bioRxiv : the preprint server for biology最新文献

{"title":"Information about task duration influences energetic cost during split-belt adaptation and retention of walking patterns post-adaptation.","authors":"S Jeffcoat, A Aragon, A Kuch, S Farrokhi, A Hooyman, R Johnson, N Sanchez","doi":"10.1101/2024.05.24.595558","DOIUrl":"10.1101/2024.05.24.595558","url":null,"abstract":"<p><p>Studies of locomotor adaptation have shown that adaptation can occur in short bouts and can continue for long bouts or across days. Information about task duration might influence the adaptation of gait features, given that task duration influences the time available to explore and adapt the aspects of gait that reduce energy cost. We hypothesized that information about task duration influences adaptation to split-belt walking based on two competing mechanisms: individuals anticipating a prolonged adaptation period may either (1) extend exploration of energetically suboptimal gait patterns, or (2) adapt toward a more energy-efficient pattern earlier to maintain an energetic reserve to sustain the task longer. We tested three groups: N=19 participants received minute-by-minute updates during a 10-minute adaptation duration (True group), N=19 participants received no updates during a 10-minute adaptation duration and were misled to expect a prolonged 30-minute adaptation duration (False group), and N=14 participants received one update halfway through a 10-minute adaptation duration (Control group). We measured step length asymmetry, leg work, and metabolic cost. Our results partially supported our hypothesis but did not confirm the underlying mechanisms. While step length asymmetry did not differ significantly between groups during adaptation, the True group generated a more effortful gait pattern with a greater increase in metabolic cost (p=0.002) and higher work with the leg on the slow belt (p=0.012). Additionally, the True group showed no association between step length asymmetry and metabolic cost (p=0.203), contrary to the Control (r=-0.55, p=0.043) and False groups (r=-0.51, p=0.027). Finally, we observed that the False group showed greater retention of the split-belt aftereffects than the Control and False groups (p<0.001). Thus, adapted locomotor and energetic patterns are influenced by information about task duration, indicating that Information about task duration should be controlled for, or can be manipulated to elicit different efforts during adaptation.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11142228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141201453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MALADAPTIVE IMMUNE-FIBROTIC AXIS DRIVES IMPAIRED LONG BONE REGENERATION UNDER MECHANICAL INSTABILITY.","authors":"Matthew D Patrick, Jaimo Ahn, Kurt D Hankenson, Ramkumar T Annamalai","doi":"10.1101/2023.10.26.564177","DOIUrl":"10.1101/2023.10.26.564177","url":null,"abstract":"<p><p>Delayed and nonhealing fractures, affecting 5-10% of incidents, result in prolonged disability and reduced quality of life for the patient. While acute inflammation initiates healing, dysregulated immune responses exacerbate bone resorption and fibrosis. Current animal models fail to replicate mechanical instability, the primary driver of clinical hypertrophic nonunion, limiting translational insights. Here, we engineer a murine delayed-healing model using tunable intramedullary nails to impose controlled interfragmentary strains, mimicking human hypertrophic nonunion. High-strain fractures (15-30%) generated larger calluses with delayed ossification, 2.9-fold increase in fibrotic tissue ( <i>p</i> = 0.0099), and inferior biomechanical strength (stiffness: 1.6-fold lower, <i>p</i> = 0.024) compared to low-strain controls (<5%). Spatial transcriptomics revealed persistent fibrotic niches in high-strain calluses enriched with fibroblast-associated genes ( <i>Pdgfrb, Lgals3</i> ) alongside dysregulated macrophage-osteoclast signaling ( <i>Spp1, Mmp9</i> ). Systemic immune profiling revealed CD206+ macrophages and CD25+ T-regulatory cells as predictive biomarkers, with early polarization determining long-term outcomes ( <i>R</i> = 0.72, <i>p</i> = 0.004). Multivariate modeling linked delayed healing to persistent CD8+ T cells and deficient Treg recruitment, perpetuating inflammation. These findings establish mechanical instability as a catalyst for pathological immune-stromal crosstalk and provide a platform for mechano-informed immunotherapies. Our work redefines hypertrophic nonunion as a disorder of mechano-immunology, offering novel diagnostic and therapeutic strategies to mitigate fibrosis and restore regeneration.