Molecular Brain最新文献

{"title":"Globus pallidus is not independent from striatal direct pathway neurons: an up-to-date review.","authors":"Fumino Fujiyama, Fuyuki Karube, Yasuharu Hirai","doi":"10.1186/s13041-024-01107-4","DOIUrl":"10.1186/s13041-024-01107-4","url":null,"abstract":"<p><p>Striatal projection neurons, which are classified into two groups-direct and indirect pathway neurons, play a pivotal role in our understanding of the brain's functionality. Conventional models propose that these two pathways operate independently and have contrasting functions, akin to an \"accelerator\" and \"brake\" in a vehicle. This analogy further elucidates how the depletion of dopamine neurons in Parkinson's disease can result in bradykinesia. However, the question arises: are these direct and indirect pathways truly autonomous? Despite being distinct types of neurons, their interdependence cannot be overlooked. Single-neuron tracing studies employing membrane-targeting signals have shown that the majority of direct pathway neurons terminate not only in the output nuclei, but also in the external segment of the globus pallidus (GP in rodents), a relay nucleus of the indirect pathway. Recent studies have unveiled the existence of arkypallidal neurons, which project solely to the striatum, in addition to prototypic neurons. This raises the question of which type of GP neurons receive these striatal axon collaterals. Our morphological and electrophysiological experiments showed that the striatal direct pathway neurons may affect prototypic neurons via the action of substance P on neurokinin-1 receptors. Conversely, another research group has reported that direct pathway neurons inhibit arkypallidal neurons via GABA. Regardless of the neurotransmitter involved, it can be concluded that the GP is not entirely independent of direct pathway neurons. This review article underscores the intricate interplay between different neuronal pathways and challenges the traditional understanding of their independence.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"17 1","pages":"34"},"PeriodicalIF":3.6,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11157709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141288331","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":"TDP43 interacts with MLH1 and MSH6 proteins in a DNA damage-inducible manner","authors":"Vincent E. Provasek, Manohar Kodavati, Brandon Kim, Joy Mitra, Muralidhar L. Hegde","doi":"10.1186/s13041-024-01108-3","DOIUrl":"https://doi.org/10.1186/s13041-024-01108-3","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy. TDP43 is a ubiquitous RNA/DNA binding protein with functional implications in a wide range of disease processes, including the repair of DNA double-strand breaks (DSBs). While TDP43 is widely known to regulate RNA metabolism, our lab has reported it also functions directly at the protein level to facilitate DNA repair. Here, we show that the TDP43 protein interacts with DNA mismatch repair (MMR) proteins MLH1 and MSH6 in a DNA damage-inducible manner. We utilized differentiated SH-SY5Y neuronal cultures to identify this inducible relationship using complementary approaches of proximity ligation assay (PLA) and co-immunoprecipitation (CoIP) assay. We observed that signals of TDP43 interaction with MLH1 and MSH6 increased significantly following a 2 h treatment of 10 μM methylmethanesulfonate (MMS), a DNA alkylating agent used to induce MMR repair. Likewise, we observed this effect was abolished in cell lines treated with siRNA directed against TDP43. Finally, we demonstrated these protein interactions were significantly increased in lumbar spinal cord samples of ALS-affected patients compared to age-matched controls. These results will inform our future studies to understand the mechanisms and consequences of this TDP43-MMR interaction in the context of ALS-affected neurons.","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"312 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141258831","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":"Dendritic spine head diameter is reduced in the prefrontal cortex of progranulin haploinsufficient mice","authors":"Anna K. Cook, Kelsey M. Greathouse, Phaedra N. Manuel, Noelle H. Cooper, Juliana M. Eberhardt, Cameron D. Freeman, Audrey J. Weber, Jeremy H. Herskowitz, Andrew E. Arrant","doi":"10.1186/s13041-024-01095-5","DOIUrl":"https://doi.org/10.1186/s13041-024-01095-5","url":null,"abstract":"Loss-of-function mutations in the progranulin (GRN) gene are an autosomal dominant cause of Frontotemporal Dementia (FTD). These mutations typically result in haploinsufficiency of the progranulin protein. Grn+/– mice provide a model for progranulin