Pub Date : 2025-12-29DOI: 10.1016/j.isci.2025.114564
Anna S. Kolodziejczak , Florian Selt , Heike Peterziel , Nora Jamaladdin , Norman Mack , Kendra Maaß , Chris Meulenbroeks , Romain Sigaud , Christel Herold-Mende , Ahmed El Damaty , Jürgen Burhenne , Shunya Ohmura , Tim Holland-Letz , Lena M. Kutscher , Aurélie Ernst , Pei-Chi Wei , Thomas G.P. Grünewald , Ina Oehme , Marcel Kool , David T.W. Jones , Till Milde
Li-Fraumeni syndrome (LFS) is characterized by constitutional pathogenic TP53 mutation and increased risk of cancer development, including Sonic Hedgehog-activated medulloblastoma (SHH-MB). In LFS patients, radiation and DNA-damaging agents can exhibit lower efficiency and cause secondary malignancies. To identify efficacious, safe chemotherapeutic approaches for LFS-associated SHH-MB, 333 compounds were screened in in vitro TP53mut brain tumor cell lines. The combination of WEE1 inhibitor adavosertib and vinca alkaloid vincristine demonstrated the highest activity, which was validated in TP53mut SHH-MB patient-derived organoids. Low genotoxicity of these compounds was determined in vitro in LFS fibroblasts, and in vivo in the LFS mouse model. Despite the drugs’ limited efficacy in the in vivo PDX model, WEE1 knockdown led to significant growth reduction in in vitro and in vivo TP53mut SHH-MB models. Our findings identify WEE1 as a promising target in LFS SHH-MB, suggesting its inhibition combined with vincristine treatment as a potential chemotherapeutic strategy.
{"title":"Preclinical drug screen identifies WEE1 inhibitor and vinca alkaloid as a combination treatment concept for Li-Fraumeni syndrome medulloblastoma","authors":"Anna S. Kolodziejczak , Florian Selt , Heike Peterziel , Nora Jamaladdin , Norman Mack , Kendra Maaß , Chris Meulenbroeks , Romain Sigaud , Christel Herold-Mende , Ahmed El Damaty , Jürgen Burhenne , Shunya Ohmura , Tim Holland-Letz , Lena M. Kutscher , Aurélie Ernst , Pei-Chi Wei , Thomas G.P. Grünewald , Ina Oehme , Marcel Kool , David T.W. Jones , Till Milde","doi":"10.1016/j.isci.2025.114564","DOIUrl":"10.1016/j.isci.2025.114564","url":null,"abstract":"<div><div>Li-Fraumeni syndrome (LFS) is characterized by constitutional pathogenic <em>TP53</em> mutation and increased risk of cancer development, including Sonic Hedgehog-activated medulloblastoma (SHH-MB). In LFS patients, radiation and DNA-damaging agents can exhibit lower efficiency and cause secondary malignancies. To identify efficacious, safe chemotherapeutic approaches for LFS-associated SHH-MB, 333 compounds were screened in <em>in vitro</em> TP53<sup>mut</sup> brain tumor cell lines. The combination of WEE1 inhibitor adavosertib and vinca alkaloid vincristine demonstrated the highest activity, which was validated in TP53<sup>mut</sup> SHH-MB patient-derived organoids. Low genotoxicity of these compounds was determined <em>in vitro</em> in LFS fibroblasts, and <em>in vivo</em> in the LFS mouse model. Despite the drugs’ limited efficacy in the <em>in vivo</em> PDX model, WEE1 knockdown led to significant growth reduction in <em>in vitro</em> and <em>in vivo</em> TP53<sup>mut</sup> SHH-MB models. Our findings identify WEE1 as a promising target in LFS SHH-MB, suggesting its inhibition combined with vincristine treatment as a potential chemotherapeutic strategy.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 2","pages":"Article 114564"},"PeriodicalIF":4.1,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-29eCollection Date: 2026-01-16DOI: 10.1016/j.isci.2025.114528
Siyuan Hao, Ye Jin Lee, Nadav Benhamou Goldfajn, Eduardo Flores, Jindayi Liang, Hannah Fuehrer, Justin Demmerle, Jennifer Lippincott-Schwartz, Zhe Liu, Shahar Sukenik, Danfeng Cai
[This corrects the article DOI: 10.1016/j.isci.2024.109927.].