</p><p><strong>Teaser: </strong>Mechanical strain hijacks immune signaling to induce fibrosis and block bone regeneration in unstable fractures.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10634904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92157590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conserved developmental rewiring of the TCR signalosome drives tolerance in innate-like lymphocytes.","authors":"Amanpreet Singh Chawla, Harriet J Watt, Stefan A Schattgen, Neema Skariah, Irene Saha, Kathrynne A Warrick, Masahito Ogawa, Jessica Strid, Frederic Lamoliatte, Alastair Copland, Sara Pryde, Elena Knatko, Kasper D Rasmussen, Kazu Kikuchi, Paul G Thomas, Chandrashekar Pasare, David Bending, Mahima Swamy","doi":"10.1101/2023.09.01.555859","DOIUrl":"10.1101/2023.09.01.555859","url":null,"abstract":"<p><p>Natural intraepithelial T lymphocytes (T-IELs) are innate-like, intestine-resident T cells essential for gut homeostasis. These cells express self-reactive T cell antigen receptors (TCRs) due to thymic agonist selection, but they do not cause autoimmunity. The mechanism underlying natural T-IELs tolerance in the gut is unclear. Using TCR reporter mouse models and phosphoproteomics, we demonstrate that TCR signaling is intrinsically suppressed in natural T-IELs. We discover that this suppression occurs post-selection in the thymus through altered expression of TCR signalosome components, a mechanism we term RePrESS (Rewiring of Proximal Elements of TCR Signalosome for Suppression). RePrESS is evolutionarily conserved and also found in autoreactive innate-like T cells from skin, breast and prostate. In coeliac disease, tolerance breakdown is associated with loss of RePrESS in natural T-IELs. Our findings reveal a distinct, conserved mechanism of tolerance involving TCR signaling rewiring, with implications for understanding barrier tissue homeostasis and autoimmune disease.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":"45 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12132402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82567093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A framework for analyzing <i>C. elegans</i> neural activity using multi-dimensional hyperbolic embedding.","authors":"Iulia Rusu, Zachary T Cecere, Javier J How, Kathleen T Quach, Eviatar Yemini, Tatyana O Sharpee, Sreekanth H Chalasani","doi":"10.1101/2021.04.09.439242","DOIUrl":"10.1101/2021.04.09.439242","url":null,"abstract":"<p><p>Neurons represent changes in external and internal environments by altering their activity patterns. While coherent brain-wide patterns of neural activity have been observed in neuronal populations, very little is known about their dimensionality, geometry, and how they are correlated with sensory inputs. Here, we recorded the activity of most head neurons in <i>Caenorhabditis elegans</i> experiencing changes in bacterial or control buffer stimuli around their nose. We first classified active neurons into six functional clusters: two sensory neuron clusters (ON and OFF responding to addition and removal of stimuli, respectively) and four motor/command neuron clusters (AVA, RME, SMDD and SMDV). Next, we estimated stimulus selectivity for each cluster and found that while sensory neurons exhibit their maximal responses within 15 seconds, changes in bacterial stimuli drive maximal responses in command and motor neuron clusters after tens of seconds. Furthermore, we show that bacterial stimuli induce neural dynamics that are best described by a hyperbolic, not Euclidean, space, of dimensionality eight. The hyperbolic space provided a better description of neural activity than the standard Euclidean space. This space can be separated into three components - one sensory, and two motor directions (forward-backward and dorsal-ventral). Collectively, we show that <i>C. elegans</i> neural activity can be effectively represented in low-dimensional hyperbolic space to describe a sensorimotor transformation.