[{"_id":"21245","doi":"10.1371/journal.pone.0332310","ddc":["570"],"intvolume":"        20","date_created":"2026-02-16T15:29:26Z","DOAJ_listed":"1","language":[{"iso":"eng"}],"year":"2025","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","file_date_updated":"2026-02-17T12:16:18Z","PlanS_conform":"1","publication":"PLOS One","type":"journal_article","acknowledgement":"This study was funded by Syntropic Medical and supported by an Austria Wirtschaftsservice (AWS) grant (grant number P2414247 to Syntropic Medical). Syntropic Medical employees were involved in study design, data collection and analysis, decision to publish, and preparation of the manuscript. AWS had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","abstract":[{"lang":"eng","text":"Flickering light is a new promising, fully non-invasive brain stimulation technique that utilizes intermittent sensory stimulation to induce brainwave synchronization (entrainment). While the effects of 40 Hz externally induced neural entrainment have been extensively described, little is known about 60 Hz entrainment in humans. This study presents preliminary observations on the neural and somatic response to flickering 60 Hz light in healthy volunteers over a 3-week period. Fourteen volunteers were randomized to receive either 60 Hz flickering white light or constant light as sham (30-min sessions, 3 weeks, 5 days/week on weekdays). Neural entrainment was assessed with EEG on days 1, 5 and 19. Salivary cortisol and C-reactive protein (CRP) levels, measured with ELISA, assessed the somatic response to stimulation. Side effects and well-being were monitored via questionnaires. EEG recordings showed neural entrainment and synchrony in response to 60 Hz flickering light across multiple cortical regions, including occipital, central, temporal, and frontal areas. The entrainment power and synchronization between different cortical regions declined significantly by day 19 compared to day 1, indicating possible neural habituation. Cortisol and CRP salivary levels were unchanged, and minor side effects were reported with equal frequency in the active and sham groups. Our findings show that 60 Hz flickering light can induce significant neural entrainment and synchrony in healthy adults and is well tolerated. The decline in entrainment strength and neural synchrony observed with repeated 60 Hz stimulations suggests plastic changes in the cortex. To the best of our knowledge, this is the first study to characterize neural and somatic responses to repeated 60 Hz flickering visual stimuli. Given the well-known connection between 60 Hz brain oscillations and cognition, neuroplasticity, and their role in neuropsychiatric disorders, additional research in both preclinical and clinical settings is warranted."}],"article_type":"original","publication_status":"published","oa":1,"article_number":"e0332310","file":[{"date_created":"2026-02-17T12:16:18Z","file_name":"2025_PlosOne_Alamalhoda.pdf","content_type":"application/pdf","checksum":"22a4e92a733152633c4553f107f66765","success":1,"relation":"main_file","file_size":1388424,"access_level":"open_access","date_updated":"2026-02-17T12:16:18Z","creator":"dernst","file_id":"21301"}],"title":"Exploring neural entrainment and synchrony in response to repeated 60 Hz flickering white light in healthy volunteers","article_processing_charge":"Yes","external_id":{"pmid":["41056352 "]},"has_accepted_license":"1","pmid":1,"author":[{"last_name":"Alamalhoda","full_name":"Alamalhoda, MohammadAmin","first_name":"MohammadAmin"},{"first_name":"Friederike","last_name":"Leesch","full_name":"Leesch, Friederike"},{"full_name":"Giovanetti, Francesca","last_name":"Giovanetti","first_name":"Francesca"},{"full_name":"Dunne, Eoghan","last_name":"Dunne","first_name":"Eoghan"},{"first_name":"Giuseppina","full_name":"Pilloni, Giuseppina","last_name":"Pilloni"},{"last_name":"Caffrey","full_name":"Caffrey, Mark","first_name":"Mark"},{"first_name":"Jack","last_name":"O’Keeffe","full_name":"O’Keeffe, Jack"},{"first_name":"Alessandro","last_name":"Venturino","orcid":"0000-0003-2356-9403","full_name":"Venturino, Alessandro","id":"41CB84B2-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Maria Teresa","full_name":"Ferretti, Maria Teresa","last_name":"Ferretti"}],"OA_place":"publisher","related_material":{"link":[{"url":"https://github.com/AminAlam/HVS","relation":"software"}]},"tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"volume":20,"date_published":"2025-10-07T00:00:00Z","department":[{"_id":"SaSi"}],"date_updated":"2026-02-17T12:19:15Z","citation":{"ieee":"M. Alamalhoda <i>et al.</i>, “Exploring neural entrainment and synchrony in response to repeated 60 Hz flickering white light in healthy volunteers,” <i>PLOS One</i>, vol. 20, no. 10. Public Library of Science, 2025.","chicago":"Alamalhoda, MohammadAmin, Friederike Leesch, Francesca Giovanetti, Eoghan Dunne, Giuseppina Pilloni, Mark Caffrey, Jack O’Keeffe, Alessandro Venturino, and Maria Teresa Ferretti. “Exploring Neural Entrainment and Synchrony in Response to Repeated 60 Hz Flickering White Light in Healthy Volunteers.” <i>PLOS One</i>. Public Library of Science, 2025. <a href=\"https://doi.org/10.1371/journal.pone.0332310\">https://doi.org/10.1371/journal.pone.0332310</a>.","mla":"Alamalhoda, MohammadAmin, et al. “Exploring Neural Entrainment and Synchrony in Response to Repeated 60 Hz Flickering White Light in Healthy Volunteers.” <i>PLOS One</i>, vol. 20, no. 10, e0332310, Public Library of Science, 2025, doi:<a href=\"https://doi.org/10.1371/journal.pone.0332310\">10.1371/journal.pone.0332310</a>.","ama":"Alamalhoda M, Leesch F, Giovanetti F, et al. Exploring neural entrainment and synchrony in response to repeated 60 Hz flickering white light in healthy volunteers. <i>PLOS One</i>. 2025;20(10). doi:<a href=\"https://doi.org/10.1371/journal.pone.0332310\">10.1371/journal.pone.0332310</a>","short":"M. Alamalhoda, F. Leesch, F. Giovanetti, E. Dunne, G. Pilloni, M. Caffrey, J. O’Keeffe, A. Venturino, M.T. Ferretti, PLOS One 20 (2025).","apa":"Alamalhoda, M., Leesch, F., Giovanetti, F., Dunne, E., Pilloni, G., Caffrey, M., … Ferretti, M. T. (2025). Exploring neural entrainment and synchrony in response to repeated 60 Hz flickering white light in healthy volunteers. <i>PLOS One</i>. Public Library of Science. <a href=\"https://doi.org/10.1371/journal.pone.0332310\">https://doi.org/10.1371/journal.pone.0332310</a>","ista":"Alamalhoda M, Leesch F, Giovanetti F, Dunne E, Pilloni G, Caffrey M, O’Keeffe J, Venturino A, Ferretti MT. 2025. Exploring neural entrainment and synchrony in response to repeated 60 Hz flickering white light in healthy volunteers. PLOS One. 20(10), e0332310."},"publisher":"Public Library of Science","status":"public","publication_identifier":{"eissn":["1932-6203"]},"OA_type":"gold","oa_version":"Published Version","quality_controlled":"1","issue":"10","day":"07","month":"10"},{"abstract":[{"text":"Prenatal immune challenges pose significant risks to human embryonic brain and eye development. However, our knowledge about the safe usage of anti-inflammatory drugs during pregnancy is still limited. While human induced pluripotent stem cells (hIPSC)-derived brain organoid models have started to explore functional consequences upon viral stimulation, these models commonly lack microglia, which are susceptible to and promote inflammation. Furthermore, microglia are actively involved in neuronal development. Here, we generate hIPSC-derived microglia precursor cells and assemble them into retinal organoids. Once the outer plexiform layer forms, these hIPSC-derived microglia (iMG) fully integrate into the retinal organoids. Since the ganglion cell survival declines by this time in 3D-retinal organoids, we adapted the model into 2D and identify that the improved ganglion cell number significantly decreases only with iMG presence. In parallel, we applied the immunostimulant POLY(I:C) to mimic a fetal viral infection. While POLY(I:C) exposure alters the iMG phenotype, it does not hinder their interaction with ganglion cells. Furthermore, iMG significantly enhance the supernatant’s inflammatory secretome and increase retinal cell proliferation. Simultaneous exposure with the non-steroidal anti-inflammatory drug (NSAID) ibuprofen dampens POLY(I:C)-mediated changes of the iMG phenotype and ameliorates cell proliferation. Remarkably, while POLY(I:C) disrupts neuronal calcium dynamics independent of iMG, ibuprofen rescues this effect only if iMG are present. Mechanistically, ibuprofen targets the enzymes cyclooxygenase 1 and 2 (COX1/PTGS1 and COX2/PTGS2) simultaneously, from which iMG mainly express COX1. Selective COX1 blockage fails to restore the calcium peak amplitude upon POLY(I:C) stimulation, suggesting ibuprofen’s beneficial effect depends on the presence and interplay of COX1 and COX2. These findings underscore the importance of microglia in the context of prenatal immune challenges and provide insight into the mechanisms by which ibuprofen exerts its protective effects during embryonic development.","lang":"eng"}],"project":[{"grant_number":"SC19-017","_id":"9B99D380-BA93-11EA-9121-9846C619BF3A","name":"How human microglia shape developing neurons during health and inflammation"},{"name":"IST Austria Open Access Fund","_id":"B67AFEDC-15C9-11EA-A837-991A96BB2854"}],"oa":1,"article_type":"original","publication_status":"published","article_number":"98","title":"Microglia determine an immune-challenged environment and facilitate ibuprofen action in human retinal organoids","file":[{"date_updated":"2025-04-22T09:46:27Z","creator":"dernst","file_id":"19607","success":1,"relation":"main_file","file_size":4482167,"access_level":"open_access","file_name":"2025_JourNeuroinflammation_Schmied.pdf","content_type":"application/pdf","checksum":"dcc355c21ab713e45fda5c61b5fa5299","date_created":"2025-04-22T09:46:27Z"}],"_id":"19593","doi":"10.1186/s12974-025-03366-x","intvolume":"        22","ddc":["570"],"acknowledged_ssus":[{"_id":"LifeSc"},{"_id":"Bio"}],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","year":"2025","date_created":"2025-04-20T22:01:28Z","language":[{"iso":"eng"}],"DOAJ_listed":"1","PlanS_conform":"1","file_date_updated":"2025-04-22T09:46:27Z","publication":"Journal of Neuroinflammation","type":"journal_article","acknowledgement":"We thank the scientific service units at ISTA, specifically the Lab Support Facility (LSF), the Molecular Biology Services/Virus Services Team, specifically Flavia Gama Gomes Leite and Mark Andrew Smyth, for the virus production, and the Imaging and Optics Facility (IOF). We thank all members of the Siegert group and Marco Benevento for their constant feedback on the project and comments on the manuscript. A special thanks to Rouven Schulz for input on statistical analysis and sharing R-scripts, Gloria Colombo for the introduction to cell sorting, Negar Vehdani and Florianne Schoot Uiterkamp for their support in cell culture. This research was supported by the Gesellschaft für Forschungsförderung Niederösterreich (grant No. Sc19-017 to V.H.).","oa_version":"Published Version","OA_type":"gold","scopus_import":"1","quality_controlled":"1","APC_amount":"3948 EUR","issue":"1","day":"03","month":"04","article_processing_charge":"Yes","external_id":{"pmid":["40181459"],"isi":["001459311800002"]},"has_accepted_license":"1","pmid":1,"author":[{"id":"32B7C918-F248-11E8-B48F-1D18A9856A87","full_name":"Hübschmann, Verena","last_name":"Hübschmann","first_name":"Verena"},{"first_name":"Medina","last_name":"Korkut","orcid":"0000-0003-4309-2251","id":"4B51CE74-F248-11E8-B48F-1D18A9856A87","full_name":"Korkut, Medina"},{"id":"41CB84B2-F248-11E8-B48F-1D18A9856A87","full_name":"Venturino, Alessandro","last_name":"Venturino","orcid":"0000-0003-2356-9403","first_name":"Alessandro"},{"first_name":"Juan Pablo","full_name":"Maya-Arteaga, Juan Pablo","id":"c815d433-1f5d-11f0-a875-dad18b1e5924","last_name":"Maya-Arteaga"},{"first_name":"Sandra","full_name":"Siegert, Sandra","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-8635-0877","last_name":"Siegert"}],"OA_place":"publisher","related_material":{"link":[{"url":"https://ista.ac.at/en/news/pink-skies/","relation":"press_release","description":"News on ISTA website"}],"record":[{"id":"20074","relation":"dissertation_contains","status":"public"}]},"date_published":"2025-04-03T00:00:00Z","volume":22,"tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"corr_author":"1","department":[{"_id":"SaSi"}],"citation":{"short":"V. Schmied, M. Korkut, A. Venturino, J.P. Maya-Arteaga, S. Siegert, Journal of Neuroinflammation 22 (2025).","apa":"Schmied, V., Korkut, M., Venturino, A., Maya-Arteaga, J. P., &#38; Siegert, S. (2025). Microglia determine an immune-challenged environment and facilitate ibuprofen action in human retinal organoids. <i>Journal of Neuroinflammation</i>. Springer Nature. <a href=\"https://doi.org/10.1186/s12974-025-03366-x\">https://doi.org/10.1186/s12974-025-03366-x</a>","ista":"Schmied V, Korkut M, Venturino A, Maya-Arteaga JP, Siegert S. 2025. Microglia determine an immune-challenged environment and facilitate ibuprofen action in human retinal organoids. Journal of Neuroinflammation. 