[此更正文章DOI: 10.1016/j.i ssn .2024.109927.]。
{"title":"Erratum: YAP condensates are highly organized hubs.","authors":"Siyuan Hao, Ye Jin Lee, Nadav Benhamou Goldfajn, Eduardo Flores, Jindayi Liang, Hannah Fuehrer, Justin Demmerle, Jennifer Lippincott-Schwartz, Zhe Liu, Shahar Sukenik, Danfeng Cai","doi":"10.1016/j.isci.2025.114528","DOIUrl":"https://doi.org/10.1016/j.isci.2025.114528","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1016/j.isci.2024.109927.].</p>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 1","pages":"114528"},"PeriodicalIF":4.1,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12803932/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145996822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-29DOI: 10.1016/j.isci.2025.114563
Atul Gopal , Okihide Hikosaka
Eye movements toward high-valued objects are executed with greater vigor. To test how neurons in the superior colliculus (SC), a subcortical structure that controls these movements, are modulated by value, we recorded four SC neuron subtypes while monkeys made saccades to objects previously associated with high or low reward volumes. High-value objects elicited greater activity in three neuron subtypes (visual, visuomotor, motor). Using a bootstrapping method, we identified three distinct activity phases: early visual response (EVIS), late visual response (LVIS), and pre-saccadic (PreSAC) motor response. Value was positively correlated with activity in the LVIS and PreSAC phases, but not in the EVIS phase, suggesting that value modulates visual and motor stages of visuomotor transformation. Additionally, we discovered a class of tonically active neurons that decrease their activity upon object onset, and remain inhibited till the end of the saccade, potentially enhancing saccade execution by disinhibiting interactions among other SC neurons.
{"title":"Multiple groups of neurons in the superior colliculus convert value signals into saccadic vigor","authors":"Atul Gopal , Okihide Hikosaka","doi":"10.1016/j.isci.2025.114563","DOIUrl":"10.1016/j.isci.2025.114563","url":null,"abstract":"<div><div>Eye movements toward high-valued objects are executed with greater vigor. To test how neurons in the superior colliculus (SC), a subcortical structure that controls these movements, are modulated by value, we recorded four SC neuron subtypes while monkeys made saccades to objects previously associated with high or low reward volumes. High-value objects elicited greater activity in three neuron subtypes (visual, visuomotor, motor). Using a bootstrapping method, we identified three distinct activity phases: early visual response (E<sub>VIS</sub>), late visual response (L<sub>VIS</sub>), and pre-saccadic (Pre<sub>SAC</sub>) motor response. Value was positively correlated with activity in the L<sub>VIS</sub> and Pre<sub>SAC</sub> phases, but not in the E<sub>VIS</sub> phase, suggesting that value modulates visual and motor stages of visuomotor transformation. Additionally, we discovered a class of tonically active neurons that decrease their activity upon object onset, and remain inhibited till the end of the saccade, potentially enhancing saccade execution by disinhibiting interactions among other SC neurons.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 2","pages":"Article 114563"},"PeriodicalIF":4.1,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-29DOI: 10.1016/j.isci.2025.114572
David J. Friedman , Sina Ramin , Tiffany Blair , Gwen Kramer , Shelly Bambina , Alejandro F. Alice , Jason Baird , Terry Medler , Kristina H. Young , Marka R. Crittenden , Michael J. Gough
Radiation therapy (RT) is recognized for its ability to induce DNA damage within cancer cells, leading to cancer cell death and promotion of anti-tumor immune responses. However, this beneficial effect is often counterbalanced by the presence of suppressive Tregs. Although factors such as RT-induced transforming growth factor β (TGF-β) can contribute to increased Treg accumulation within the tumor, the dynamics of Treg movement, and recruitment in the post-RT tumor microenvironment are not fully understood. Our study examined Treg migration following RT, revealing that RT disrupts Treg migration to the tumor-draining lymph node (TdLN) and alters their phenotype. Combining RT with anti-CCR8 therapy, which selectively depletes Tregs within the tumor, significantly reduced tumor burden, and increased survival in preclinical models. This combination also proved effective against distant and unirradiated tumors. Additionally, efficacy of combination therapy was CD8 T cell dependent. These findings highlight the potential of combining RT with Treg-targeting therapies to enhance anti-tumor immunity.