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12132397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88626297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A GATA factor radiation in <i>Caenorhabditis</i> rewired the endoderm specification network.","authors":"Antonia C Darragh, Rachel Weinstein, Jessica R Bloom, Scott A Rifkin","doi":"10.1101/2022.05.20.492851","DOIUrl":"10.1101/2022.05.20.492851","url":null,"abstract":"<p><p>Although similar developmental regulatory networks can produce diverse phenotypes, different networks can also produce the same phenotype. In theory, as long as development can produce an acceptable end phenotype, the details of the process could be shielded from selection, leading to the possibility of developmental system drift, where the developmental mechanisms underlying a stable phenotype continue to evolve. Many examples exist of divergent developmental genetics underlying conserved traits. However, studies that elucidate how these differences arose and how other features of development accommodated them are rarer. In <i>Caenorhabditis elegans</i>, six transcription factors that bind motifs with a GATA core sequence (GATA factors) comprise the zygotic part of the endoderm specification network. Here we show that the core of this network - five of the genes - originated within the genus during a brief but explosive radiation of this gene family and that at least three of them evolved from a single ancestral gene with at least two different spatio-temporal expression patterns. Based on analyses of their evolutionary history, gene structure, expression, and sequence, we explain how these GATA factors were integrated into this network. Our results show how gene duplication fueled the developmental system drift of the endoderm network in a phylogenetically brief period in developmentally canalized nematodes.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12132343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82701855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SF3B1-targeted Splicing Inhibition Triggers Transcriptional Stress Response and Global Alterations in R-Loop Landscape.","authors":"Daisy Castillo-Guzman, Stella R Hartono, Meghan Frederick, Lionel A Sanz, Tadas Sereiva, Frédéric Chédin","doi":"10.1101/2020.06.08.130583","DOIUrl":"10.1101/2020.06.08.130583","url":null,"abstract":"<p><p>Efficient co-transcriptional splicing is thought to suppress genome-destabilizing R-loops. Inhibition of SF3B1, a core U2 spliceosome component, by Pladienolide B (PladB) in human K562 cells caused widespread intron retention and modest R-loops gains. Minimal overlap existed between these events, suggesting that unspliced introns by themselves do not cause excessive R-loops. R-loop gains were instead driven by extensive readthrough transcription at a subset of stress-response genes, defining a new class of aberrant \"downstream of genes\" (DoG) R-loops. Such DoG R-loops were temporally and spatially uncoupled from loci experiencing DNA damage. Unexpectedly, the predominant response to splicing inhibition was a global R-loop loss. This resulted from increased promoter-proximal pausing and defective transcription elongation associated with premature termination. Similar results were observed upon depletion of Aquarius, a U2 spliceosome-associated factor previously thought to suppress R-loops. Thus, U2 spliceosome-targeted splicing inhibition triggered profound alterations in transcriptional dynamics, leading to unexpected disruptions in R-loop landscapes.</p><p><strong>Highlights: </strong>Intron retention caused by SF3B1 inhibition does not trigger excessive R-loopsStress-response genes shows readthrough transcription and R-loop gainsR-loop gains and DNA damage are temporally and spatially uncoupledU2 snRNP inhibition causes broad reduction in transcription and dominant R-loop loss.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":"56 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12132491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80069149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ciliary ARL13B is essential for body weight regulation in adult mice.","authors":"Tiffany T Terry, Eduardo D Gigante, Coralie M Alexandre, Kathryn M Brewer, Xinyu Yue, Nicolas F Berbari, Christian Vaisse, Tamara Caspary","doi":"10.1101/2023.08.02.551695","DOIUrl":"10.1101/2023.08.02.551695","url":null,"abstract":"<p><p>Cilia are near ubiquitous cellular appendages critical for cell-to-cell communication and involved in diverse developmental and homeostatic processes. ARL13B is a regulatory GTPase enriched in cilia. We engineered an <i>Arl13b</i> mouse allele, <i>Arl13b</i> ^<i>V358A</i> , which retains ARL13B biochemical activities but renders ARL13B undetectable in cilia. Surprisingly, these mice are hyperphagic and become obese and insulin resistant. In addition to its GTPase function, ARL13B acts as a guanine nucleotide exchange factor (GEF) for ARL3. To test whether ARL13B's GEF activity is required to regulate body weight, we analyzed the body weight of mice expressing