22(1), 98.","ieee":"V. Schmied, M. Korkut, A. Venturino, J. P. Maya-Arteaga, and S. Siegert, “Microglia determine an immune-challenged environment and facilitate ibuprofen action in human retinal organoids,” <i>Journal of Neuroinflammation</i>, vol. 22, no. 1. Springer Nature, 2025.","mla":"Schmied, Verena, et al. “Microglia Determine an Immune-Challenged Environment and Facilitate Ibuprofen Action in Human Retinal Organoids.” <i>Journal of Neuroinflammation</i>, vol. 22, no. 1, 98, Springer Nature, 2025, doi:<a href=\"https://doi.org/10.1186/s12974-025-03366-x\">10.1186/s12974-025-03366-x</a>.","chicago":"Schmied, Verena, Medina Korkut, Alessandro Venturino, Juan Pablo Maya-Arteaga, and Sandra Siegert. “Microglia Determine an Immune-Challenged Environment and Facilitate Ibuprofen Action in Human Retinal Organoids.” <i>Journal of Neuroinflammation</i>. Springer Nature, 2025. <a href=\"https://doi.org/10.1186/s12974-025-03366-x\">https://doi.org/10.1186/s12974-025-03366-x</a>.","ama":"Schmied V, Korkut M, Venturino A, Maya-Arteaga JP, Siegert S. Microglia determine an immune-challenged environment and facilitate ibuprofen action in human retinal organoids. <i>Journal of Neuroinflammation</i>. 2025;22(1). doi:<a href=\"https://doi.org/10.1186/s12974-025-03366-x\">10.1186/s12974-025-03366-x</a>"},"publisher":"Springer Nature","date_updated":"2026-05-06T12:49:37Z","status":"public","isi":1,"publication_identifier":{"eissn":["1742-2094"]}},{"file_date_updated":"2025-07-30T09:29:09Z","type":"dissertation","_id":"20074","ddc":["570"],"doi":"10.15479/AT-ISTA-20074","date_created":"2025-07-24T12:37:22Z","language":[{"iso":"eng"}],"user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","year":"2025","publication_status":"published","oa":1,"title":" Human microglia impact neuronal development in retinal organoids","file":[{"file_id":"20086","date_updated":"2025-07-30T08:47:53Z","creator":"vhuebsch","file_size":43566093,"access_level":"closed","relation":"source_file","checksum":"d09f9984002353ad7442358394919bf3","content_type":"application/x-zip-compressed","file_name":"PhD_Thesis_Schmied.zip","date_created":"2025-07-30T08:47:53Z"},{"file_id":"20087","creator":"vhuebsch","date_updated":"2025-07-30T09:29:09Z","access_level":"open_access","file_size":13120922,"relation":"main_file","checksum":"4833690d7283c587f518ba98eeb2c946","content_type":"application/pdf","file_name":"PhD_Thesis_Schmied.pdf","date_created":"2025-07-30T08:47:46Z"}],"degree_awarded":"PhD","page":"151","alternative_title":["ISTA Thesis"],"abstract":[{"lang":"eng","text":"Prenatal immune challenges pose significant risks to human embryonic brain and eye development. However, we still lack knowledge about the safe usage of anti-inflammatory drugs during pregnancy. Human induced pluripotent stem cell (hIPSC)-derived brain organoid models provide a unique opportunity to investigate neuronal development and have started to explore functional consequences upon viral infection. However, brain organoids usually lack microglia, the brain-resident immune cells. They are present in the early human embryonic brain and actively participate in neuronal circuit development. At the same time, microglia are known for their immune-sensing properties and will influence viral-mediated effects. In my thesis, I was interested to study the multifunctional role of human microglia during retinal development. \r\nIn chapter 1, I characterize the innate occurrence of IBA1+-microglia-like cells within the retinal organoid differentiation (Bartalska et al., 2022). Therefore, we differentiate hIPSC using an unguided retinal organoid differentiation protocol and observe the presence of IBA1+-microglia-like cells alongside retinal cups between week 3 and 4 in 2.5D culture. However, instead of infiltrating the neuroectodermal sides, they enrich within non-pigmented, 3D-cystic compartments that develop in low numbers parallel to 3D-retinal organoids. To enrich for IBA1+-microglia precursors (preMG), we guided the differentiation with a low-dosed BMP4 application, which prevents retinal cup development and enhances microglia and 3D-cysts formation. We characterize the differentiated preMG for their microglia-like identity and validated their functionality. In parallel, mass spectrometry identifies the 3D-cysts to express mesenchymal and epithelial markers. We confirm that comparable 3D-cysts are also the preferential environment for IBA1+-microglia-like cells within the unguided retinal organoid differentiation. \r\nIn chapter 2, I investigate how microglia influence retinal development and whether they contribute to viral-mediated consequences (Schmied et al., 2025). Here, we assemble preMG, which we have characterized in chapter 1, into 3D-retinal organoids. Once the outer plexiform layer forms, microglia-like cells (iMG) populate them and interact with retinal cell types. However, at this developmental stage, the ganglion cell number decreases in 3D-retinal organoids. Thus, we adapted the model into 2D which promotes their survival. Integrated iMG engulf ganglion cells and control their cell number. In parallel, we apply the immunostimulant POLY(I:C) to mimic a fetal viral infection. Although POLY(I:C) stimulation affects iMG phenotype, it does not influence their interaction with ganglion cells. Furthermore, iMG presence significantly contributes to the supernatant’s inflammatory secretome and increases retinal cell proliferation. Simultaneous exposure to the non-steroidal anti-inflammatory drug (NSAID) ibuprofen dampens POLY(I:C)-mediated consequences of the iMG phenotype and ameliorates cell proliferation. Remarkably, while POLY(I:C) disrupts neuronal calcium dynamics independent of iMG presence, ibuprofen rescues this effect only in the presence of iMG. Mechanistically, ibuprofen blocks the enzymes cyclooxygenase 1 and 2 (COX1/ PTGS1 and COX2/ PTGS2) simultaneously, from which iMG predominantly express COX1. Selective inhibition of COX1 does not restore the calcium peak amplitude upon POLY(I:C) stimulation, indicating ibuprofen’s effect depends on the presence and interplay of both, COX1 and COX2. \r\nIn summary, we characterized the 3D-retinal organoid model for the occurrence of IBA1+-microglia like cells. As the innately developing IBA1+-cells enrich in mesenchymal over retinal structures, we optimized a protocol to differentiate IBA1+-microglia precursors. By combining these two models we generate microglia-assembled retinal organoids. Our results underscore the importance of microglia during neurodevelopment, in the context of prenatal immune challenges and provide insight into the mechanisms by which ibuprofen exerts its protective effects during embryonic development."}],"supervisor":[{"first_name":"Sandra","orcid":"0000-0001-8635-0877","last_name":"Siegert","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","full_name":"Siegert, Sandra"}],"project":[{"_id":"9B99D380-BA93-11EA-9121-9846C619BF3A","grant_number":"SC19-017","name":"How human microglia shape developing neurons during health and inflammation"}],"department":[{"_id":"GradSch"},{"_id":"SaSi"}],"corr_author":"1","date_updated":"2026-05-06T12:49:36Z","citation":{"ieee":"V. Schmied, “ Human microglia impact neuronal development in retinal organoids,” Institute of Science and Technology Austria, 2025.","mla":"Schmied, Verena. <i> Human Microglia Impact Neuronal Development in Retinal Organoids</i>. Institute of Science and Technology Austria, 2025, doi:<a href=\"https://doi.org/10.15479/AT-ISTA-20074\">10.15479/AT-ISTA-20074</a>.","chicago":"Schmied, Verena. “ Human Microglia Impact Neuronal Development in Retinal Organoids.” Institute of Science and Technology Austria, 2025. <a href=\"https://doi.org/10.15479/AT-ISTA-20074\">https://doi.org/10.15479/AT-ISTA-20074</a>.","ama":"Schmied V.  Human microglia impact neuronal development in retinal organoids. 2025. doi:<a href=\"https://doi.org/10.15479/AT-ISTA-20074\">10.15479/AT-ISTA-20074</a>","short":"V. Schmied,  Human Microglia Impact Neuronal Development in Retinal Organoids, Institute of Science and Technology Austria, 2025.","apa":"Schmied, V. (2025). <i> Human microglia impact neuronal development in retinal organoids</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT-ISTA-20074\">https://doi.org/10.15479/AT-ISTA-20074</a>","ista":"Schmied V. 2025.  Human microglia impact neuronal development in retinal organoids. Institute of Science and Technology Austria."},"publisher":"Institute of Science and Technology Austria","status":"public","publication_identifier":{"isbn":["978-3-99078-060-2"],"issn":["2663-337X"]},"has_accepted_license":"1","article_processing_charge":"No","author":[{"first_name":"Verena","id":"32B7C918-F248-11E8-B48F-1D18A9856A87","full_name":"Hübschmann, Verena","last_name":"Hübschmann"}],"related_material":{"record":[{"status":"public","id":"11478","relation":"part_of_dissertation"},{"status":"public","id":"19593","relation":"part_of_dissertation"}]},"OA_place":"publisher","tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"date_published":"2025-07-24T00:00:00Z","day":"24","month":"07","oa_version":"Published Version"},{"publication":"Investigative Ophthalmology & Visual Science","acknowledgement":"The authors thank the Scientific Service Units (SSU) of ISTA for the provided resources, specifically the Imaging and Optics Facility (IOF), the Lab Support Facility (LSF), and the Pre-Clinical Facility (PCF) team, specifically Sonja Haslinger, Claudia Gold, and Michael Schunn, for mouse colony management and support. We thank all members of the Siegert group for constant feedback on the project and the manuscript. \r\nSupported in whole or in part by the Austrian Science Fund (FWF) [10.55776/P37131]. For open access purposes, the author has applied a CC BY public copyright license to any author-accepted manuscript version arising from this submission. ","type":"journal_article","file_date_updated":"2025-04-15T13:49:10Z","language":[{"iso":"eng"}],"date_created":"2025-04-15T13:40:35Z","DOAJ_listed":"1","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"},{"_id":"PreCl"}],"year":"2025","_id":"19566","intvolume":"        66","ddc":["570"],"doi":"10.1167/iovs.66.3.49","file":[{"file_id":"19567","date_updated":"2025-04-15T13:49:10Z","creator":"dernst","file_size":2721477,"access_level":"open_access","success":1,"relation":"main_file","content_type":"application/pdf","checksum":"e8722ce5792f6c08fe1e191f7de6f147","file_name":"2025_IOVS_SchootUiterkamp.pdf","date_created":"2025-04-15T13:49:10Z"}],"title":"Optic nerve crush does not induce retinal ganglion cell loss in the contralateral eye","publication_status":"published","article_type":"original","oa":1,"article_number":"49","project":[{"grant_number":"P37131","_id":"7be82147-9f16-11ee-852c-f44682d73140","name":"Dissecting the morpho-functional relationship of microglia"},{"name":"FWF Open Access Fund","call_identifier":"FWF","_id":"3AC91DDA-15DF-11EA-824D-93A3E7B544D1"}],"abstract":[{"lang":"eng","text":"Purpose: Optic nerve crush (ONC) is a model for studying optic nerve trauma. Unilateral ONC induces massive retinal ganglion cell (RGC) degeneration in the affected eye, leading to vision loss within a month. A common assumption has been that the non-injured contralateral eye is unaffected due to the minimal retino-retinal projections of the RGCs at the chiasm. Yet, recently, microglia, the brain-resident macrophages, have shown a responsive phenotype in the contralateral eye after ONC. Whether RGC loss accompanies this phenotype is still controversial.\r\n\r\nMethods: Using the available RGCode algorithm and developing our own RGC-Quant deep-learning-based tool, we quantify RGC's total number and density across the entire retina after ONC.\r\n\r\nResults: We confirm a short-term microglia response in the contralateral eye after ONC, but this did not affect the microglia number. Furthermore, we cannot confirm the previously reported RGC loss between naïve and contralateral retinas 5 weeks after ONC induction across the commonly used Cx3cr1creERT2 and C57BL6/J mouse models. Neither sex nor the direct comparison of the RGC markers Brn3a and RBPMS, with Brn3a co-labeling, on average, 89% of the RBPMS+-cells, explained this discrepancy, suggesting that the early microglia-responsive phenotype does not have immediate consequences on the RGC number.\r\n\r\nConclusions: Our results corroborate that unilateral optic nerve injury elicits a microglial response in the uninjured contralateral eye but without RGC loss. Therefore, the contralateral eye should be treated separately and not as an ONC control."}],"status":"public","publication_identifier":{"issn":["1552-5783"]},"department":[{"_id":"SaSi"}],"corr_author":"1","date_updated":"2026-05-20T06:37:12Z","publisher":"Association for Research in Vision and Ophthalmology","citation":{"short":"F.E. Miteva, M.E. Maes, M. Alamalhoda, A. Firoozi, G. Colombo, S. Siegert, Investigative Ophthalmology &#38; Visual Science 66 (2025).","ista":"Miteva FE, Maes ME, Alamalhoda M, Firoozi A, Colombo G, Siegert S. 2025. Optic nerve crush does not induce retinal ganglion cell loss in the contralateral eye. Investigative Ophthalmology &#38; Visual Science. 