{"title":"Fluorescence tracking Treg movement identifies anti-CCR8 and radiation as a therapeutic combination","authors":"David J. Friedman , Sina Ramin , Tiffany Blair , Gwen Kramer , Shelly Bambina , Alejandro F. Alice , Jason Baird , Terry Medler , Kristina H. Young , Marka R. Crittenden , Michael J. Gough","doi":"10.1016/j.isci.2025.114572","DOIUrl":"10.1016/j.isci.2025.114572","url":null,"abstract":"<div><div>Radiation therapy (RT) is recognized for its ability to induce DNA damage within cancer cells, leading to cancer cell death and promotion of anti-tumor immune responses. However, this beneficial effect is often counterbalanced by the presence of suppressive Tregs. Although factors such as RT-induced transforming growth factor β (TGF-β) can contribute to increased Treg accumulation within the tumor, the dynamics of Treg movement, and recruitment in the post-RT tumor microenvironment are not fully understood. Our study examined Treg migration following RT, revealing that RT disrupts Treg migration to the tumor-draining lymph node (TdLN) and alters their phenotype. Combining RT with anti-CCR8 therapy, which selectively depletes Tregs within the tumor, significantly reduced tumor burden, and increased survival in preclinical models. This combination also proved effective against distant and unirradiated tumors. Additionally, efficacy of combination therapy was CD8 T cell dependent. These findings highlight the potential of combining RT with Treg-targeting therapies to enhance anti-tumor immunity.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 2","pages":"Article 114572"},"PeriodicalIF":4.1,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-29DOI: 10.1016/j.isci.2025.114566
Alberto Felix-Lopez , Joaquin Lopez-Orozco , Mohamed Elaish , Nawell Fayad , Zaikun Xu , Tekeleselassie Woldemariam , Bardes B. Hassan , Rashmi Panigrahi , Juveriya Qamar Khan , Megha Rohamare , Irv Mayers , J.N. Mark Glover , Joyce A. Wilson , Darryl Falzarano , Anil Kumar , Tom C. Hobman
SARS-CoV-2 is the causative agent of COVID-19, and although vaccines have reduced disease severity, emerging variants remain a significant public health issue. Broadly effective therapeutics, particularly those targeting host pathways essential for coronavirus infection, are still needed. Here, we used a CRISPR knockout screen to identify druggable host factors required for SARS-CoV-2 infection. The screen revealed NAE1 and FGFR1 as key contributors to infection. Inhibitors, either FDA-approved or those in clinical trials, of these pathways reduced replication of both ancestral and contemporary viral variants. Mechanistic studies showed that FGFR1 promotes viral replication through downstream MEK/ERK signaling, while neddylation appears to support viral entry or infectivity rather than replication itself. In a murine model of severe COVID-19, inhibitors of NAE1 and FGFR1 significantly decreased viral load and lung pathology. These findings support the development of host-targeted antiviral strategies.
{"title":"FGFR signaling and neddylation facilitate SARS-CoV-2 infection by modulating interferon induction and viral entry, respectively","authors":"Alberto Felix-Lopez , Joaquin Lopez-Orozco , Mohamed Elaish , Nawell Fayad , Zaikun Xu , Tekeleselassie Woldemariam , Bardes B. Hassan , Rashmi Panigrahi , Juveriya Qamar Khan , Megha Rohamare , Irv Mayers , J.N. Mark Glover , Joyce A. Wilson , Darryl Falzarano , Anil Kumar , Tom C. Hobman","doi":"10.1016/j.isci.2025.114566","DOIUrl":"10.1016/j.isci.2025.114566","url":null,"abstract":"<div><div>SARS-CoV-2 is the causative agent of COVID-19, and although vaccines have reduced disease severity, emerging variants remain a significant public health issue. Broadly effective therapeutics, particularly those targeting host pathways essential for coronavirus infection, are still needed. Here, we used a CRISPR knockout screen to identify druggable host factors required for SARS-CoV-2 infection. The screen revealed NAE1 and FGFR1 as key contributors to infection. Inhibitors, either FDA-approved or those in clinical trials, of these pathways reduced replication of both ancestral and contemporary viral variants. Mechanistic studies showed that FGFR1 promotes viral replication through downstream MEK/ERK signaling, while neddylation appears to support viral entry or infectivity rather than replication itself. In a murine model of severe COVID-19, inhibitors of NAE1 and FGFR1 significantly decreased viral load and lung pathology. These findings support the development of host-targeted antiviral strategies.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 2","pages":"Article 114566"},"PeriodicalIF":4.1,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-29DOI: 10.1016/j.isci.2025.114561
Deepankar Chakroborty , Katri Vaparanta , Bishwa Ghimire , Ilkka Paatero , Kari J. Kurppa , Klaus Elenius
Existing cancer-associated variant databases contain biases arising from duplicate entries and the inclusion of targeted sequencing panels, which interfere with accurate estimation somatic mutation frequency in cancer cohorts. To address this, we developed the Database of Recurrent Mutations (DORM), a web resource derived exclusively from whole-genome and whole-exome sequencing data. By filtering out targeted screens and non-recurrent variants, our analysis reveals that mutation recurrence significantly correlates with oncogenic activity, loss of tumor suppressor function, and unfavorable patient prognosis. In a pan-cancer analysis of EGFR, DORM identified frequent mutations outside the kinase domain that are underrepresented in other databases. This resource offers a streamlined, unbiased platform for mutation frequency analysis, enhancing biomarker discovery and the assessment of clinical variant significance.
