a model-free multivariate analysis.","authors":"Sanae Inokuchi-Sakata, Ryo Narita, Yukari Takahashi, Yozo Ishiuji, Akihiko Asahina, Fusao Kato","doi":"10.1186/s13041-024-01101-w","DOIUrl":"10.1186/s13041-024-01101-w","url":null,"abstract":"<p><p>Itch is a protective/defensive function with divalent motivational drives. Itch itself elicits an unpleasant experience, which triggers the urge to scratch, relieving the itchiness. Still, it can also result in dissatisfaction when the scratch is too intense and painful or unsatisfactory due to insufficient scratch effect. Therefore, it is likely that the balance between the unpleasantness/pleasure and satisfaction/unsatisfaction associated with itch sensation and scratching behavior is determined by complex brain mechanisms. The physiological/pathological mechanisms underlying this balance remain largely elusive. To address this issue, we targeted the \"reward center\" of the brain, the nucleus accumbens (NAc), in which itch-responsive neurons have been found in rodents. We examined how neurons in the NAc are activated or suppressed during histamine-induced scratching behaviors in mice. The mice received an intradermal injection of histamine or saline at the neck, and the scratching number was analyzed by recording the movement of the bilateral hind limbs for about 45 min after injection. To experimentally manipulate the scratch efficacy in these histamine models, we compared histamine's behavioral and neuronal effects between mice with intact and clipped nails on the hind paws. As expected, the clipping of the hind limb nail increased the number of scratches after the histamine injection. In the brains of mice exhibiting scratching behaviors, we analyzed the expression of the c-fos gene (Fos) as a readout of an immediate activation of neurons during itch/scratch and dopamine receptors (Drd1 and Drd2) using multiplex single-molecule fluorescence in situ hybridization (RNAscope) in the NAc and surrounding structures. We performed a model-free analysis of gene expression in geometrically divided NAc subregions without assuming the conventional core-shell divisions. The results indicated that even within the NAc, multiple subregions responded differentially to various itch/scratch conditions. We also found different clusters with neurons showing similar or opposite changes in Fos expression and the correlation between scratch number and Fos expression in different itch/scratch conditions. These regional differences and clusters would provide a basis for the complex role of the NAc and surrounding structures in encoding the outcomes of scratching behavior and itchy sensations.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11119306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141087946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Broad proteomics analysis of seeding-induced aggregation of α-synuclein in M83 neurons reveals remodeling of proteostasis mechanisms that might contribute to Parkinson's disease pathogenesis.","authors":"Casey J Lumpkin, Hiral Patel, Gregory K Potts, Shilpi Chaurasia, Lauren Gibilisco, Gyan P Srivastava, Janice Y Lee, Nathan J Brown, Patricia Amarante, Jon D Williams, Eric Karran, Matthew Townsend, Dori Woods, Brinda Ravikumar","doi":"10.1186/s13041-024-01099-1","DOIUrl":"10.1186/s13041-024-01099-1","url":null,"abstract":"<p><p>Aggregation of misfolded α-synuclein (α-syn) is a key characteristic feature of Parkinson's disease (PD) and related synucleinopathies. The nature of these aggregates and their contribution to cellular dysfunction is still not clearly elucidated. We employed mass spectrometry-based total and phospho-proteomics to characterize the underlying molecular and biological changes due to α-syn aggregation using the M83 mouse primary neuronal model of PD. We identified gross changes in the proteome that coincided with the formation of large Lewy body-like α-syn aggregates in these neurons. We used protein-protein interaction (PPI)-based network analysis to identify key protein clusters modulating specific biological pathways that may be dysregulated and identified several mechanisms that regulate protein homeostasis (proteostasis). The observed changes in the proteome may include both homeostatic compensation and dysregulation due to α-syn aggregation and a greater understanding of both processes and their role in α-syn-related proteostasis may lead to improved therapeutic options for patients with PD and related disorders.