66(3), 49.","apa":"Miteva, F. E., Maes, M. E., Alamalhoda, M., Firoozi, A., Colombo, G., &#38; Siegert, S. (2025). Optic nerve crush does not induce retinal ganglion cell loss in the contralateral eye. <i>Investigative Ophthalmology &#38; Visual Science</i>. Association for Research in Vision and Ophthalmology. <a href=\"https://doi.org/10.1167/iovs.66.3.49\">https://doi.org/10.1167/iovs.66.3.49</a>","mla":"Miteva, Florianne E., et al. “Optic Nerve Crush Does Not Induce Retinal Ganglion Cell Loss in the Contralateral Eye.” <i>Investigative Ophthalmology &#38; Visual Science</i>, vol. 66, no. 3, 49, Association for Research in Vision and Ophthalmology, 2025, doi:<a href=\"https://doi.org/10.1167/iovs.66.3.49\">10.1167/iovs.66.3.49</a>.","chicago":"Miteva, Florianne E, Margaret E Maes, Mohammad Alamalhoda, Arsalan Firoozi, Gloria Colombo, and Sandra Siegert. “Optic Nerve Crush Does Not Induce Retinal Ganglion Cell Loss in the Contralateral Eye.” <i>Investigative Ophthalmology &#38; Visual Science</i>. Association for Research in Vision and Ophthalmology, 2025. <a href=\"https://doi.org/10.1167/iovs.66.3.49\">https://doi.org/10.1167/iovs.66.3.49</a>.","ieee":"F. E. Miteva, M. E. Maes, M. Alamalhoda, A. Firoozi, G. Colombo, and S. Siegert, “Optic nerve crush does not induce retinal ganglion cell loss in the contralateral eye,” <i>Investigative Ophthalmology &#38; Visual Science</i>, vol. 66, no. 3. Association for Research in Vision and Ophthalmology, 2025.","ama":"Miteva FE, Maes ME, Alamalhoda M, Firoozi A, Colombo G, Siegert S. Optic nerve crush does not induce retinal ganglion cell loss in the contralateral eye. <i>Investigative Ophthalmology &#38; Visual Science</i>. 2025;66(3). doi:<a href=\"https://doi.org/10.1167/iovs.66.3.49\">10.1167/iovs.66.3.49</a>"},"related_material":{"record":[{"status":"public","relation":"dissertation_contains","id":"20467"}],"link":[{"relation":"software","url":"https://github.com/siegert-lab/RGC-Quant"}]},"OA_place":"publisher","tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"volume":66,"date_published":"2025-03-01T00:00:00Z","has_accepted_license":"1","external_id":{"pmid":["40126507"]},"article_processing_charge":"Yes","author":[{"first_name":"Florianne E","id":"3526230C-F248-11E8-B48F-1D18A9856A87","full_name":"Schoot Uiterkamp, Florianne E","last_name":"Schoot Uiterkamp"},{"first_name":"Margaret E","orcid":"0000-0001-9642-1085","last_name":"Maes","id":"3838F452-F248-11E8-B48F-1D18A9856A87","full_name":"Maes, Margaret E"},{"first_name":"Mohammad","last_name":"Alamalhoda","full_name":"Alamalhoda, Mohammad"},{"first_name":"Arsalan","full_name":"Firoozi, Arsalan","last_name":"Firoozi"},{"first_name":"Gloria","id":"3483CF6C-F248-11E8-B48F-1D18A9856A87","full_name":"Colombo, Gloria","last_name":"Colombo","orcid":"0000-0001-9434-8902"},{"orcid":"0000-0001-8635-0877","last_name":"Siegert","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","full_name":"Siegert, Sandra","first_name":"Sandra"}],"pmid":1,"month":"03","day":"01","issue":"3","oa_version":"Published Version","scopus_import":"1","OA_type":"gold","APC_amount":"2236,02 EUR","quality_controlled":"1"},{"alternative_title":["ISTA Thesis"],"degree_awarded":"PhD","page":"99","file":[{"relation":"main_file","file_size":13668588,"access_level":"closed","date_updated":"2025-10-17T11:13:25Z","creator":"fschootu","embargo_to":"open_access","file_id":"20484","date_created":"2025-10-17T11:09:11Z","embargo":"2026-10-14","file_name":"2025_Miteva_Florianne_thesis.pdf","content_type":"application/pdf","checksum":"03537697be8c688d3a05cf948288e48f"},{"access_level":"closed","file_size":28991918,"relation":"source_file","file_id":"20525","creator":"fschootu","date_updated":"2025-10-23T11:33:06Z","date_created":"2025-10-23T11:33:06Z","content_type":"application/vnd.openxmlformats-officedocument.wordprocessingml.document","checksum":"df4930d7211cf9cfe1254b77204dc1d3","file_name":"2025_Miteva_florianne_thesis.docx"}],"title":"The role of cyclooxygenase 1 on microglial response to inflammatory stressors","publication_status":"published","project":[{"grant_number":"P37131","_id":"7be82147-9f16-11ee-852c-f44682d73140","name":"Dissecting the morpho-functional relationship of microglia"}],"supervisor":[{"orcid":"0000-0001-8635-0877","last_name":"Siegert","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","full_name":"Siegert, Sandra","first_name":"Sandra"}],"acknowledgement":"The work presented in this Thesis was carried out at the Institute of Science and Technology\r\nAustria (ISTA), and was supported by the Austrian Science Fund (FWF) [10.55776/P37131].\r\nI would like to thank the Scientific Service Units (SSU) of ISTA for the provided resources,\r\nspecifically the Imaging and Optics Facility (IOF), the Lab Support Facility (LSF), and the\r\nPre-Clinical Facility (PCF) team, specifically Sonja Haslinger, Claudia Gold, and Michael\r\nSchunn, for mouse colony management and support. ","type":"dissertation","file_date_updated":"2025-10-23T11:33:06Z","user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","acknowledged_ssus":[{"_id":"Bio"},{"_id":"SSU"},{"_id":"PreCl"},{"_id":"LifeSc"}],"year":"2025","date_created":"2025-10-14T10:24:41Z","language":[{"iso":"eng"}],"ddc":["570"],"doi":"10.15479/AT-ISTA-20467","_id":"20467","month":"10","day":"14","oa_version":"Published Version","publication_identifier":{"issn":["2663-337X"]},"status":"public","publisher":"Institute of Science and Technology Austria","citation":{"short":"F.E. Miteva, The Role of Cyclooxygenase 1 on Microglial Response to Inflammatory Stressors, Institute of Science and Technology Austria, 2025.","ista":"Miteva FE. 2025. The role of cyclooxygenase 1 on microglial response to inflammatory stressors. Institute of Science and Technology Austria.","apa":"Miteva, F. E. (2025). <i>The role of cyclooxygenase 1 on microglial response to inflammatory stressors</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT-ISTA-20467\">https://doi.org/10.15479/AT-ISTA-20467</a>","chicago":"Miteva, Florianne E. “The Role of Cyclooxygenase 1 on Microglial Response to Inflammatory Stressors.” Institute of Science and Technology Austria, 2025. <a href=\"https://doi.org/10.15479/AT-ISTA-20467\">https://doi.org/10.15479/AT-ISTA-20467</a>.","mla":"Miteva, Florianne E. <i>The Role of Cyclooxygenase 1 on Microglial Response to Inflammatory Stressors</i>. Institute of Science and Technology Austria, 2025, doi:<a href=\"https://doi.org/10.15479/AT-ISTA-20467\">10.15479/AT-ISTA-20467</a>.","ieee":"F. E. Miteva, “The role of cyclooxygenase 1 on microglial response to inflammatory stressors,” Institute of Science and Technology Austria, 2025.","ama":"Miteva FE. The role of cyclooxygenase 1 on microglial response to inflammatory stressors. 2025. doi:<a href=\"https://doi.org/10.15479/AT-ISTA-20467\">10.15479/AT-ISTA-20467</a>"},"date_updated":"2026-05-20T06:37:12Z","corr_author":"1","department":[{"_id":"GradSch"},{"_id":"SaSi"}],"date_published":"2025-10-14T00:00:00Z","tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"related_material":{"record":[{"relation":"part_of_dissertation","id":"19566","status":"public"}]},"OA_place":"publisher","author":[{"full_name":"Miteva, Florianne E","id":"3526230C-F248-11E8-B48F-1D18A9856A87","last_name":"Miteva","first_name":"Florianne E"}],"article_processing_charge":"No","has_accepted_license":"1"},{"month":"07","day":"01","scopus_import":"1","oa_version":"Published Version","OA_type":"hybrid","quality_controlled":"1","status":"public","isi":1,"publication_identifier":{"issn":["1087-0156"],"eissn":["1546-1696"]},"department":[{"_id":"SaSi"},{"_id":"GaNo"},{"_id":"PeJo"},{"_id":"JoDa"},{"_id":"Bio"},{"_id":"RySh"}],"corr_author":"1","date_updated":"2026-04-14T08:34:35Z","citation":{"short":"J.M. Michalska, J. Lyudchik, P. Velicky, H. Korinkova, J. Watson, A. Cenameri, C.M. Sommer, N. Amberg, A. Venturino, K. Roessler, T. Czech, R. Höftberger, S. Siegert, G. Novarino, P.M. Jonas, J.G. Danzl, Nature Biotechnology 42 (2024) 1051–1064.","ista":"Michalska JM, Lyudchik J, Velicky P, Korinkova H, Watson J, Cenameri A, Sommer CM, Amberg N, Venturino A, Roessler K, Czech T, Höftberger R, Siegert S, Novarino G, Jonas PM, Danzl JG. 2024. Imaging brain tissue architecture across millimeter to nanometer scales. Nature Biotechnology. 42, 1051–1064.","apa":"Michalska, J. M., Lyudchik, J., Velicky, P., Korinkova, H., Watson, J., Cenameri, A., … Danzl, J. G. (2024). Imaging brain tissue architecture across millimeter to nanometer scales. <i>Nature Biotechnology</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41587-023-01911-8\">https://doi.org/10.1038/s41587-023-01911-8</a>","mla":"Michalska, Julia M., et al. “Imaging Brain Tissue Architecture across Millimeter to Nanometer Scales.” <i>Nature Biotechnology</i>, vol. 42, Springer Nature, 2024, pp. 1051–64, doi:<a href=\"https://doi.org/10.1038/s41587-023-01911-8\">10.1038/s41587-023-01911-8</a>.","chicago":"Michalska, Julia M, Julia Lyudchik, Philipp Velicky, Hana Korinkova, Jake Watson, Alban Cenameri, Christoph M Sommer, et al. “Imaging Brain Tissue Architecture across Millimeter to Nanometer Scales.” <i>Nature Biotechnology</i>. Springer Nature, 2024. <a href=\"https://doi.org/10.1038/s41587-023-01911-8\">https://doi.org/10.1038/s41587-023-01911-8</a>.","ieee":"J. M. Michalska <i>et al.</i>, “Imaging brain tissue architecture across millimeter to nanometer scales,” <i>Nature Biotechnology</i>, vol. 42. Springer Nature, pp. 1051–1064, 2024.","ama":"Michalska JM, Lyudchik J, Velicky P, et al. Imaging brain tissue architecture across millimeter to nanometer scales. <i>Nature Biotechnology</i>. 2024;42:1051-1064. doi:<a href=\"https://doi.org/10.1038/s41587-023-01911-8\">10.1038/s41587-023-01911-8</a>"},"publisher":"Springer Nature","related_material":{"link":[{"url":"https://github.com/danzllab/CATS","relation":"software"}],"record":[{"status":"deleted","id":"18660","relation":"dissertation_contains"},{"status":"public","relation":"research_data","id":"13126"},{"relation":"dissertation_contains","id":"18674","status":"public"}]},"OA_place":"publisher","tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"date_published":"2024-07-01T00:00:00Z","volume":42,"article_processing_charge":"Yes (in subscription journal)","external_id":{"pmid":["37653226"],"isi":["001065254200001"]},"has_accepted_license":"1","author":[{"orcid":"0000-0003-3862-1235","last_name":"Michalska","full_name":"Michalska, Julia M","id":"443DB6DE-F248-11E8-B48F-1D18A9856A87","first_name":"Julia M"},{"id":"46E28B80-F248-11E8-B48F-1D18A9856A87","full_name":"Lyudchik, Julia","last_name":"Lyudchik","first_name":"Julia"},{"id":"39BDC62C-F248-11E8-B48F-1D18A9856A87","full_name":"Velicky, Philipp","orcid":"0000-0002-2340-7431","last_name":"Velicky","first_name":"Philipp"},{"id":"ee3cb6ca-ec98-11ea-ae11-ff703e2254ed","full_name":"Korinkova, Hana","last_name":"Korinkova","first_name":"Hana"},{"last_name":"Watson","orcid":"0000-0002-8698-3823","id":"63836096-4690-11EA-BD4E-32803DDC885E","full_name":"Watson, Jake","first_name":"Jake"},{"id":"9ac8f577-2357-11eb-997a-e566c5550886","full_name":"Cenameri, Alban","last_name":"Cenameri","first_name":"Alban"},{"last_name":"Sommer","orcid":"0000-0003-1216-9105","full_name":"Sommer, Christoph M","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87","first_name":"Christoph M"},{"first_name":"Nicole","orcid":"0000-0002-3183-8207","last_name":"Amberg","id":"4CD6AAC6-F248-11E8-B48F-1D18A9856A87","full_name":"Amberg, Nicole"},{"first_name":"Alessandro","orcid":"0000-0003-2356-9403","last_name":"Venturino","id":"41CB84B2-F248-11E8-B48F-1D18A9856A87","full_name":"Venturino, Alessandro"},{"first_name":"Karl","last_name":"Roessler","full_name":"Roessler, Karl"},{"last_name":"Czech","full_name":"Czech, Thomas","first_name":"Thomas"},{"last_name":"Höftberger","full_name":"Höftberger, Romana","first_name":"Romana"},{"first_name":"Sandra","last_name":"Siegert","orcid":"0000-0001-8635-0877","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","full_name":"Siegert, Sandra"},{"orcid":"0000-0002-7673-7178","last_name":"Novarino","full_name":"Novarino, Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","first_name":"Gaia"},{"orcid":"0000-0001-5001-4804","last_name":"Jonas","full_name":"Jonas, Peter M","id":"353C1B58-F248-11E8-B48F-1D18A9856A87","first_name":"Peter M"},{"first_name":"Johann G","full_name":"Danzl, Johann G","id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","last_name":"Danzl","orcid":"0000-0001-8559-3973"}],"pmid":1,"title":"Imaging brain tissue architecture across millimeter to nanometer scales","file":[{"date_created":"2025-01-09T07:48:01Z","file_name":"2024_NatureBiotech_Michalska.pdf","checksum":"57d5fafb16f02dcb9f7dddb1bd7e2a71","content_type":"application/pdf","relation":"main_file","success":1,"file_size":26065165,"access_level":"open_access","date_updated":"2025-01-09T07:48:01Z","creator":"dernst","file_id":"18784"}],"page":"1051-1064","article_type":"original","publication_status":"published","oa":1,"project":[{"grant_number":"I03600","_id":"265CB4D0-B435-11E9-9278-68D0E5697425","call_identifier":"FWF","name":"Optical control of synaptic function via adhesion molecules"},{"name":"Molecular Drug Targets","_id":"2548AE96-B435-11E9-9278-68D0E5697425","grant_number":"W1232","call_identifier":"FWF"},{"grant_number":"Z00312","_id":"25C5A090-B435-11E9-9278-68D0E5697425","call_identifier":"FWF","name":"Synaptic communication in neuronal microcircuits"},{"_id":"23889792-32DE-11EA-91FC-C7463DDC885E","grant_number":"LS18-022","name":"High content imaging to decode human immune cell interactions in health and allergic disease"},{"call_identifier":"H2020","grant_number":"715508","_id":"25444568-B435-11E9-9278-68D0E5697425","name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models"},{"_id":"25B7EB9E-B435-11E9-9278-68D0E5697425","grant_number":"692692","call_identifier":"H2020","name":"Biophysics and circuit function of a giant cortical glutamatergic synapse"},{"grant_number":"665385","call_identifier":"H2020","_id":"2564DBCA-B435-11E9-9278-68D0E5697425","name":"International IST Doctoral Program"},{"name":"Synaptic computations of the hippocampal CA3 circuitry","call_identifier":"H2020","_id":"fc2be41b-9c52-11eb-aca3-faa90aa144e9","grant_number":"101026635"}],"ec_funded":1,"abstract":[{"lang":"eng","text":"Mapping the complex and dense arrangement of cells and their connectivity in brain tissue demands nanoscale spatial resolution imaging. Super-resolution optical microscopy excels at visualizing specific molecules and individual cells but fails to provide tissue context. Here we developed Comprehensive Analysis of Tissues across Scales (CATS), a technology to densely map brain tissue architecture from millimeter regional to nanometer synaptic scales in diverse chemically fixed brain preparations, including rodent and human. CATS uses fixation-compatible extracellular labeling and optical imaging, including stimulated emission depletion or expansion microscopy, to comprehensively delineate cellular structures. It enables three-dimensional reconstruction of single synapses and mapping of synaptic connectivity by identification and analysis of putative synaptic cleft regions. Applying CATS to the mouse hippocampal mossy fiber circuitry, we reconstructed and quantified the synaptic input and output structure of identified neurons. We furthermore demonstrate applicability to clinically derived human tissue samples, including formalin-fixed paraffin-embedded routine diagnostic specimens, for visualizing the cellular architecture of brain tissue in health and disease."