{"title":"Database of recurrent mutations, an unbiased web resource to browse recurrent mutations in cancers","authors":"Deepankar Chakroborty , Katri Vaparanta , Bishwa Ghimire , Ilkka Paatero , Kari J. Kurppa , Klaus Elenius","doi":"10.1016/j.isci.2025.114561","DOIUrl":"10.1016/j.isci.2025.114561","url":null,"abstract":"<div><div>Existing cancer-associated variant databases contain biases arising from duplicate entries and the inclusion of targeted sequencing panels, which interfere with accurate estimation somatic mutation frequency in cancer cohorts. To address this, we developed the Database of Recurrent Mutations (DORM), a web resource derived exclusively from whole-genome and whole-exome sequencing data. By filtering out targeted screens and non-recurrent variants, our analysis reveals that mutation recurrence significantly correlates with oncogenic activity, loss of tumor suppressor function, and unfavorable patient prognosis. In a pan-cancer analysis of EGFR, DORM identified frequent mutations outside the kinase domain that are underrepresented in other databases. This resource offers a streamlined, unbiased platform for mutation frequency analysis, enhancing biomarker discovery and the assessment of clinical variant significance.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 2","pages":"Article 114561"},"PeriodicalIF":4.1,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145924366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thermopower, a key parameter in thermoelectric performance, is often linked to either specific heat or entropy, yet the governing quantity has remained elusive. Here we present a unified framework showing that entropy per carrier, not specific heat, is the universal driver of thermopower in both closed and open systems. Using thermodynamic identities and the Onsager-Kelvin relation, we demonstrate that apparent links to specific heat arise only when heat capacity follows a power-law temperature dependence. Extending the framework, we derive a general expression for magnon-drag thermopower valid for both massive (ferromagnetic) and massless (antiferromagnetic) magnons using a relativistic energy-momentum tensor. We also explore how frustration, flat-band physics, and altermagnetism can sustain entropy at low temperatures or generate Berry-curvature-driven transport, indirectly enhancing thermopower. Case studies of magnetic materials, superconducting niobium, and single-molecule junctions validate the framework, establishing entropy per carrier as a unifying principle for next-generation thermoelectric materials.