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11110445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141080331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A method for selective and efficient isolation of gray matter astrocytes from the spinal cord of adult mice.","authors":"Ryoma Iwasaki, Yuta Kohro, Makoto Tsuda","doi":"10.1186/s13041-024-01097-3","DOIUrl":"10.1186/s13041-024-01097-3","url":null,"abstract":"<p><p>A growing body of evidence indicates intra- and inter-regional heterogeneity of astrocytes in the brain. However, because of a lack of an efficient method for isolating astrocytes from the spinal cord, little is known about how much spinal cord astrocytes are heterogeneous in adult mice. In this study, we developed a new method for isolating spinal astrocytes from adult mice using a cold-active protease from Bacillus licheniformis with an astrocyte cell surface antigen-2 (ACSA-2) antibody. Using fluorescence-activated cell sorting, isolated spinal ACSA-2⁺ cells were divided into two distinct populations, ACSA-2^high and ACSA-2^low. By analyzing the expression of cell-type marker genes, the ACSA-2^high and ACSA-2^low populations were identified as astrocytes and ependymal cells, respectively. Furthermore, ACSA-2^high cells had mRNAs encoding genes that were abundantly expressed in the gray matter (GM) but not white matter astrocytes. By optimizing enzymatic isolation procedures, the yield of GM astrocytes also increased. Therefore, our newly established method enabled the selective and efficient isolation of GM astrocytes from the spinal cord of adult mice and may be useful for bulk- or single-cell RNA-sequencing under physiological and pathological conditions.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11106874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141076207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatiotemporal dynamics of the CD11c⁺ microglial population in the mouse brain and spinal cord from developmental to adult stages.","authors":"Kohei Nomaki, Risako Fujikawa, Takahiro Masuda, Makoto Tsuda","doi":"10.1186/s13041-024-01098-2","DOIUrl":"10.1186/s13041-024-01098-2","url":null,"abstract":"<p><p>CD11c-positive (CD11c⁺) microglia have attracted considerable attention because of their potential implications in central nervous system (CNS) development, homeostasis, and disease. However, the spatiotemporal dynamics of the proportion of CD11c⁺ microglia in individual CNS regions are poorly understood. Here, we investigated the proportion of CD11c⁺ microglia in six CNS regions (forebrain, olfactory bulb, diencephalon/midbrain, cerebellum, pons/medulla, and spinal cord) from the developmental to adult stages by flow cytometry and immunohistochemical analyses using a CD11c reporter transgenic mouse line, Itgax-Venus. We found that the proportion of CD11c⁺ microglia in total microglia varied between CNS regions during postnatal development. Specifically, the proportion was high in the olfactory bulb and cerebellum at postnatal day P(4) and P7, respectively, and approximately half of the total microglia were CD11c⁺. The proportion declined sharply in all regions to P14, and the low percentage persisted over P56. In the spinal cord, the proportion of CD11c⁺ microglia was also high at P4 and declined to P14, but increased again at P21 and thereafter. Interestingly, the distribution pattern of CD11c⁺ microglia in the spinal cord markedly changed from gray matter at P4 to white matter at P21. Collectively, our findings reveal the differences in the spatiotemporal dynamics of the proportion of CD11c⁺ microglia among CNS regions from early development to adult stages in normal mice. These findings improve our understanding of the nature of microglial heterogeneity and its dynamics in the CNS.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11102220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140958385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Moxibustion ameliorates chronic inflammatory visceral pain via spinal circRNA-miRNA-mRNA networks: a central mechanism study","authors":"Dan Zhang, Xiaoqing Dong, Xiaoying Li, Yanting Yang, Hongna Li, Yue Hong, Guang Yang, Xiehe Kong, Xuejun Wang, Xiaopeng Ma","doi":"10.1186/s13041-024-01093-7","DOIUrl":"https://doi.org/10.1186/s13041-024-01093-7","url":null,"abstract":"This study aimed to unveil the central mechanism of moxibustion treating chronic inflammatory visceral pain (CIVP) from the angle of circRNA-miRNA-mRNA networks in the spinal cord. The rat CIVP model was established using a mixture of 5% (w/v) 2,4,6-trinitrobenzene sulfonic acid and 50% ethanol at a volume ratio of 2:1 via enema. Rats in the moxibustion group received herb-partitioned moxibustion at Tianshu (ST25, bilateral) and Qihai (CV6) points. The abdominal withdrawal reflex (AWR), mechanical withdrawal threshold (MWT), and thermal withdrawal latency (TWL) were adopted for pain behavior observation and pain sensitivity assessment. The circRNA, miRNA, and mRNA expression profiles were detected using the high-throughput sequencing technique. Relevant databases and bioinformatics