}],"publication":"Nature Biotechnology","acknowledgement":"We thank J. Vorlaufer, N. Agudelo-Dueñas, W. Jahr and A. Wartak for microscope maintenance and troubleshooting; C. Kreuzinger, A. Freeman and I. Erber for technical assistance; and M. Tomschik for support with obtaining human samples. We gratefully acknowledge E. Miguel for setting up webKnossos and M. Šuplata for computational support and hardware control. We are grateful to R. Shigemoto and B. Bickel for generous support and M. Sixt and S. Boyd (Stanford University) for discussions and critical reading of the paper. PSD95-HaloTag mice were kindly provided by S. Grant (University of Edinburgh). We acknowledge expert support by Institute of Science and Technology Austria’s scientific computing, imaging and optics, preclinical and lab support facilities and by the Miba machine shop and library. We gratefully acknowledge funding by the following sources: Austrian Science Fund (FWF) grant I3600-B27 (J.G.D.); Austrian Science Fund (FWF) grant DK W1232 (J.G.D. and J.M.M.); Austrian Science Fund (FWF) grant Z 312-B27, Wittgenstein award (P.J.); Austrian Science Fund (FWF) projects I4685-B, I6565-B (SYNABS) and DOC 33-B27 (R.H.); Gesellschaft für Forschungsförderung NÖ (NFB) grant LSC18-022 (J.G.D.); European Union’s Horizon 2020 research and innovation programme, European Research Council (ERC) grant 715508 – REVERSEAUTISM (G.N.); European Union’s Horizon 2020 research and innovation programme, European Research Council (ERC) grant 692692 – GIANTSYN (P.J.); Marie Skłodowska-Curie Actions Fellowship GA no. 665385 under the EU Horizon 2020 program (J.M.M. and J.L.); and Marie Skłodowska-Curie Actions Individual Fellowship no. 101026635 under the EU Horizon 2020 program (J.F.W.).","type":"journal_article","file_date_updated":"2025-01-09T07:48:01Z","language":[{"iso":"eng"}],"date_created":"2023-09-03T22:01:15Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","year":"2024","acknowledged_ssus":[{"_id":"ScienComp"},{"_id":"Bio"},{"_id":"PreCl"},{"_id":"LifeSc"},{"_id":"M-Shop"},{"_id":"E-Lib"}],"_id":"14257","intvolume":"        42","doi":"10.1038/s41587-023-01911-8","ddc":["570"]},{"author":[{"id":"1d390868-f128-11eb-9611-a0ca5f7833b5","full_name":"Murmann, Julie Stefanie","last_name":"Murmann","first_name":"Julie Stefanie"}],"has_accepted_license":"1","article_processing_charge":"No","tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"date_published":"2024-05-02T00:00:00Z","OA_place":"publisher","date_updated":"2026-04-07T13:05:00Z","publisher":"Institute of Science and Technology Austria","citation":{"ieee":"J. S. Murmann, “Investigating acute microglia response to seizure activity in vivo: Combining 2-Photon imaging and EEG recording,” Institute of Science and Technology Austria, 2024.","chicago":"Murmann, Julie Stefanie. “Investigating Acute Microglia Response to Seizure Activity in Vivo: Combining 2-Photon Imaging and EEG Recording.” Institute of Science and Technology Austria, 2024. <a href=\"https://doi.org/10.15479/at:ista:15352\">https://doi.org/10.15479/at:ista:15352</a>.","mla":"Murmann, Julie Stefanie. <i>Investigating Acute Microglia Response to Seizure Activity in Vivo: Combining 2-Photon Imaging and EEG Recording</i>. Institute of Science and Technology Austria, 2024, doi:<a href=\"https://doi.org/10.15479/at:ista:15352\">10.15479/at:ista:15352</a>.","ama":"Murmann JS. Investigating acute microglia response to seizure activity in vivo: Combining 2-Photon imaging and EEG recording. 2024. doi:<a href=\"https://doi.org/10.15479/at:ista:15352\">10.15479/at:ista:15352</a>","short":"J.S. Murmann, Investigating Acute Microglia Response to Seizure Activity in Vivo: Combining 2-Photon Imaging and EEG Recording, Institute of Science and Technology Austria, 2024.","apa":"Murmann, J. S. (2024). <i>Investigating acute microglia response to seizure activity in vivo: Combining 2-Photon imaging and EEG recording</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/at:ista:15352\">https://doi.org/10.15479/at:ista:15352</a>","ista":"Murmann JS. 2024. Investigating acute microglia response to seizure activity in vivo: Combining 2-Photon imaging and EEG recording. Institute of Science and Technology Austria."},"department":[{"_id":"SaSi"},{"_id":"GradSch"}],"corr_author":"1","publication_identifier":{"issn":["2791-4585"]},"status":"public","oa_version":"Published Version","day":"02","month":"05","ddc":["570"],"doi":"10.15479/at:ista:15352","_id":"15352","date_created":"2024-05-02T08:31:38Z","language":[{"iso":"eng"}],"user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"},{"_id":"PreCl"}],"year":"2024","file_date_updated":"2025-05-02T22:30:04Z","type":"dissertation","abstract":[{"lang":"eng","text":"Epilepsy affects about 50 to 65 million people globally. It summarizes a spectrum of neurological\r\ndisorders that have in common a hyperactivity of the neuronal network resulting in seizures. A common\r\nassumption is that an imbalance between neuronal excitation and inhibition is a key mechanism in\r\nseizure generation and epileptogeneisis. In at least one-third of the patients, current therapies have\r\nproven unsuccessful in treating seizure progression. One potential reason could be that the therapies\r\nonly focus on neurons. Recent studies suggest that neuronal hyperactivity causes a microglial\r\nresponse, which reinstates brain homeostasis. Additionally, interactions between microglia and neurons\r\nhave been shown to inhibit neuronal firing and dampen seizure activity. However, the exact relationship\r\nbetween microglia and seizure progression in epilepsy is yet to be elucidated. A main bottleneck is that\r\nseveral studies investigate microglia dynamics in ex vivo slice models, which can severely affect the\r\nmicroglia dynamics due to their rapid response to environmental changes. On the other hand, in vivo\r\nstudies focus mostly on behavior characterization of the epileptic seizure phenotype and their long-term\r\nconsequences on microglia activity leaving out the direct consequences of acute seizure activity on\r\nmicroglia dynamics.\r\nHere, we perform a pilot study to combine electroencephalography (EEG) and in vivo live imaging to\r\ndirectly monitor and correlate the onset of seizure activity with microglia response. To induce seizures,\r\nwe take advantage of the kainic acid (KA) model, which represents similar neuropathological and\r\nelectroencephalographic features seen in human patients with temporal lobe epilepsy (TLE). After\r\nconfirmation of induction of the seizure and microglia activity in the hippocampus as a focal point, we\r\ninvestigated whether these changes also reached the primary visual cortex (V1) as a secondary\r\ngeneralized seizure activity. Indeed, we found that microglia changed their morphology at high doses\r\nof KA in the V1. Next, we optimized each of the two methodological components: for the EEG recording,\r\nour initial attempts under the microscope suffered from extensive electrical noise, which overlaid the\r\nactual signal. Thus, we built a customized Faraday-cage and confirmed that the signal-to-noise ratio\r\nwas sufficiently reduced to be able to record brain oscillatory activity. For the in vivo live imaging of\r\nmicroglia, we had to optimize the imaging parameters, so that we would be able to detect microglial\r\nprocesses in a sufficient resolution to track their process changes. Finally, we combined both\r\nmethodologies with the KA model. We confirmed that KA induced seizure activity and found first\r\nindication that those correlate with microglia volume changes.\r\nOverall, we have developed a first methodological approach, which allows the analysis of the acute\r\neffects of seizure onset on microglia. Future studies will have to continue to optimize the drift during\r\nimaging recording and the post-image analysis. "}],"supervisor":[{"id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","full_name":"Siegert, Sandra","orcid":"0000-0001-8635-0877","last_name":"Siegert","first_name":"Sandra"}],"publication_status":"published","oa":1,"file":[{"embargo":"2025-05-02","date_created":"2024-05-02T12:26:13Z","file_name":"Murmann_Thesis_final_2024_2.pdf","content_type":"application/pdf","checksum":"095817a6c944954ac3f277e547031a33","relation":"main_file","access_level":"open_access","file_size":5936142,"creator":"cchlebak","date_updated":"2025-05-02T22:30:04Z","file_id":"15354"},{"date_created":"2024-05-02T12:37:56Z","content_type":"application/x-zip-compressed","checksum":"43b632255372973a437ac87739cfd4db","file_name":"Murmann_Thesis_final_2024.zip","file_size":20645510,"access_level":"closed","relation":"source_file","file_id":"15355","date_updated":"2025-05-02T22:30:04Z","creator":"cchlebak","embargo_to":"open_access"}],"title":"Investigating acute microglia response to seizure activity in vivo: Combining 2-Photon imaging and EEG recording","page":"54","alternative_title":["ISTA Master's Thesis"],"degree_awarded":"MS"},{"abstract":[{"text":"Mitochondrial networks remodel their connectivity, content, and subcellular localization to support optimized energy production in conditions of increased environmental or cellular stress. Microglia rely on mitochondria to respond to these stressors, however our knowledge about mitochondrial networks and their adaptations in microglia in vivo is limited. Here, we generate a mouse model that selectively labels mitochondria in microglia. We identify that mitochondrial networks are more fragmented with increased content and perinuclear localization in vitro vs. in vivo. Mitochondrial networks adapt similarly in microglia closest to the injury site after optic nerve crush. Preventing microglial UCP2 increase after injury by selective knockout induces cellular stress. This results in mitochondrial hyperfusion in male microglia, a phenotype absent in females due to circulating estrogens. Our results establish the foundation for mitochondrial network analysis of microglia in vivo, emphasizing the importance of mitochondrial-based sex effects of microglia in other pathologies.","lang":"eng"}],"file":[{"file_name":"2023_iScience_Maes.pdf","checksum":"be1a560efdd96d20712311f4fc54aac2","content_type":"application/pdf","date_created":"2023-11-07T08:53:21Z","date_updated":"2023-11-07T08:53:21Z","creator":"dernst","file_id":"14497","success":1,"relation":"main_file","file_size":8197935,"access_level":"open_access"}],"title":"Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout","oa":1,"publication_status":"published","article_type":"original","article_number":"107780","year":"2023","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"},{"_id":"PreCl"}],"date_created":"2023-09-24T22:01:11Z","language":[{"iso":"eng"}],"_id":"14363","doi":"10.1016/j.isci.2023.107780","ddc":["570"],"intvolume":"        26","publication":"iScience","type":"journal_article","acknowledgement":"We thank the Scientific Service Units (SSU) of ISTA through resources provided by the Imaging and Optics Facility (IOF), the Lab Support Facility (LSF), and the Pre-Clinical Facility (PCF) team, specifically Sonja Haslinger and Michael Schunn for excellent mouse colony management and support. This research was supported by the FWF Sonderforschungsbereich F83 (to E.E.P). We thank Bálint Nagy, Ryan John A. Cubero, Marco Benevento and all members of the Siegert group for constant feedback on the project and article.","file_date_updated":"2023-11-07T08:53:21Z","issue":"10","oa_version":"Published Version","scopus_import":"1","quality_controlled":"1","month":"10","day":"20","date_published":"2023-10-20T00:00:00Z","volume":26,"tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"has_accepted_license":"1","external_id":{"pmid":["37731609"],"isi":["001080403500001"]},"article_processing_charge":"Yes","pmid":1,"author":[{"last_name":"Maes","orcid":"0000-0001-9642-1085","id":"3838F452-F248-11E8-B48F-1D18A9856A87","full_name":"Maes, Margaret E","first_name":"Margaret E"},{"id":"3483CF6C-F248-11E8-B48F-1D18A9856A87","full_name":"Colombo, Gloria","last_name":"Colombo","orcid":"0000-0001-9434-8902","first_name":"Gloria"},{"last_name":"Schoot Uiterkamp","full_name":"Schoot Uiterkamp, Florianne E","id":"3526230C-F248-11E8-B48F-1D18A9856A87","first_name":"Florianne E"},{"first_name":"Felix","full_name":"Sternberg, Felix","last_name":"Sternberg"},{"first_name":"Alessandro","full_name":"Venturino, Alessandro","id":"41CB84B2-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-2356-9403","last_name":"Venturino"},{"full_name":"Pohl, Elena E.","last_name":"Pohl","first_name":"Elena E."