{"title":"Unifying thermopower: entropy and specific heat in magnetic, superconducting, nanoscale, and frustrated systems","authors":"Morteza Jazandari , Jahanfar Abouie , Daryoosh Vashaee","doi":"10.1016/j.isci.2025.114565","DOIUrl":"10.1016/j.isci.2025.114565","url":null,"abstract":"<div><div>Thermopower, a key parameter in thermoelectric performance, is often linked to either specific heat or entropy, yet the governing quantity has remained elusive. Here we present a unified framework showing that entropy per carrier, not specific heat, is the universal driver of thermopower in both closed and open systems. Using thermodynamic identities and the Onsager-Kelvin relation, we demonstrate that apparent links to specific heat arise only when heat capacity follows a power-law temperature dependence. Extending the framework, we derive a general expression for magnon-drag thermopower valid for both massive (ferromagnetic) and massless (antiferromagnetic) magnons using a relativistic energy-momentum tensor. We also explore how frustration, flat-band physics, and altermagnetism can sustain entropy at low temperatures or generate Berry-curvature-driven transport, indirectly enhancing thermopower. Case studies of magnetic materials, superconducting niobium, and single-molecule junctions validate the framework, establishing entropy per carrier as a unifying principle for next-generation thermoelectric materials.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 2","pages":"Article 114565"},"PeriodicalIF":4.1,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-29DOI: 10.1016/j.isci.2025.114554
Celia Kjaerby , Tessa Radovanovic , Eszter Rebeka Kovács , Zuzanna Bojarowska , Klaudia Anna Tokarska , Anastasia Tsopanidou , Elise Schiøler Nielsen , Mie Andersen , Yulong Li , Pia Weikop , Verena Untiet , Maiken Nedergaard
Neurotransmitters and neuromodulators regulate brain states through diverse mechanisms, yet how their activities are coordinated during sleep remains unresolved. Using in vivo fiber photometry in adult mice expressing genetically encoded fluorescent biosensors, combined with EEG/EMG recordings, we investigated the temporal organization of multiple neuromodulators during sleep in barrel cortex, with norepinephrine (NE) as a reference signal. All five neuromodulators examined, acetylcholine, serotonin, dopamine, histamine, and NE, exhibited synchronized infraslow cortical oscillations during NREM sleep. Optogenetic suppression of locus coeruleus (LC) neurons abolished NE oscillations and selectively reduced acetylcholine fluctuations in barrel cortex, whereas targeted inhibition of basal forebrain cholinergic neurons attenuated REM-associated acetylcholine elevations without disrupting NREM-related oscillations or NE dynamics. The synchronized infraslow cortical oscillations spanning multiple neuromodulators reveal a previously unrecognized mechanism for organizing sleep architecture.
{"title":"Coordinated infraslow cortical oscillations of neuromodulators during NREM sleep","authors":"Celia Kjaerby , Tessa Radovanovic , Eszter Rebeka Kovács , Zuzanna Bojarowska , Klaudia Anna Tokarska , Anastasia Tsopanidou , Elise Schiøler Nielsen , Mie Andersen , Yulong Li , Pia Weikop , Verena Untiet , Maiken Nedergaard","doi":"10.1016/j.isci.2025.114554","DOIUrl":"10.1016/j.isci.2025.114554","url":null,"abstract":"<div><div>Neurotransmitters and neuromodulators regulate brain states through diverse mechanisms, yet how their activities are coordinated during sleep remains unresolved. Using <em>in vivo</em> fiber photometry in adult mice expressing genetically encoded fluorescent biosensors, combined with EEG/EMG recordings, we investigated the temporal organization of multiple neuromodulators during sleep in barrel cortex, with norepinephrine (NE) as a reference signal. All five neuromodulators examined, acetylcholine, serotonin, dopamine, histamine, and NE, exhibited synchronized infraslow cortical oscillations during NREM sleep. Optogenetic suppression of locus coeruleus (LC) neurons abolished NE oscillations and selectively reduced acetylcholine fluctuations in barrel cortex, whereas targeted inhibition of basal forebrain cholinergic neurons attenuated REM-associated acetylcholine elevations without disrupting NREM-related oscillations or NE dynamics. The synchronized infraslow cortical oscillations spanning multiple neuromodulators reveal a previously unrecognized mechanism for organizing sleep architecture.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 2","pages":"Article 114554"},"PeriodicalIF":4.1,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-29DOI: 10.1016/j.isci.2025.114567
Shayna Singh , Lihua Yao , Kimberly J. Dougherty
Locomotion in vertebrates is generated in the spinal cord but initiated by supraspinal centers. Spinal interneurons expressing Shox2 include putative locomotor rhythm generating neurons in mice. Reticulospinal neurons directly provide drive to spinal rhythm generating interneurons, which then convey rhythmic output. Excitatory neurons in the lateral paragigantocellular nucleus (LPGi) have been shown to provide this descending drive during locomotor initiation. Here, we performed viral tracing and electrophysiology to test for direct connections between the LPGi and lumbar Shox2 interneurons in adult mice. Using monosynaptic-restricted rabies tracing, we show that excitatory neurons from the LPGi make direct synaptic connections onto lumbar Shox2 interneurons. This connection from the ventral caudal medulla to Shox2 interneurons was confirmed via anterograde tracing and recordings of excitatory postsynaptic potentials in Shox2 interneurons. Thus, a subset of Shox2 interneurons receives monosynaptic excitatory input from the LPGi, which may provide the substrate for locomotor initiation.