analysis methods were used to screen for differentially expressed (DE) RNAs and build a circRNA-miRNA-mRNA (competing endogenous RNA) ceRNA regulatory network. The real-time quantitative PCR was employed to verify the sequencing result. CIVP rat models had a significantly higher AWR and lower TWL and MWT than normal rats. Between normal and model rats, there were 103 DE-circRNAs, 16 DE-miRNAs, and 397 DE-mRNAs in the spinal cord. Compared with the model group, the moxibustion group had a lower AWR and higher TWL and MWT; between these two groups, there were 118 DE-circRNAs, 15 DE-miRNAs, and 804 DE-mRNAs in the spinal cord. Two ceRNA networks were chosen to be verified. As a result, moxibustion’s analgesic effect on visceral pain in CIVP rats may be associated with regulating the circRNA_02767/rno-miR-483-3p/Gfap network in the spinal cord and improving central sensitization.","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140925869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic pain enhances excitability of corticotropin-releasing factor-expressing neurons in the oval part of the bed nucleus of the stria terminalis","authors":"Ryoko Uchida, Yasutaka Mukai, Taiju Amano, Kenji Sakimura, Keiichi Itoi, Akihiro Yamanaka, Masabumi Minami","doi":"10.1186/s13041-024-01094-6","DOIUrl":"https://doi.org/10.1186/s13041-024-01094-6","url":null,"abstract":"We previously reported that enhanced corticotropin-releasing factor (CRF) signaling in the bed nucleus of the stria terminalis (BNST) caused the aversive responses during acute pain and suppressed the brain reward system during chronic pain. However, it remains to be examined whether chronic pain alters the excitability of CRF neurons in the BNST. In this study we investigated the chronic pain-induced changes in excitability of CRF-expressing neurons in the oval part of the BNST (ovBNSTCRF neurons) by whole-cell patch-clamp electrophysiology. CRF-Cre; Ai14 mice were used to visualize CRF neurons by tdTomato. Electrophysiological recordings from brain slices prepared from a mouse model of neuropathic pain revealed that rheobase and firing threshold were significantly decreased in the chronic pain group compared with the sham-operated control group. Firing rate of the chronic pain group was higher than that of the control group. These data indicate that chronic pain elevated neuronal excitability of ovBNSTCRF neurons.","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140839095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"L-DOPA regulates neuroinflammation and Aβ pathology through NEP and ADAM17 in a mouse model of AD","authors":"Hyun-ju Lee, JinHan Nam, Jeong-Woo Hwang, Jin-Hee Park, Yoo Joo Jeong, Ji-Yeong Jang, Su-Jeong Kim, A-Ran Jo, Hyang-Sook Hoe","doi":"10.1186/s13041-024-01092-8","DOIUrl":"https://doi.org/10.1186/s13041-024-01092-8","url":null,"abstract":"Dopamine plays important roles in cognitive function and inflammation and therefore is involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). Drugs that increase or maintain dopamine levels in the brain could be a therapeutic strategy for AD. However, the effects of dopamine and its precursor levodopa (L-DOPA) on Aβ/tau pathology in vivo and the underlying molecular mechanisms have not been studied in detail. Here, we investigated whether L-DOPA treatment alters neuroinflammation, Aβ pathology, and tau phosphorylation in 5xFAD mice, a model of AD. We found that L-DOPA administration significantly reduced microgliosis and astrogliosis in 5xFAD mice. In addition, L-DOPA treatment significantly decreased Aβ plaque number by upregulating NEP and ADAM17 levels in 5xFAD mice. However, L-DOPA-treated 5xFAD mice did not exhibit changes in tau hyperphosphorylation or tau kinase levels. These data suggest that L-DOPA alleviates neuroinflammatory responses and Aβ pathology but not tau pathology in this mouse model of AD.","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140838987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peripheral-central network analysis of cancer cachexia status accompanied by the polarization of hypothalamic microglia with low expression of inhibitory immune checkpoint receptors","authors":"Yukari Suda, Keiko Nakamura, Fukiko Matsuyama, Yusuke Hamada, Hitoshi Makabe, Michiko Narita, Yasuyuki Nagumo, Tomohisa Mori, Naoko Kuzumaki, Minoru Narita","doi":"10.1186/s13041-024-01091-9","DOIUrl":"https://doi.org/10.1186/s13041-024-01091-9","url":null,"abstract":"While the excessive inflammation in cancer cachexia is well-known to be induced by the overproduction of inflammatory mediators in the periphery, microflora disruption and brain dysfunction are also considered to contribute to the induction of cancer cachexia. Hypothalamic microglia play a crucial role in brain inflammation and