},{"first_name":"Sandra","orcid":"0000-0001-8635-0877","last_name":"Siegert","full_name":"Siegert, Sandra","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87"}],"status":"public","isi":1,"publication_identifier":{"eissn":["2589-0042"]},"corr_author":"1","department":[{"_id":"SaSi"}],"publisher":"Elsevier","citation":{"ieee":"M. E. Maes <i>et al.</i>, “Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout,” <i>iScience</i>, vol. 26, no. 10. Elsevier, 2023.","chicago":"Maes, Margaret E, Gloria Colombo, Florianne E Schoot Uiterkamp, Felix Sternberg, Alessandro Venturino, Elena E. Pohl, and Sandra Siegert. “Mitochondrial Network Adaptations of Microglia Reveal Sex-Specific Stress Response after Injury and UCP2 Knockout.” <i>IScience</i>. Elsevier, 2023. <a href=\"https://doi.org/10.1016/j.isci.2023.107780\">https://doi.org/10.1016/j.isci.2023.107780</a>.","mla":"Maes, Margaret E., et al. “Mitochondrial Network Adaptations of Microglia Reveal Sex-Specific Stress Response after Injury and UCP2 Knockout.” <i>IScience</i>, vol. 26, no. 10, 107780, Elsevier, 2023, doi:<a href=\"https://doi.org/10.1016/j.isci.2023.107780\">10.1016/j.isci.2023.107780</a>.","ama":"Maes ME, Colombo G, Schoot Uiterkamp FE, et al. Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout. <i>iScience</i>. 2023;26(10). doi:<a href=\"https://doi.org/10.1016/j.isci.2023.107780\">10.1016/j.isci.2023.107780</a>","short":"M.E. Maes, G. Colombo, F.E. Schoot Uiterkamp, F. Sternberg, A. Venturino, E.E. Pohl, S. Siegert, IScience 26 (2023).","apa":"Maes, M. E., Colombo, G., Schoot Uiterkamp, F. E., Sternberg, F., Venturino, A., Pohl, E. E., &#38; Siegert, S. (2023). Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout. <i>IScience</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.isci.2023.107780\">https://doi.org/10.1016/j.isci.2023.107780</a>","ista":"Maes ME, Colombo G, Schoot Uiterkamp FE, Sternberg F, Venturino A, Pohl EE, Siegert S. 2023. Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout. iScience. 26(10), 107780."},"date_updated":"2024-10-09T21:07:01Z"},{"day":"26","month":"09","quality_controlled":"1","scopus_import":"1","oa_version":"Published Version","date_updated":"2025-04-23T13:09:05Z","citation":{"chicago":"Maes, Margaret E, Ryan J. Donahue, Cassandra L. Schlamp, Olivia J. Marola, Richard T. Libby, and Robert W. Nickells. “BAX Activation in Mouse Retinal Ganglion Cells Occurs in Two Temporally and Mechanistically Distinct Steps.” <i>Molecular Neurodegeneration</i>. Springer Nature, 2023. <a href=\"https://doi.org/10.1186/s13024-023-00659-8\">https://doi.org/10.1186/s13024-023-00659-8</a>.","mla":"Maes, Margaret E., et al. “BAX Activation in Mouse Retinal Ganglion Cells Occurs in Two Temporally and Mechanistically Distinct Steps.” <i>Molecular Neurodegeneration</i>, vol. 18, 67, Springer Nature, 2023, doi:<a href=\"https://doi.org/10.1186/s13024-023-00659-8\">10.1186/s13024-023-00659-8</a>.","ieee":"M. E. Maes, R. J. Donahue, C. L. Schlamp, O. J. Marola, R. T. Libby, and R. W. Nickells, “BAX activation in mouse retinal ganglion cells occurs in two temporally and mechanistically distinct steps,” <i>Molecular Neurodegeneration</i>, vol. 18. Springer Nature, 2023.","ama":"Maes ME, Donahue RJ, Schlamp CL, Marola OJ, Libby RT, Nickells RW. BAX activation in mouse retinal ganglion cells occurs in two temporally and mechanistically distinct steps. <i>Molecular Neurodegeneration</i>. 2023;18. doi:<a href=\"https://doi.org/10.1186/s13024-023-00659-8\">10.1186/s13024-023-00659-8</a>","short":"M.E. Maes, R.J. Donahue, C.L. Schlamp, O.J. Marola, R.T. Libby, R.W. Nickells, Molecular Neurodegeneration 18 (2023).","ista":"Maes ME, Donahue RJ, Schlamp CL, Marola OJ, Libby RT, Nickells RW. 2023. BAX activation in mouse retinal ganglion cells occurs in two temporally and mechanistically distinct steps. Molecular Neurodegeneration. 18, 67.","apa":"Maes, M. E., Donahue, R. J., Schlamp, C. L., Marola, O. J., Libby, R. T., &#38; Nickells, R. W. (2023). BAX activation in mouse retinal ganglion cells occurs in two temporally and mechanistically distinct steps. <i>Molecular Neurodegeneration</i>. Springer Nature. <a href=\"https://doi.org/10.1186/s13024-023-00659-8\">https://doi.org/10.1186/s13024-023-00659-8</a>"},"publisher":"Springer Nature","department":[{"_id":"SaSi"}],"isi":1,"publication_identifier":{"eissn":["1750-1326"]},"status":"public","pmid":1,"author":[{"last_name":"Maes","orcid":"0000-0001-9642-1085","id":"3838F452-F248-11E8-B48F-1D18A9856A87","full_name":"Maes, Margaret E","first_name":"Margaret E"},{"first_name":"Ryan J.","last_name":"Donahue","full_name":"Donahue, Ryan J."},{"last_name":"Schlamp","full_name":"Schlamp, Cassandra L.","first_name":"Cassandra L."},{"first_name":"Olivia J.","last_name":"Marola","full_name":"Marola, Olivia J."},{"last_name":"Libby","full_name":"Libby, Richard T.","first_name":"Richard T."},{"first_name":"Robert W.","last_name":"Nickells","full_name":"Nickells, Robert W."}],"article_processing_charge":"Yes","external_id":{"isi":["001071403800001"],"pmid":["37752598"]},"has_accepted_license":"1","tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"volume":18,"date_published":"2023-09-26T00:00:00Z","article_number":"67","article_type":"original","publication_status":"published","oa":1,"file":[{"checksum":"3aa218ddea4a082d8fd5e196ae55ca06","content_type":"application/pdf","file_name":"2023_MolecularNeurodegeneration_Maes.pdf","date_created":"2024-01-30T14:33:31Z","file_id":"14917","creator":"dernst","date_updated":"2024-01-30T14:33:31Z","access_level":"open_access","file_size":11568350,"relation":"main_file","success":1}],"title":"BAX activation in mouse retinal ganglion cells occurs in two temporally and mechanistically distinct steps","abstract":[{"text":"Background: \r\nPro-apoptotic BAX is a central mediator of retinal ganglion cell (RGC) death after optic nerve damage. BAX activation occurs in two stages including translocation of latent BAX to the mitochondrial outer membrane (MOM) and then permeabilization of the MOM to facilitate the release of apoptotic signaling molecules. As a critical component of RGC death, BAX is an attractive target for neuroprotective therapies and an understanding of the kinetics of BAX activation and the mechanisms controlling the two stages of this process in RGCs is potentially valuable in informing the development of a neuroprotective strategy.\r\nMethods:\r\nThe kinetics of BAX translocation were assessed by both static and live-cell imaging of a GFP-BAX fusion protein introduced into RGCs using AAV2-mediated gene transfer in mice. Activation of BAX was achieved using an acute optic nerve crush (ONC) protocol. Live-cell imaging of GFP-BAX was achieved using explants of mouse retina harvested 7 days after ONC. Kinetics of translocation in RGCs were compared to GFP-BAX translocation in 661W tissue culture cells. Permeabilization of GFP-BAX was assessed by staining with the 6A7 monoclonal antibody, which recognizes a conformational change in this protein after MOM insertion. Assessment of individual kinases associated with both stages of activation was made using small molecule inhibitors injected into the vitreous either independently or in concert with ONC surgery. The contribution of the Dual Leucine Zipper-JUN-N-Terminal Kinase cascade was evaluated using mice with a double conditional knock-out of both Mkk4 and Mkk7.\r\nResults:\r\nONC induces the translocation of GFP-BAX in RGCs at a slower rate and with less intracellular synchronicity than 661W cells, but exhibits less variability among mitochondrial foci within a single cell. GFP-BAX was also found to translocate in all compartments of an RGC including the dendritic arbor and axon. Approximately 6% of translocating RGCs exhibited retrotranslocation of BAX immediately following translocation. Unlike tissue culture cells, which exhibit simultaneous translocation and permeabilization, RGCs exhibited a significant delay between these two stages, similar to detached cells undergoing anoikis. Translocation, with minimal permeabilization could be induced in a subset of RGCs using an inhibitor of Focal Adhesion Kinase (PF573228). Permeabilization after ONC, in a majority of RGCs, could be inhibited with a broad spectrum kinase inhibitor (sunitinib) or a selective inhibitor for p38/MAPK14 (SB203580). Intervention of DLK-JNK axis signaling abrogated GFP-BAX translocation after ONC.\r\nConclusions:\r\nA comparison between BAX activation kinetics in tissue culture cells and in cells of a complex tissue environment shows distinct differences indicating that caution should be used when translating findings from one condition to the other. RGCs exhibit both a delay between translocation and permeabilization and the ability for translocated BAX to be retrotranslocated, suggesting several stages at which intervention of the activation process could be exploited in the design of a therapeutic strategy.","lang":"eng"}],"file_date_updated":"2024-01-30T14:33:31Z","acknowledgement":"The authors would like to thank Mr. Joel Dietz for management of the mouse colony and helpful advice for conducting quantitative PCR studies and Mr. Santoshi Kinoshita at the Translational Research Initiative in Pathology laboratory at the University of Wisconsin-Madison for cutting sections analyzed in this study.\r\nThis work was supported by National Eye Institute grants R01 EY030123 (RWN), R01 EY018606 (RTL), P30 EY016665 (Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison), T32 EY027721 (RJD) and F31 EY030739 (OJM). Additional funding was provided by the BrightFocus Foundation (RWN) and unrestricted grants from Research to Prevent Blindness, Inc to the Department of Ophthalmology and Visual Sciences (University of Wisconsin-Madison) and to the Department of Ophthalmology (University of Rochester).","type":"journal_article","publication":"Molecular Neurodegeneration","ddc":["570"],"intvolume":"        18","doi":"10.1186/s13024-023-00659-8","_id":"14401","date_created":"2023-10-08T22:01:15Z","language":[{"iso":"eng"}],"year":"2023","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87"},{"doi":"10.15479/AT:ISTA:13126","ddc":["610"],"_id":"13126","year":"2023","acknowledged_ssus":[{"_id":"ScienComp"},{"_id":"Bio"},{"_id":"PreCl"},{"_id":"LifeSc"},{"_id":"M-Shop"},{"_id":"E-Lib"}],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","date_created":"2023-06-07T07:15:12Z","file_date_updated":"2023-08-04T13:19:47Z","acknowledgement":"We thank Jakob Vorlaufer, Nathalie Agudelo-Dueñas, Wiebke Jahr, Andreas Wartak for microscope maintenance and troubleshooting, Caroline Kreuzinger, Anna Freeman, and Irene Erber for technical assistance and Matthias Tomschik for support with obtaining human samples. We gratefully acknowledge Eder Miguel for setting up webKnossos and Marek Šuplata for computational support and hardware control. We are grateful to Ryuichi Shigemoto and Bernd Bickel for generous support, and Michael Sixt and Scott Boyd (Stanford University) for discussions and critical reading of the manuscript. PSD95-HaloTag mice were kindly provided by Seth Grant (University of Edinburgh). We acknowledge expert support by IST Austria’s scientific computing, imaging and optics, preclinical, and lab support facilities, and by the Library and Miba machine shop.