an ARL13B variant lacking ARL3 GEF activity ( <i>Arl13b</i> ^<i>R79Q</i> ). We found no difference in body weight, indicating ARL13B is unlikely to regulate weight via its ARL3 GEF activity. Ciliary ARL13B could control energy homeostasis through a role in development or in adult mice. We induced wildtype ARL13B expression, which localizes to cilia, in 4-week-old <i>Arl13b</i> ^{<i>V358A/V358A</i>} mice and found the obesity phenotype and associated metabolic impairments were rescued, consistent with ARL13B regulating homeostatic signaling within cilia in adult mice. These results show that ciliary ARL13B functions to control body weight. Our ability to genetically control the subcellular localization of ARL13B by removing and introducing it into cilia enables us to define the cilia-specific role of ARL13B and provides key information for understanding how cilia act as a signaling hub critical for energy homeostasis.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/3f/24/nihpp-2023.08.02.551695v1.PMC10418222.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10394985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glucose-stimulated KIF5B-driven microtubule sliding organizes microtubule networks in pancreatic β cells.","authors":"Kai M Bracey, Margret Fye, Alisa Cario, Kung-Hsien Ho, Pi'illani Noguchi, Guoqiang Gu, Irina Kaverina","doi":"10.1101/2023.06.25.546468","DOIUrl":"10.1101/2023.06.25.546468","url":null,"abstract":"<p><p>In pancreatic islet β cells, molecular motors use cytoskeletal polymers microtubules as tracks for intracellular transport of insulin secretory granules. The β-cell microtubule network has a complex architecture and is non-directional, which provides insulin granules at the cell periphery for rapid secretion response, yet to avoid over-secretion and subsequent hypoglycemia. We have previously characterized a peripheral sub-membrane microtubule array, which is critical for the withdrawal of excessive insulin granules from the secretion sites. Microtubules in β cells originate at the Golgi in the cell interior, and how the peripheral array is formed is unknown. Using real-time imaging and photo-kinetics approaches in clonal mouse pancreatic β cells MIN6, we now demonstrate that kinesin KIF5B, a motor protein with a capacity to transport microtubules as cargos, slides existing microtubules to the cell periphery and aligns them to each other along the plasma membrane. Moreover, like many physiological β-cell features, microtubule sliding is facilitated by a high glucose stimulus. These new data, together with our previous report that in high glucose sub-membrane MT array is destabilized to allow for robust secretion, indicate that MT sliding is another integral part of glucose-triggered microtubule remodeling, likely replacing destabilized peripheral microtubules to prevent their loss over time and β-cell malfunction.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ae/fa/nihpp-2023.06.25.546468v1.PMC10327020.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10168225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The carbapenem inoculum effect provides insight into the molecular mechanisms underlying carbapenem resistance in Enterobacterales.","authors":"Alexis Jaramillo Cartagena, Kyra L Taylor, Leslie C Lopez, Jennifer Su, Joshua T Smith, Abigail L Manson, Jonathan D Chen, Virginia M Pierce, Ashlee M Earl, Roby P Bhattacharyya","doi":"10.1101/2023.05.23.541813","DOIUrl":"10.1101/2023.05.23.541813","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Carbapenem-resistant Enterobacterales (CRE) are important pathogens that can develop resistance via multiple molecular mechanisms, including hydrolysis or reduced antibiotic influx. Identifying these mechanisms can improve pathogen surveillance, infection control, and patient care. We investigated, both phenomenologically and mechanistically, how resistance mechanisms influence the carbapenem inoculum effect (IE), a phenomenon where inoculum size affects antimicrobial susceptibility testing (AST). We demonstrated that any of seven different carbapenemases were sufficient to impart a meropenem IE when transformed into a laboratory strain of &lt;i&gt;Escherichia coli&lt;/i&gt; . Across 106 clinical CRE isolates spanning 6 genera and 12 species, the carbapenem IE strictly depended on resistance mechanism: all 36 carbapenemase-producing CRE (CP-CRE) exhibited a clear IE, whereas 43 porin-deficient CRE displayed none. 27 isolates with both carbapenemase production and porin deficiency exhibited high-level resistance at all inocula, and