central-peripheral immune circuits via the production of inflammatory mediators. In the present study, we evaluated possible changes in excessive secretion of gut microbiota-derived endotoxin and the expression timeline of several inflammation-regulatory mediators and their inhibiting modulators in hypothalamic microglia of a mouse model of cancer cachexia following transplantation of pancreatic cancer cells. We demonstrated that the plasma level of lipopolysaccharide (LPS) was significantly increased with an increase in anaerobic bacteria, especially Firmicutes, in the gut at the late stage of tumor-bearing mice that exhibited dramatic appetite loss, sarcopenia and severe peripheral immune suppression. At the early stage, in which tumor-bearing mice had not yet displayed “cachexia symptoms”, the mRNA expression of pro-inflammatory cytokines, but not of the neurodegenerative and severe inflammatory modulator lipocalin-2 (LCN2), was significantly increased, whereas at the late “cachexia stage”, the level of LCN2 mRNA was significantly increased along with significant decreases in levels of inhibitory immune checkpoint receptors programmed death receptor-1 (PD-1) and CD112R in hypothalamic microglia. In addition, a high density of activated neurons in the paraventricular nucleus (PVN) of the hypothalamus region and a significant increase in corticosterone secretion were found in cachexia model mice. Related to the cachexia state, released corticosterone was clearly increased in normal mice with specific activation of PVN neurons. A marked decrease in the natural killer cell population was also observed in the spleen of mice with robust activation of PVN neurons as well as mice with cancer cachexia. On the other hand, in vivo administration of LPS in normal mice induced hypothalamic microglia with low expression of inhibitory immune checkpoint receptors. These findings suggest that the induction of cancer cachexia may parallel exacerbation of the hypothalamic inflammatory status with polarization to microglia expressed with low levels of inhibitory immune checkpoint receptors following LPS release from the gut microflora.","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140811926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Toll-like receptor 4 deficiency ameliorates β2-microglobulin induced age-related cognition decline due to neuroinflammation in mice","authors":"Q. Zhong, Yufeng Zou, Hongchao Liu, Tingting Chen, F. Zheng, Yifei Huang, Chang Chen, Zongze Zhang","doi":"10.1186/s13041-024-01090-w","DOIUrl":"https://doi.org/10.1186/s13041-024-01090-w","url":null,"abstract":"","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140668161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The 37TrillionCells initiative for improving global healthcare via cell-based interception and precision medicine: focus on neurodegenerative diseases","authors":"Benoit Coulombe, Thomas M. Durcan, Geneviève Bernard, Asmae Moursli, Christian Poitras, Denis Faubert, Maxime Pinard","doi":"10.1186/s13041-024-01088-4","DOIUrl":"https://doi.org/10.1186/s13041-024-01088-4","url":null,"abstract":"One of the main burdens in the treatment of diseases is imputable to the delay between the appearance of molecular dysfunctions in the first affected disease cells and their presence in sufficient number for detection in specific tissues or organs. This delay obviously plays in favor of disease progression to an extent that makes efficient treatments difficult, as they arrive too late. The development of a novel medical strategy, termed cell-based interception and precision medicine, seeks to identify dysfunctional cells early, when tissue damages are not apparent and symptoms not yet present, and develop therapies to treat diseases early. Central to this strategy is the use of single-cell technologies that allow detection of molecular changes in cells at the time of phenotypical bifurcation from health to disease. In this article we describe a general procedure to support such an approach applied to neurodegenerative disorders. This procedure combines four components directed towards highly complementary objectives: 1) a high-performance single-cell proteomics (SCP) method (Detect), 2) the development of disease experimental cell models and predictive computational models of cell trajectories (Understand), 3) the discovery of specific targets and personalized therapies (Cure), and 4) the creation of a community of collaborating laboratories to accelerate the development of this novel medical paradigm (Collaborate). A global initiative named 37TrillionCells (37TC) was launched to advance the development of cell-based interception and precision medicine.","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140602564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}