\r\nWe gratefully acknowledge funding by the following sources: \r\nAustrian Science Fund (FWF) grant I3600-B27 (JGD)\r\nAustrian Science Fund (FWF) grant DK W1232 (JGD, JMM)\r\nAustrian Science Fund (FWF) grant Z 312-B27, Wittgenstein award (PJ)\r\nAustrian Science Funds (FWF) projects I4685-B, I6565-B (SYNABS) and DOC 33-B27 (RH)\r\nGesellschaft für Forschungsförderung NÖ (NFB) grant LSC18-022 (JGD)\r\nEuropean Union’s Horizon 2020 research and innovation programme, European Research Council (ERC) grant 715508 – REVERSEAUTISM (GN)\r\nEuropean Union’s Horizon 2020 research and innovation programme, European Research Council (ERC) grant 692692 – GIANTSYN (PJ)\r\nMarie Skłodowska-Curie Actions Fellowship GA no. 665385 under the EU Horizon 2020 program (JMM, JL)\r\nMarie Skłodowska-Curie Actions Individual Fellowship 101026635 under the EU Horizon 2020 program (JFW)","type":"research_data","contributor":[{"last_name":"Michalska","id":"443DB6DE-F248-11E8-B48F-1D18A9856A87","first_name":"Julia M"},{"first_name":"Julia","last_name":"Lyudchik","id":"46E28B80-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Philipp","orcid":"0000-0002-2340-7431","last_name":"Velicky","id":"39BDC62C-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Hana","id":"ee3cb6ca-ec98-11ea-ae11-ff703e2254ed","last_name":"Stefanickova"},{"id":"63836096-4690-11EA-BD4E-32803DDC885E","orcid":"0000-0002-8698-3823","last_name":"Watson","first_name":"Jake"},{"last_name":"Cenameri","id":"9ac8f577-2357-11eb-997a-e566c5550886","first_name":"Alban"},{"last_name":"Sommer","orcid":"0000-0003-1216-9105","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87","first_name":"Christoph M"},{"id":"4CD6AAC6-F248-11E8-B48F-1D18A9856A87","last_name":"Amberg","orcid":"0000-0002-3183-8207","first_name":"Nicole"},{"first_name":"Alessandro","id":"41CB84B2-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-2356-9403","last_name":"Venturino"},{"last_name":"Roessler","first_name":"Karl"},{"first_name":"Thomas","last_name":"Czech"},{"first_name":"Romana","last_name":"Höftberger"},{"first_name":"Sandra","last_name":"Siegert","orcid":"0000-0001-8635-0877","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87"},{"orcid":"0000-0002-7673-7178","last_name":"Novarino","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","first_name":"Gaia"},{"first_name":"Peter M","orcid":"0000-0001-5001-4804","last_name":"Jonas","id":"353C1B58-F248-11E8-B48F-1D18A9856A87"}],"abstract":[{"lang":"eng","text":"Mapping the complex and dense arrangement of cells and their connectivity in brain tissue demands nanoscale spatial resolution imaging. Super-resolution optical microscopy excels at visualizing specific molecules and individual cells but fails to provide tissue context. Here, we developed Comprehensive Analysis of Tissues across Scales (CATS), a technology to densely map brain tissue architecture from millimeter regional to nanometer synaptic scales in diverse chemically fixed brain preparations, including rodent and human. CATS uses fixation-compatible extracellular labeling and optical imaging, including stimulated emission depletion or expansion microscopy, to comprehensively delineate cellular structures. It enables three-dimensional reconstruction of single synapses and mapping of synaptic connectivity by identification and analysis of putative synaptic cleft regions. Applying CATS to the mouse hippocampal mossy fiber circuitry, we reconstructed and quantified the synaptic input and output structure of identified neurons. We furthermore demonstrate applicability to clinically derived human tissue samples, including formalin-fixed paraffin-embedded routine diagnostic specimens, for visualizing the cellular architecture of brain tissue in health and disease."}],"ec_funded":1,"project":[{"name":"Optical control of synaptic function via adhesion molecules","call_identifier":"FWF","_id":"265CB4D0-B435-11E9-9278-68D0E5697425","grant_number":"I03600"},{"call_identifier":"FWF","grant_number":"W1232-B24","_id":"26AA4EF2-B435-11E9-9278-68D0E5697425","name":"Molecular Drug Targets"},{"name":"Synaptic communication in neuronal microcircuits","call_identifier":"FWF","_id":"25C5A090-B435-11E9-9278-68D0E5697425","grant_number":"Z00312"},{"name":"High content imaging to decode human immune cell interactions in health and allergic disease","grant_number":"LS18-022","_id":"23889792-32DE-11EA-91FC-C7463DDC885E"},{"call_identifier":"H2020","grant_number":"715508","_id":"25444568-B435-11E9-9278-68D0E5697425","name":"Probing 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Danzl, (2023)."},"date_updated":"2026-04-14T08:34:35Z","corr_author":"1","department":[{"_id":"JoDa"},{"_id":"SaSi"},{"_id":"GaNo"},{"_id":"PeJo"},{"_id":"Bio"},{"_id":"RySh"}],"status":"public","oa_version":"Published Version","day":"04","month":"08"},{"type":"research_data","status":"public","contributor":[{"first_name":"Sandra","contributor_type":"contact_person","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-8635-0877","last_name":"Siegert"}],"file_date_updated":"2022-07-08T10:56:52Z","date_updated":"2025-04-15T07:27:21Z","publisher":"Institute of Science and Technology Austria","citation":{"ieee":"R. Schulz, “Source Data (Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses).” Institute of Science and Technology Austria, 2022.","mla":"Schulz, Rouven. <i>Source Data (Chimeric GPCRs Mimic Distinct Signaling Pathways and Modulate Microglia Responses)</i>. Institute of Science and Technology Austria, 2022, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:11542\">10.15479/AT:ISTA:11542</a>.","chicago":"Schulz, Rouven. “Source Data (Chimeric GPCRs Mimic Distinct Signaling Pathways and Modulate Microglia Responses).” Institute of Science and Technology Austria, 2022. <a href=\"https://doi.org/10.15479/AT:ISTA:11542\">https://doi.org/10.15479/AT:ISTA:11542</a>.","ama":"Schulz R. Source Data (Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses). 2022. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:11542\">10.15479/AT:ISTA:11542</a>","short":"R. Schulz, (2022).","apa":"Schulz, R. (2022). Source Data (Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses). Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:11542\">https://doi.org/10.15479/AT:ISTA:11542</a>","ista":"Schulz R. 2022. Source Data (Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses), Institute of Science and Technology Austria, <a href=\"https://doi.org/10.15479/AT:ISTA:11542\">10.15479/AT:ISTA:11542</a>."},"department":[{"_id":"GradSch"},{"_id":"SaSi"}],"corr_author":"1","date_created":"2022-07-08T11:03:02Z","tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"date_published":"2022-01-01T00:00:00Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","year":"2022","related_material":{"link":[{"relation":"contains","url":"https://www.biorxiv.org/content/10.1101/2021.06.21.449162v1"}],"record":[{"status":"public","id":"11995","relation":"used_in_publication"}]},"doi":"10.15479/AT:ISTA:11542","author":[{"id":"4C5E7B96-F248-11E8-B48F-1D18A9856A87","full_name":"Schulz, Rouven","orcid":"0000-0001-5297-733X","last_name":"Schulz","first_name":"Rouven"}],"article_processing_charge":"No","has_accepted_license":"1","_id":"11542","file":[{"relation":"main_file","success":1,"access_level":"open_access","file_size":135784571,"creator":"rschulz","date_updated":"2022-07-08T10:56:52Z","file_id":"11543","date_created":"2022-07-08T10:56:52Z","file_name":"Source Data.xlsx","content_type":"application/vnd.openxmlformats-officedocument.spreadsheetml.sheet","checksum":"71e8186583f3adbb6c69a88ac9e6e49b"}],"title":"Source Data (Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses)","oa":1,"oa_version":"None"},{"scopus_import":"1","oa_version":"Published Version","quality_controlled":"1","issue":"4","day":"16","keyword":["General Immunology and Microbiology","General Biochemistry","Genetics and Molecular Biology","General Neuroscience"],"month":"12","article_processing_charge":"No","has_accepted_license":"1","external_id":{"pmid":["36595902"]},"pmid":1,"author":[{"full_name":"Hübschmann, Verena","id":"32B7C918-F248-11E8-B48F-1D18A9856A87","last_name":"Hübschmann","first_name":"Verena"},{"id":"4B51CE74-F248-11E8-B48F-1D18A9856A87","full_name":"Korkut, Medina","orcid":"0000-0003-4309-2251","last_name":"Korkut","first_name":"Medina"},{"first_name":"Sandra","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","full_name":"Siegert, Sandra","last_name":"Siegert","orcid":"0000-0001-8635-0877"}],"related_material":{"record":[{"status":"public","id":"11478","relation":"other"}]},"volume":3,"date_published":"2022-12-16T00:00:00Z","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","image":"/images/cc_by_nc_nd.png","short":"CC BY-NC-ND (4.0)"},"corr_author":"1","department":[{"_id":"SaSi"},{"_id":"GradSch"}],"citation":{"short":"V. Hübschmann, M. Korkut, S. Siegert, STAR Protocols 3 (2022).","apa":"Hübschmann, V., Korkut, M., &#38; Siegert, S. (2022). Assessing human iPSC-derived microglia identity and function by immunostaining, phagocytosis, calcium activity, and inflammation assay. <i>STAR Protocols</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.xpro.2022.101866\">https://doi.org/10.1016/j.xpro.2022.101866</a>","ista":"Hübschmann V, Korkut M, Siegert S. 2022. Assessing human iPSC-derived microglia identity and function by immunostaining, phagocytosis, calcium activity, and inflammation assay. STAR Protocols. 3(4), 101866.","ieee":"V. Hübschmann, M. Korkut, and S. Siegert, “Assessing human iPSC-derived microglia identity and function by immunostaining, phagocytosis, calcium activity, and inflammation assay,” <i>STAR Protocols</i>, vol. 3, no. 4. Elsevier, 2022.","mla":"Hübschmann, Verena, et al. “Assessing Human IPSC-Derived Microglia Identity and Function by Immunostaining, Phagocytosis, Calcium Activity, and Inflammation Assay.” <i>STAR Protocols</i>, vol. 3, no. 4, 101866, Elsevier, 2022, doi:<a href=\"https://doi.org/10.1016/j.xpro.2022.101866\">10.1016/j.xpro.2022.101866</a>.","chicago":"Hübschmann, Verena, Medina Korkut, and Sandra Siegert. “Assessing Human IPSC-Derived Microglia Identity and Function by Immunostaining, Phagocytosis, Calcium Activity, and Inflammation Assay.” <i>STAR Protocols</i>. Elsevier, 2022. <a href=\"https://doi.org/10.1016/j.xpro.2022.101866\">https://doi.org/10.1016/j.xpro.2022.101866</a>.","ama":"Hübschmann V, Korkut M, Siegert S. Assessing human iPSC-derived microglia identity and function by immunostaining, phagocytosis, calcium activity, and inflammation assay. <i>STAR Protocols</i>. 2022;3(4). doi:<a href=\"https://doi.org/10.1016/j.xpro.2022.101866\">10.1016/j.xpro.2022.101866</a>"},"publisher":"Elsevier","date_updated":"2025-06-11T13:58:47Z","status":"public","publication_identifier":{"issn":["2666-1667"]},"abstract":[{"lang":"eng","text":"To understand how potential gene manipulations affect in vitro microglia, we provide a set of short protocols to evaluate microglia identity and function. We detail steps for immunostaining to determine microglia identity. We describe three functional assays for microglia: phagocytosis, calcium response following ATP stimulation, and cytokine expression upon inflammatory stimuli. We apply these protocols to human induced-pluripotent-stem-cell (hiPSC)-derived microglia, but they can be also applied to other in vitro microglial models including primary mouse microglia.\r\nFor complete details on the use and execution of this protocol, please refer to Bartalska et al. (2022).1"}],"project":[{"call_identifier":"H2020","_id":"25D4A630-B435-11E9-9278-68D0E5697425","grant_number":"715571","name":"Microglia action towards neuronal circuit formation and function in health and disease"},{"name":"How human microglia shape developing neurons during health and inflammation","_id":"9B99D380-BA93-11EA-9121-9846C619BF3A","grant_number":"SC19-017"}],"ec_funded":1,"oa":1,"article_type":"letter_note","publication_status":"published","article_number":"101866","file":[{"file_name":"2022_STARProtocols_Huebschmann.pdf","checksum":"3c71b8a60633d42c2f77c49025d5559b","content_type":"application/pdf","date_created":"2023-01-23T09:50:51Z","creator":"dernst","date_updated":"2023-01-23T09:50:51Z","file_id":"12340","relation":"main_file","success":1,"access_level":"open_access","file_size":6251945}],"title":"Assessing human iPSC-derived microglia identity and function by immunostaining, phagocytosis, calcium activity, and inflammation assay","_id":"12117","intvolume":"         3","doi":"10.1016/j.xpro.2022.101866","ddc":["570"],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","year":"2022","acknowledged_ssus":[{"_id":"Bio"}],"language":[{"iso":"eng"}],"date_created":"2023-01-12T11:56:38Z","file_date_updated":"2023-01-23T09:50:51Z","publication":"STAR Protocols","type":"journal_article","acknowledgement":"This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant No. 715571 to S.S.) and from the Gesellschaft für Forschungsförderung Niederösterreich (grant No. Sc19-017 to V.H.). We thank Rouven Schulz and Alessandro Venturino for their insights into functional assays and data analysis, Verena Seiboth for insights into necessary institutional permission, and ISTA imaging & optics facility (IOF) especially Bernhard Hochreiter for their support."