haploinsufficiency and develop FTD-like behavioral abnormalities by 9–10 months of age. In previous work, we demonstrated that Grn+/– mice develop a low dominance phenotype in the tube test that is associated with reduced dendritic arborization of layer II/III pyramidal neurons in the prelimbic region of the medial prefrontal cortex (mPFC), a region key for social dominance behavior in the tube test assay. In this study, we investigated whether progranulin haploinsufficiency induced changes in dendritic spine density and morphology. Individual layer II/III pyramidal neurons in the prelimbic mPFC of 9–10 month old wild-type or Grn+/– mice were targeted for iontophoretic microinjection of fluorescent dye, followed by high-resolution confocal microscopy and 3D reconstruction for morphometry analysis. Dendritic spine density in Grn+/– mice was comparable to wild-type littermates, but the apical dendrites in Grn+/– mice had a shift in the proportion of spine types, with fewer stubby spines and more thin spines. Additionally, apical dendrites of Grn+/– mice had longer spines and smaller thin spine head diameter in comparison to wild-type littermates. These changes in spine morphology may contribute to altered circuit-level activity and social dominance deficits in Grn+/– mice.","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"53 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141258859","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 unpredictable stress induces autophagic death of adult hippocampal neural stem cells.","authors":"Seongwon Choe, Hyeonjeong Jeong, Jieun Choi, Seong-Woon Yu","doi":"10.1186/s13041-024-01105-6","DOIUrl":"10.1186/s13041-024-01105-6","url":null,"abstract":"<p><p>Chronic psychological stress is a critical factor for neurological complications like anxiety disorders, dementia, and depression. Our previous results show that chronic restraint stress causes cognitive deficits and mood dysregulation by inducing autophagic death of adult hippocampal neural stem cells (NSCs). However, it is unknown whether other models of psychological stress also induce autophagic death of adult hippocampal NSCs. Here, we show that chronic unpredictable stress (CUS) for 10 days impaired memory function and increased anxiety in mice. Immunohistochemical staining with SOX2 and KI67 revealed a significant reduction in the number of NSCs in the hippocampus following exposure to CUS. However, these deficits were prevented by NSC-specific, inducible conditional deletion of Atg7. These findings suggest that autophagic death of adult hippocampal NSCs is a critical pathogenic mechanism underlying stress-induced brain disorders.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"17 1","pages":"31"},"PeriodicalIF":3.6,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11145853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141238067","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":"Hypothalamic protein profiling from mice subjected to social defeat stress.","authors":"Shiladitya Mitra, Ghantasala S Sameer Kumar, Anumita Samanta, Mathias V Schmidt, Suman S Thakur","doi":"10.1186/s13041-024-01096-4","DOIUrl":"10.1186/s13041-024-01096-4","url":null,"abstract":"<p><p>The Hypothalmic-Pituitary-Adrenal axis also known as the HPA axis is central to stress response. It also acts as the relay center between the body and the brain. We analysed hypothalamic proteome from mice subjected to chronic social defeat paradigm using iTRAQ based quantitative proteomics to identify changes associated with stress response. We identified greater than 2000 proteins after processing our samples analysed through Q-Exactive (Thermo) and Orbitrap Velos (Thermo) at 5% FDR. Analysis of data procured from the runs showed that the proteins whose levels were affected belonged primarily to mitochondrial and metabolic processes, translation, complement pathway among others. We also found increased levels of fibrinogen, myelin basic protein (MBP) and neurofilaments (NEFL, NEFM, NEFH) in the hypothalamus from socially defeated mice. Interestingly, research indicates that these proteins are upregulated in blood and CSF of subjects exposed to trauma and stress. Since hypothalamus secreted proteins can be found in blood and CSF, their utility as biomarkers in depression holds an impressive probability and should be validated in clinical samples.