still displayed an IE, albeit smaller in magnitude than CP-CRE with intact porins. Mechanistically, we found that clinical CP-CRE release carbapenemase activity into culture supernatant to protect other cells. Further, this released activity markedly increased upon exposure to lethal antibiotic doses, functionally consistent with altruism. Concerningly, 50% and 24% of CP-CRE isolates changed susceptibility classification to meropenem and ertapenem, respectively, across the allowable inoculum range in clinical testing guidelines. The meropenem IE, and the ratio of ertapenem to meropenem minimal inhibitory concentration (MIC) at standard inoculum, reliably identified CP-CRE. Understanding how resistance mechanisms affect AST could improve diagnosis and guide therapies for CRE infections.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;Infections caused by carbapenem-resistant Enterobacterales (CRE) pose significant threats to patients and public health worldwide. Carbapenem resistance can occur through several molecular mechanisms, including enzymatic hydrolysis by carbapenemases and reduced influx via porin mutations. Identifying carbapenemase-producing isolates could enable tailored antibiotic selection to improve patient outcomes, and infection control measures to prevent further carbapenemase transmission. In a large collection of CRE isolates, we found that only carbapenemase-producing CRE exhibit an inoculum effect, in which their measured resistance varies markedly with cell density, which risks misdiagnosis. Further, this inoculum effect occurs under conditions where bacteria release carbapenemases to the community upon exposure to antibiotic that results in cell death, functionally consistent with altruism. Measuring this inoculum effect, or integrating other data from routine antimicrobial susceptibility testing, enhances carbapenem resistance detection, paving the way for more effective strategies to combat this growing public he","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10245868/pdf/nihpp-2023.05.23.541813v3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10084345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Asymmetric cortical projections to striatal direct and indirect pathways distinctly control actions.","authors":"Jason R Klug, Xunyi Yan, Hilary A Hoffman, Max D Engelhardt, Fumitaka Osakada, Edward M Callaway, Xin Jin","doi":"10.1101/2023.10.02.560589","DOIUrl":"10.1101/2023.10.02.560589","url":null,"abstract":"<p><p>The striatal direct and indirect pathways constitute the core for basal ganglia function in action control. Although both striatal D1- and D2-spiny projection neurons (SPNs) receive excitatory inputs from the cerebral cortex, whether or not they share inputs from the same cortical neurons, and how pathway-specific corticostriatal projections control behavior remain largely unknown. Here using a G-deleted rabies system in mice, we found that more than two-thirds of excitatory inputs to D2-SPNs also target D1-SPNs, while only one-third do so <i>vice versa</i> . Optogenetic stimulation of striatal D1- vs. D2-SPN-projecting cortical neurons differently regulate locomotion, reinforcement learning and sequence behavior, implying the functional dichotomy of pathway-specific corticostriatal subcircuits. These results reveal the partially segregated yet asymmetrically overlapping cortical projections on striatal D1- vs. D2-SPNs, and that the pathway-specific corticostriatal subcircuits distinctly control behavior. It has important implications in a wide range of neurological and psychiatric diseases affecting cortico-basal ganglia circuitry.</p><p><strong>In brief: </strong>Klug, Yan et al. employed a modified rabies system in combination with slice physiology, optogenetics and behavioral tests to reveal that pathway-specific corticostriatal subcircuits distinctly control actions.</p><p><strong>Highlights: </strong>One-third of the excitatory inputs to D1-SPNs project to D2-SPNs, while two-third of the excitatory inputs to D2-SPNs also target D1-SPNsActivation of D1-SPN projecting cortical neurons triggers behavioral effects in line with postsynaptic striatal direct pathway activationActivation of D2-SPN projecting cortical neurons causes behavioral effects similar with co-activation of both direct and indirect pathwaysCorticostriatal subcircuits control actions in a brain-region and pathway-specific manner.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10592949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49694453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}