},{"scopus_import":"1","oa_version":"Published Version","quality_controlled":"1","issue":"7","day":"15","month":"07","has_accepted_license":"1","article_processing_charge":"Yes","external_id":{"isi":["000830428500005"],"pmid":["35789843"]},"author":[{"first_name":"Katarina","id":"4D883232-F248-11E8-B48F-1D18A9856A87","full_name":"Bartalska, Katarina","last_name":"Bartalska"},{"first_name":"Verena","id":"32B7C918-F248-11E8-B48F-1D18A9856A87","full_name":"Hübschmann, Verena","last_name":"Hübschmann"},{"orcid":"0000-0003-4309-2251","last_name":"Korkut","id":"4B51CE74-F248-11E8-B48F-1D18A9856A87","full_name":"Korkut, Medina","first_name":"Medina"},{"id":"850B2E12-9CD4-11E9-837F-E719E6697425","full_name":"Cubero, Ryan J","orcid":"0000-0003-0002-1867","last_name":"Cubero","first_name":"Ryan J"},{"id":"41CB84B2-F248-11E8-B48F-1D18A9856A87","full_name":"Venturino, Alessandro","last_name":"Venturino","orcid":"0000-0003-2356-9403","first_name":"Alessandro"},{"last_name":"Rössler","full_name":"Rössler, Karl","first_name":"Karl"},{"first_name":"Thomas","full_name":"Czech, Thomas","last_name":"Czech"},{"first_name":"Sandra","orcid":"0000-0001-8635-0877","last_name":"Siegert","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","full_name":"Siegert, Sandra"}],"pmid":1,"related_material":{"record":[{"status":"public","id":"12117","relation":"other"},{"id":"20074","relation":"dissertation_contains","status":"public"}]},"tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"date_published":"2022-07-15T00:00:00Z","volume":25,"department":[{"_id":"SaSi"}],"corr_author":"1","date_updated":"2026-04-07T11:51:43Z","citation":{"short":"K. Bartalska, V. Hübschmann, M. Korkut, R.J. Cubero, A. Venturino, K. Rössler, T. Czech, S. Siegert, IScience 25 (2022).","ista":"Bartalska K, Hübschmann V, Korkut M, Cubero RJ, Venturino A, Rössler K, Czech T, Siegert S. 2022. A systematic characterization of microglia-like cell occurrence during retinal organoid differentiation. iScience. 25(7), 104580.","apa":"Bartalska, K., Hübschmann, V., Korkut, M., Cubero, R. J., Venturino, A., Rössler, K., … Siegert, S. (2022). A systematic characterization of microglia-like cell occurrence during retinal organoid differentiation. <i>IScience</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.isci.2022.104580\">https://doi.org/10.1016/j.isci.2022.104580</a>","mla":"Bartalska, Katarina, et al. “A Systematic Characterization of Microglia-like Cell Occurrence during Retinal Organoid Differentiation.” <i>IScience</i>, vol. 25, no. 7, 104580, Elsevier, 2022, doi:<a href=\"https://doi.org/10.1016/j.isci.2022.104580\">10.1016/j.isci.2022.104580</a>.","chicago":"Bartalska, Katarina, Verena Hübschmann, Medina Korkut, Ryan J Cubero, Alessandro Venturino, Karl Rössler, Thomas Czech, and Sandra Siegert. “A Systematic Characterization of Microglia-like Cell Occurrence during Retinal Organoid Differentiation.” <i>IScience</i>. Elsevier, 2022. <a href=\"https://doi.org/10.1016/j.isci.2022.104580\">https://doi.org/10.1016/j.isci.2022.104580</a>.","ieee":"K. Bartalska <i>et al.</i>, “A systematic characterization of microglia-like cell occurrence during retinal organoid differentiation,” <i>iScience</i>, vol. 25, no. 7. Elsevier, 2022.","ama":"Bartalska K, Hübschmann V, Korkut M, et al. A systematic characterization of microglia-like cell occurrence during retinal organoid differentiation. <i>iScience</i>. 2022;25(7). doi:<a href=\"https://doi.org/10.1016/j.isci.2022.104580\">10.1016/j.isci.2022.104580</a>"},"publisher":"Elsevier","status":"public","publication_identifier":{"eissn":["2589-0042"]},"isi":1,"abstract":[{"lang":"eng","text":"Cerebral organoids differentiated from human-induced pluripotent stem cells (hiPSC) provide a unique opportunity to investigate brain development. However, organoids usually lack microglia, brain-resident immune cells, which are present in the early embryonic brain and participate in neuronal circuit development. Here, we find IBA1+ microglia-like cells alongside retinal cups between week 3 and 4 in 2.5D culture with an unguided retinal organoid differentiation protocol. Microglia do not infiltrate the neuroectoderm and instead enrich within non-pigmented, 3D-cystic compartments that develop in parallel to the 3D-retinal organoids. When we guide the retinal organoid differentiation with low-dosed BMP4, we prevent cup development and enhance microglia and 3D-cysts formation. Mass spectrometry identifies these 3D-cysts to express mesenchymal and epithelial markers. We confirmed this microglia-preferred environment also within the unguided protocol, providing insight into microglial behavior and migration and offer a model to study how they enter and distribute within the human brain."}],"project":[{"_id":"25D4A630-B435-11E9-9278-68D0E5697425","call_identifier":"H2020","grant_number":"715571","name":"Microglia action towards neuronal circuit formation and function in health and disease"},{"name":"IST Austria Open Access Fund","_id":"B67AFEDC-15C9-11EA-A837-991A96BB2854"},{"grant_number":"SC19-017","_id":"9B99D380-BA93-11EA-9121-9846C619BF3A","name":"How human microglia shape developing neurons during health and inflammation"}],"ec_funded":1,"publication_status":"published","article_type":"original","oa":1,"article_number":"104580","file":[{"file_name":"2022_iScience_Bartalska.pdf","content_type":"application/pdf","checksum":"a470b74e1b3796c710189c81a4cd4329","date_created":"2022-07-04T08:19:25Z","creator":"cchlebak","date_updated":"2022-07-04T08:19:25Z","file_id":"11480","relation":"main_file","success":1,"access_level":"open_access","file_size":19400048}],"title":"A systematic characterization of microglia-like cell occurrence during retinal organoid differentiation","_id":"11478","doi":"10.1016/j.isci.2022.104580","intvolume":"        25","ddc":["610"],"language":[{"iso":"eng"}],"date_created":"2022-07-03T22:01:33Z","year":"2022","acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"}],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","file_date_updated":"2022-07-04T08:19:25Z","publication":"iScience","acknowledgement":"We thank the scientific service units at ISTA, specifically the lab support facility and imaging & optics facility for their support; Nicolas Armel for performing the Mass Spectrometry. We thank Alexandra Lang and Tanja Peilnsteiner for their help in human brain tissue collection, Rouven Schulz for his insights into the functional assays We thank all members of the Siegert group for constant feedback on the project and Margaret Maes, Rouven Schulz, and Marco Benevento for feedback on the manuscript. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant No. 715571 to S.S.) and from the Gesellschaft für Forschungsförderung Niederösterreich (grant No. Sc19-017 to V.H.).","type":"journal_article"},{"abstract":[{"lang":"eng","text":"G protein-coupled receptors (GPCRs) regulate processes ranging from immune responses to neuronal signaling. However, ligands for many GPCRs remain unknown, suffer from off-target effects or have poor bioavailability. Additionally, dissecting cell type-specific responses is challenging when the same GPCR is expressed on different cells within a tissue. Here, we overcome these limitations by engineering DREADD-based GPCR chimeras that bind clozapine-N-oxide and mimic a GPCR-of-interest. We show that chimeric DREADD-β2AR triggers responses comparable to β2AR on second messenger and kinase activity, post-translational modifications, and protein-protein interactions. Moreover, we successfully recapitulate β2AR-mediated filopodia formation in microglia, an immune cell capable of driving central nervous system inflammation. When dissecting microglial inflammation, we included two additional DREADD-based chimeras mimicking microglia-enriched GPR65 and GPR109A. DREADD-β2AR and DREADD-GPR65 modulate the inflammatory response with high similarity to endogenous β2AR, while DREADD-GPR109A shows no impact. Our DREADD-based approach allows investigation of cell type-dependent pathways without known endogenous ligands."}],"project":[{"name":"Modulating microglia through G protein-coupled receptor (GPCR) signaling","_id":"267F75D8-B435-11E9-9278-68D0E5697425"}],"publication_status":"published","article_type":"original","oa":1,"article_number":"4728","file":[{"file_size":7317396,"access_level":"open_access","relation":"main_file","success":1,"file_id":"12002","date_updated":"2022-08-29T06:44:30Z","creator":"cchlebak","date_created":"2022-08-29T06:44:30Z","content_type":"application/pdf","checksum":"191d9db0266e14a28d3a56dc7f65da84","file_name":"2022_NatComm_Schulz.pdf"}],"title":"Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses","_id":"11995","intvolume":"        13","ddc":["570"],"doi":"10.1038/s41467-022-32390-1","date_created":"2022-08-28T22:01:59Z","language":[{"iso":"eng"}],"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","acknowledged_ssus":[{"_id":"PreCl"},{"_id":"Bio"},{"_id":"LifeSc"}],"year":"2022","file_date_updated":"2022-08-29T06:44:30Z","publication":"Nature Communications","type":"journal_article","acknowledgement":"The authors thank the Scientific Service Units at ISTA, in particular the Molecular Biology Service of the Lab Support Facility, Imaging & Optics Facility, and the Preclinical Facility, and the Novarino group, Harald Janoviak, and Marco Benevento for sharing reagents and expertise. This research was supported by a DOC Fellowship (24979) awarded to R.S. by the Austrian Academy of Sciences.","scopus_import":"1","oa_version":"Published Version","quality_controlled":"1","day":"15","month":"08","article_processing_charge":"No","has_accepted_license":"1","external_id":{"pmid":["35970889"],"isi":["000840984400032"]},"author":[{"first_name":"Rouven","last_name":"Schulz","orcid":"0000-0001-5297-733X","full_name":"Schulz, Rouven","id":"4C5E7B96-F248-11E8-B48F-1D18A9856A87"},{"orcid":"0000-0003-4309-2251","last_name":"Korkut","full_name":"Korkut, Medina","id":"4B51CE74-F248-11E8-B48F-1D18A9856A87","first_name":"Medina"},{"first_name":"Alessandro","full_name":"Venturino, Alessandro","id":"41CB84B2-F248-11E8-B48F-1D18A9856A87","last_name":"Venturino","orcid":"0000-0003-2356-9403"},{"first_name":"Gloria","id":"3483CF6C-F248-11E8-B48F-1D18A9856A87","full_name":"Colombo, Gloria","orcid":"0000-0001-9434-8902","last_name":"Colombo"},{"id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","full_name":"Siegert, Sandra","orcid":"0000-0001-8635-0877","last_name":"Siegert","first_name":"Sandra"}],"pmid":1,"related_material":{"link":[{"description":"News on ISTA website","url":"https://ista.ac.at/en/news/dreaddful-mimicry/","relation":"press_release"}],"record":[{"id":"11542","relation":"research_data","status":"public"},{"status":"public","id":"11945","relation":"part_of_dissertation"}]},"tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"date_published":"2022-08-15T00:00:00Z","volume":13,"department":[{"_id":"SaSi"}],"corr_author":"1","date_updated":"2026-04-07T14:17:58Z","publisher":"Springer Nature","citation":{"ieee":"R. Schulz, M. Korkut, A. Venturino, G. Colombo, and S. Siegert, “Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses,” <i>Nature Communications</i>, vol. 13. Springer Nature, 2022.","chicago":"Schulz, Rouven, Medina Korkut, Alessandro Venturino, Gloria Colombo, and Sandra Siegert. “Chimeric GPCRs Mimic Distinct Signaling Pathways and Modulate Microglia Responses.” <i>Nature Communications</i>. Springer Nature, 2022. <a href=\"https://doi.org/10.1038/s41467-022-32390-1\">https://doi.org/10.1038/s41467-022-32390-1</a>.","mla":"Schulz, Rouven, et al. “Chimeric GPCRs Mimic Distinct Signaling Pathways and Modulate Microglia Responses.” <i>Nature Communications</i>, vol. 13, 4728, Springer Nature, 2022, doi:<a href=\"https://doi.org/10.1038/s41467-022-32390-1\">10.1038/s41467-022-32390-1</a>.","ama":"Schulz R, Korkut M, Venturino A, Colombo G, Siegert S. Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses. <i>Nature Communications</i>. 2022;13. doi:<a href=\"https://doi.org/10.1038/s41467-022-32390-1\">10.1038/s41467-022-32390-1</a>","short":"R. Schulz, M. Korkut, A. Venturino, G. Colombo, S. Siegert, Nature Communications 13 (2022).","apa":"Schulz, R., Korkut, M., Venturino, A., Colombo, G., &#38; Siegert, S. (2022). Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses. <i>Nature Communications</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41467-022-32390-1\">https://doi.org/10.1038/s41467-022-32390-1</a>","ista":"Schulz R, Korkut M, Venturino A, Colombo G, Siegert S. 2022. Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses. Nature Communications. 13, 4728."},"status":"public","isi":1,"publication_identifier":{"eissn":["2041-1723"]}},{"project":[{"name":"Modulating microglia through G protein-coupled receptor (GPCR) signaling","_id":"267F75D8-B435-11E9-9278-68D0E5697425"}],"supervisor":[{"first_name":"Sandra","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","full_name":"Siegert, Sandra","orcid":"0000-0001-8635-0877","last_name":"Siegert"}],"abstract":[{"text":"G protein-coupled receptors (GPCRs) respond to specific ligands and regulate multiple processes ranging from cell growth and immune responses to neuronal signal transmission. However, ligands for many GPCRs remain unknown, suffer from off-target effects or have poor bioavailability. Additional challenges exist to dissect cell-type specific responses when the same GPCR is expressed on several cell types within the body. Here, we overcome these limitations by engineering DREADD-based GPCR chimeras that selectively bind their agonist clozapine-N-oxide (CNO) and mimic a GPCR-of-interest in a desired cell type.\r\nWe validated our approach with β2-adrenergic receptor (β2AR/ADRB2) and show that our chimeric DREADD-β2AR triggers comparable responses on second messenger and kinase activity, post-translational modifications, and protein-protein interactions. Since β2AR is also enriched in microglia, which can drive inflammation in the central nervous system, we expressed chimeric DREADD-β2AR in primary microglia and successfully recapitulate β2AR-mediated filopodia formation through CNO stimulation. To dissect the role of selected GPCRs during microglial inflammation, we additionally generated DREADD-based chimeras for microglia-enriched GPR65 and GPR109A/HCAR2. In a microglia cell line, DREADD-β2AR and DREADD-GPR65 both modulated the inflammatory response with a similar profile as endogenously expressed β2AR, while DREADD-GPR109A showed no impact.