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"17 1","pages":"30"},"PeriodicalIF":3.6,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11131206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141158287","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":"S100 proteins: a new frontier in fibromyalgia research.","authors":"María Teresa Vega-Ramírez, Enrique Becerril-Villanueva, José Luis Maldonado-García, Lenin Pavón, Gilberto Pérez-Sánchez","doi":"10.1186/s13041-024-01102-9","DOIUrl":"10.1186/s13041-024-01102-9","url":null,"abstract":"<p><p>Fibromyalgia (FM) is a chronic condition that causes widespread pain, fatigue, and other symptoms that significantly affect quality of life. The underlying mechanisms of fibromyalgia involve both the immune system and the central nervous system. It has been proposed that changes in multiple ascending and descending pathways in the central nervous system may contribute to increased pain sensitivity in individuals with this condition. Recent research has identified S100 proteins as a new area of interest in fibromyalgia studies. These proteins are a group of small molecular weight proteins involved in inflammation and various functions inside and outside of cells, and they may play a critical role in the development and progression of FM. Although S100B has been the most studied in FM patients, other studies have reported that S100A7, S100A8, S100A9, and S100A12 may also be useful as potential biomarkers or for a deeper understanding of FM pathophysiology. The potential role of S100 proteins in the pathophysiology of fibromyalgia could be mediated by RAGE and TLR4, which signal through JNK, ERK, and p38 to activate AP-1 and NF-κB and induce the release of proinflammatory cytokines, thereby producing the inflammation, fatigue, and chronic pain characteristic of fibromyalgia. To gain new perspectives on targeted therapeutic approaches, it is crucial to understand how S100 proteins could impact the pathophysiology of fibromyalgia. This review examines the potential role of S100 proteins in fibromyalgia and their impact on improving our comprehension of the condition, as well as facilitating further research on this interesting topic.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"17 1","pages":"29"},"PeriodicalIF":3.6,"publicationDate":"2024-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11129469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141154091","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 novel mouse model for investigating α-synuclein aggregates in oligodendrocytes: implications for the glial cytoplasmic inclusions in multiple system atrophy.","authors":"Tomoyuki Ishimoto, Miki Oono, Seiji Kaji, Takashi Ayaki, Katsuya Nishida, Itaru Funakawa, Takakuni Maki, Shu-Ichi Matsuzawa, Ryosuke Takahashi, Hodaka Yamakado","doi":"10.1186/s13041-024-01104-7","DOIUrl":"10.1186/s13041-024-01104-7","url":null,"abstract":"<p><p>The aggregated alpha-synuclein (αsyn) in oligodendrocytes (OLGs) is one of the pathological hallmarks in multiple system atrophy (MSA). We have previously reported that αsyn accumulates not only in neurons but also in OLGs long after the administration of αsyn preformed fibrils (PFFs) in mice. However, detailed spatial and temporal analysis of oligodendroglial αsyn aggregates was technically difficult due to the background neuronal αsyn aggregates. The aim of this study is to create a novel mouse that easily enables sensitive and specific detection of αsyn aggregates in OLGs and the comparable analysis of the cellular tropism of αsyn aggregates in MSA brains. To this end, we generated transgenic (Tg) mice expressing human αsyn-green fluorescent protein (GFP) fusion proteins in OLGs under the control of the 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) promoter (CNP-SNCAGFP Tg mice). Injection of αsyn PFFs in these mice induced distinct GFP-positive aggregates in the processes of OLGs as early as one month post-inoculation (mpi), and their number and size increased in a centripetal manner. Moreover, MSA-brain homogenates (BH) induced significantly more oligodendroglial αsyn aggregates than neuronal αsyn aggregates compared to DLB-BH in CNP-SNCAGFP Tg mice, suggestive of their potential tropism of αsyn seeds for OLGs. In conclusion, CNP-SNCAGFP Tg mice are useful for studying the development and tropism of αsyn aggregates in OLGs and could contribute to the development of therapeutics targeting αsyn aggregates in OLGs.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"17 1","pages":"28"},"PeriodicalIF":3.3,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11127389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141093765","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":"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":"17 1","pages":"27"},"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":"17 1","pages":"26"},"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":"17 1","pages":"25"},"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}