{"title":"Lumbar spinal Shox2 interneurons receive monosynaptic excitatory input from the lateral paragigantocellular nucleus in mouse","authors":"Shayna Singh , Lihua Yao , Kimberly J. Dougherty","doi":"10.1016/j.isci.2025.114567","DOIUrl":"10.1016/j.isci.2025.114567","url":null,"abstract":"<div><div>Locomotion in vertebrates is generated in the spinal cord but initiated by supraspinal centers. Spinal interneurons expressing Shox2 include putative locomotor rhythm generating neurons in mice. Reticulospinal neurons directly provide drive to spinal rhythm generating interneurons, which then convey rhythmic output. Excitatory neurons in the lateral paragigantocellular nucleus (LPGi) have been shown to provide this descending drive during locomotor initiation. Here, we performed viral tracing and electrophysiology to test for direct connections between the LPGi and lumbar Shox2 interneurons in adult mice. Using monosynaptic-restricted rabies tracing, we show that excitatory neurons from the LPGi make direct synaptic connections onto lumbar Shox2 interneurons. This connection from the ventral caudal medulla to Shox2 interneurons was confirmed via anterograde tracing and recordings of excitatory postsynaptic potentials in Shox2 interneurons. Thus, a subset of Shox2 interneurons receives monosynaptic excitatory input from the LPGi, which may provide the substrate for locomotor initiation.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 2","pages":"Article 114567"},"PeriodicalIF":4.1,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-29DOI: 10.1016/j.isci.2025.114571
Moritz Mückschel , Jasmin Mayer , Bernhard Hommel , Christian Beste
Understanding how intentional behavior emerges from neural dynamics requires linking cognitive theories with neurobiology. We combined auricular transcutaneous vagus nerve stimulation (atVNS) with EEG-based directed connectivity analyses to probe action-effect integration in a canonical theta-band network comprising the anterior temporal lobe (ATL), insular cortex (IC), and inferior frontal cortex (IFC). We show that this core network supports action-effect processing, but atVNS additionally recruited posterior temporal/ventral stream regions (PTL) and altered directed information transfer in the network. While some network properties (e.g., IFC-PTL asymmetry) were involved in both action-effect perception and planning, others (e.g., IC-IFC coupling) were specific to only one of these processes, suggesting that ideomotor theory would benefit from process-specific assumptions regarding the cortical dynamics. The results can be interpreted as reflecting enhanced GABAergic transmission underlying atVNS effects, providing further neurobiological foundation for ideomotor theory on the basis of directed cortical communication and neuromodulation.
{"title":"Auricular transcutaneous vagus nerve stimulation alters directed cortical communication during intentional actions","authors":"Moritz Mückschel , Jasmin Mayer , Bernhard Hommel , Christian Beste","doi":"10.1016/j.isci.2025.114571","DOIUrl":"10.1016/j.isci.2025.114571","url":null,"abstract":"<div><div>Understanding how intentional behavior emerges from neural dynamics requires linking cognitive theories with neurobiology. We combined auricular transcutaneous vagus nerve stimulation (atVNS) with EEG-based directed connectivity analyses to probe action-effect integration in a canonical theta-band network comprising the anterior temporal lobe (ATL), insular cortex (IC), and inferior frontal cortex (IFC). We show that this core network supports action-effect processing, but atVNS additionally recruited posterior temporal/ventral stream regions (PTL) and altered directed information transfer in the network. While some network properties (e.g., IFC-PTL asymmetry) were involved in both action-effect perception and planning, others (e.g., IC-IFC coupling) were specific to only one of these processes, suggesting that ideomotor theory would benefit from process-specific assumptions regarding the cortical dynamics. The results can be interpreted as reflecting enhanced GABAergic transmission underlying atVNS effects, providing further neurobiological foundation for ideomotor theory on the basis of directed cortical communication and neuromodulation.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 2","pages":"Article 114571"},"PeriodicalIF":4.1,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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