\r\nOur DREADD-based approach provides the means to obtain mechanistic and functional insights into GPCR signaling on a cell-type specific level.","lang":"eng"}],"degree_awarded":"PhD","page":"133","alternative_title":["ISTA Thesis"],"file":[{"date_created":"2022-08-25T08:59:57Z","checksum":"61b1b666a210ff7cdd0e95ea75207a13","content_type":"application/pdf","file_name":"Thesis_Rouven_Schulz_2022_final.pdf","file_size":28079331,"access_level":"open_access","success":1,"relation":"main_file","file_id":"11970","date_updated":"2022-08-25T08:59:57Z","creator":"rschulz"},{"relation":"source_file","access_level":"closed","file_size":27226963,"creator":"rschulz","date_updated":"2022-08-25T09:33:31Z","file_id":"11971","date_created":"2022-08-25T09:00:11Z","file_name":"Thesis_Rouven_Schulz_2022_final.docx","checksum":"2b8f95ea1c134dbdb927b41b1dbeeeb5","content_type":"application/vnd.openxmlformats-officedocument.wordprocessingml.document"}],"title":"Chimeric G protein-coupled receptors mimic distinct signaling pathways and modulate microglia function","oa":1,"publication_status":"published","year":"2022","user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","acknowledged_ssus":[{"_id":"Bio"},{"_id":"PreCl"},{"_id":"LifeSc"}],"date_created":"2022-08-23T11:33:11Z","language":[{"iso":"eng"}],"_id":"11945","doi":"10.15479/at:ista:11945","ddc":["570"],"type":"dissertation","file_date_updated":"2022-08-25T09:33:31Z","oa_version":"Published Version","month":"08","day":"23","OA_place":"publisher","related_material":{"record":[{"status":"public","relation":"dissertation_contains","id":"11995"}]},"date_published":"2022-08-23T00:00:00Z","tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"article_processing_charge":"No","has_accepted_license":"1","author":[{"id":"4C5E7B96-F248-11E8-B48F-1D18A9856A87","full_name":"Schulz, Rouven","orcid":"0000-0001-5297-733X","last_name":"Schulz","first_name":"Rouven"}],"status":"public","publication_identifier":{"issn":["2663-337X"]},"corr_author":"1","department":[{"_id":"GradSch"},{"_id":"SaSi"}],"publisher":"Institute of Science and Technology Austria","citation":{"ama":"Schulz R. Chimeric G protein-coupled receptors mimic distinct signaling pathways and modulate microglia function. 2022. doi:<a href=\"https://doi.org/10.15479/at:ista:11945\">10.15479/at:ista:11945</a>","chicago":"Schulz, Rouven. “Chimeric G Protein-Coupled Receptors Mimic Distinct Signaling Pathways and Modulate Microglia Function.” Institute of Science and Technology Austria, 2022. <a href=\"https://doi.org/10.15479/at:ista:11945\">https://doi.org/10.15479/at:ista:11945</a>.","mla":"Schulz, Rouven. <i>Chimeric G Protein-Coupled Receptors Mimic Distinct Signaling Pathways and Modulate Microglia Function</i>. Institute of Science and Technology Austria, 2022, doi:<a href=\"https://doi.org/10.15479/at:ista:11945\">10.15479/at:ista:11945</a>.","ieee":"R. Schulz, “Chimeric G protein-coupled receptors mimic distinct signaling pathways and modulate microglia function,” Institute of Science and Technology Austria, 2022.","ista":"Schulz R. 2022. Chimeric G protein-coupled receptors mimic distinct signaling pathways and modulate microglia function. Institute of Science and Technology Austria.","apa":"Schulz, R. (2022). <i>Chimeric G protein-coupled receptors mimic distinct signaling pathways and modulate microglia function</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/at:ista:11945\">https://doi.org/10.15479/at:ista:11945</a>","short":"R. Schulz, Chimeric G Protein-Coupled Receptors Mimic Distinct Signaling Pathways and Modulate Microglia Function, Institute of Science and Technology Austria, 2022."},"date_updated":"2026-04-07T14:17:59Z"},{"oa_version":"Preprint","abstract":[{"text":"Mapping the complex and dense arrangement of cells and their connectivity in brain tissue demands nanoscale spatial resolution imaging. Super-resolution optical microscopy excels at visualizing specific molecules and individual cells but fails to provide tissue context. Here we developed Comprehensive Analysis of Tissues across Scales (CATS), a technology to densely map brain tissue architecture from millimeter regional to nanoscopic synaptic scales in diverse chemically fixed brain preparations, including rodent and human. CATS leverages fixation-compatible extracellular labeling and advanced optical readout, in particular stimulated-emission depletion and expansion microscopy, to comprehensively delineate cellular structures. It enables 3D-reconstructing single synapses and mapping synaptic connectivity by identification and tailored analysis of putative synaptic cleft regions. Applying CATS to the hippocampal mossy fiber circuitry, we demonstrate its power to reveal the system’s molecularly informed ultrastructure across spatial scales and assess local connectivity by reconstructing and quantifying the synaptic input and output structure of identified neurons.","lang":"eng"}],"title":"Uncovering brain tissue architecture across scales with super-resolution light microscopy","month":"08","publication_status":"draft","main_file_link":[{"open_access":"1","url":"https://doi.org/10.1101/2022.08.17.504272"}],"oa":1,"day":"18","related_material":{"record":[{"id":"12470","relation":"dissertation_contains","status":"public"}]},"date_created":"2022-08-24T08:24:52Z","language":[{"iso":"eng"}],"date_published":"2022-08-18T00:00:00Z","year":"2022","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","article_processing_charge":"No","_id":"11950","author":[{"first_name":"Julia M","last_name":"Michalska","orcid":"0000-0003-3862-1235","full_name":"Michalska, Julia M","id":"443DB6DE-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Julia","last_name":"Lyudchik","id":"46E28B80-F248-11E8-B48F-1D18A9856A87","full_name":"Lyudchik, Julia"},{"first_name":"Philipp","last_name":"Velicky","orcid":"0000-0002-2340-7431","id":"39BDC62C-F248-11E8-B48F-1D18A9856A87","full_name":"Velicky, Philipp"},{"first_name":"Hana","full_name":"Korinkova, Hana","id":"ee3cb6ca-ec98-11ea-ae11-ff703e2254ed","last_name":"Korinkova"},{"first_name":"Jake","full_name":"Watson, Jake","id":"63836096-4690-11EA-BD4E-32803DDC885E","orcid":"0000-0002-8698-3823","last_name":"Watson"},{"first_name":"Alban","last_name":"Cenameri","id":"9ac8f577-2357-11eb-997a-e566c5550886","full_name":"Cenameri, Alban"},{"first_name":"Christoph M","last_name":"Sommer","orcid":"0000-0003-1216-9105","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87","full_name":"Sommer, Christoph M"},{"first_name":"Alessandro","full_name":"Venturino, Alessandro","id":"41CB84B2-F248-11E8-B48F-1D18A9856A87","last_name":"Venturino","orcid":"0000-0003-2356-9403"},{"last_name":"Roessler","full_name":"Roessler, Karl","first_name":"Karl"},{"first_name":"Thomas","full_name":"Czech, Thomas","last_name":"Czech"},{"orcid":"0000-0001-8635-0877","last_name":"Siegert","full_name":"Siegert, Sandra","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","first_name":"Sandra"},{"first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","full_name":"Novarino, Gaia","last_name":"Novarino","orcid":"0000-0002-7673-7178"},{"first_name":"Peter M","orcid":"0000-0001-5001-4804","last_name":"Jonas","full_name":"Jonas, Peter M","id":"353C1B58-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Danzl, Johann G","id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","last_name":"Danzl","orcid":"0000-0001-8559-3973","first_name":"Johann G"}],"doi":"10.1101/2022.08.17.504272","status":"public","publication":"bioRxiv","type":"preprint","department":[{"_id":"SaSi"},{"_id":"GaNo"},{"_id":"PeJo"},{"_id":"JoDa"}],"corr_author":"1","date_updated":"2026-06-13T22:30:37Z","publisher":"Cold Spring Harbor Laboratory","citation":{"ama":"Michalska JM, Lyudchik J, Velicky P, et al. Uncovering brain tissue architecture across scales with super-resolution light microscopy. <i>bioRxiv</i>. doi:<a href=\"https://doi.org/10.1101/2022.08.17.504272\">10.1101/2022.08.17.504272</a>","ieee":"J. M. Michalska <i>et al.</i>, “Uncovering brain tissue architecture across scales with super-resolution light microscopy,” <i>bioRxiv</i>. Cold Spring Harbor Laboratory.","chicago":"Michalska, Julia M, Julia Lyudchik, Philipp Velicky, Hana Korinkova, Jake Watson, Alban Cenameri, Christoph M Sommer, et al. “Uncovering Brain Tissue Architecture across Scales with Super-Resolution Light Microscopy.” <i>BioRxiv</i>. Cold Spring Harbor Laboratory, n.d. <a href=\"https://doi.org/10.1101/2022.08.17.504272\">https://doi.org/10.1101/2022.08.17.504272</a>.","mla":"Michalska, Julia M., et al. “Uncovering Brain Tissue Architecture across Scales with Super-Resolution Light Microscopy.” <i>BioRxiv</i>, Cold Spring Harbor Laboratory, doi:<a href=\"https://doi.org/10.1101/2022.08.17.504272\">10.1101/2022.08.17.504272</a>.","apa":"Michalska, J. M., Lyudchik, J., Velicky, P., Korinkova, H., Watson, J., Cenameri, A., … Danzl, J. G. (n.d.). Uncovering brain tissue architecture across scales with super-resolution light microscopy. <i>bioRxiv</i>. Cold Spring Harbor Laboratory. <a href=\"https://doi.org/10.1101/2022.08.17.504272\">https://doi.org/10.1101/2022.08.17.504272</a>","ista":"Michalska JM, Lyudchik J, Velicky P, Korinkova H, Watson J, Cenameri A, Sommer CM, Venturino A, Roessler K, Czech T, Siegert S, Novarino G, Jonas PM, Danzl JG. Uncovering brain tissue architecture across scales with super-resolution light microscopy. bioRxiv, <a href=\"https://doi.org/10.1101/2022.08.17.504272\">10.1101/2022.08.17.504272</a>.","short":"J.M. Michalska, J. Lyudchik, P. Velicky, H. Korinkova, J. Watson, A. Cenameri, C.M. Sommer, A. Venturino, K. Roessler, T. Czech, S. Siegert, G. Novarino, P.M. Jonas, J.G. Danzl, BioRxiv (n.d.)."}},{"issue":"10","scopus_import":"1","oa_version":"Published Version","quality_controlled":"1","keyword":["General Neuroscience"],"month":"10","day":"01","related_material":{"link":[{"description":"News on ISTA website","url":"https://ista.ac.at/en/news/morphomics-revealing-the-hidden-meaning-of-microglia-shape/","relation":"press_release"}],"record":[{"status":"public","relation":"dissertation_contains","id":"12378"}]},"tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"volume":25,"date_published":"2022-10-01T00:00:00Z","external_id":{"isi":["000862214700001"],"pmid":["36180790"]},"article_processing_charge":"No","has_accepted_license":"1","author":[{"first_name":"Gloria","full_name":"Colombo, Gloria","id":"3483CF6C-F248-11E8-B48F-1D18A9856A87","last_name":"Colombo","orcid":"0000-0001-9434-8902"},{"first_name":"Ryan J","last_name":"Cubero","orcid":"0000-0003-0002-1867","id":"850B2E12-9CD4-11E9-837F-E719E6697425","full_name":"Cubero, Ryan J"},{"last_name":"Kanari","full_name":"Kanari, Lida","first_name":"Lida"},{"first_name":"Alessandro","id":"41CB84B2-F248-11E8-B48F-1D18A9856A87","full_name":"Venturino, Alessandro","orcid":"0000-0003-2356-9403","last_name":"Venturino"},{"last_name":"Schulz","orcid":"0000-0001-5297-733X","full_name":"Schulz, Rouven","id":"4C5E7B96-F248-11E8-B48F-1D18A9856A87","first_name":"Rouven"},{"first_name":"Martina","full_name":"Scolamiero, Martina","last_name":"Scolamiero"},{"first_name":"Jens","full_name":"Agerberg, Jens","last_name":"Agerberg"},{"first_name":"Hansruedi","full_name":"Mathys, Hansruedi","last_name":"Mathys"},{"full_name":"Tsai, Li-Huei","last_name":"Tsai","first_name":"Li-Huei"},{"first_name":"Wojciech","last_name":"Chachólski","full_name":"Chachólski, Wojciech"},{"full_name":"Hess, Kathryn","last_name":"Hess","first_name":"Kathryn"},{"last_name":"Siegert","orcid":"0000-0001-8635-0877","full_name":"Siegert, Sandra","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","first_name":"Sandra"}],"pmid":1,"status":"public","isi":1,"publication_identifier":{"eissn":["1546-1726"],"issn":["1097-6256"]},"department":[{"_id":"SaSi"}],"corr_author":"1","date_updated":"2026-06-13T22:30:40Z","citation":{"ieee":"G. Colombo <i>et al.</i>, “A tool for mapping microglial morphology, morphOMICs, reveals brain-region and sex-dependent phenotypes,” <i>Nature Neuroscience</i>, vol. 25, no. 10. Springer Nature, pp. 1379–1393, 2022.","mla":"Colombo, Gloria, et al. “A Tool for Mapping Microglial Morphology, MorphOMICs, Reveals Brain-Region and Sex-Dependent Phenotypes.” <i>Nature Neuroscience</i>, vol. 25, no. 10, Springer Nature, 2022, pp. 1379–93, doi:<a href=\"https://doi.org/10.1038/s41593-022-01167-6\">10.1038/s41593-022-01167-6</a>.","chicago":"Colombo, Gloria, Ryan J Cubero, Lida Kanari, Alessandro Venturino, Rouven Schulz, Martina Scolamiero, Jens Agerberg, et al. “A Tool for Mapping Microglial Morphology, MorphOMICs, Reveals Brain-Region and Sex-Dependent Phenotypes.” <i>Nature Neuroscience</i>. Springer Nature, 2022. <a href=\"https://doi.org/10.1038/s41593-022-01167-6\">https://doi.org/10.1038/s41593-022-01167-6</a>.","ama":"Colombo G, Cubero RJ, Kanari L, et al. A tool for mapping microglial morphology, morphOMICs, reveals brain-region and sex-dependent phenotypes. <i>Nature Neuroscience</i>. 2022;25(10):1379-1393. doi:<a href=\"https://doi.org/10.1038/s41593-022-01167-6\">10.1038/s41593-022-01167-6</a>","short":"G. Colombo, R.J. Cubero, L. Kanari, A. Venturino, R. Schulz, M. Scolamiero, J. Agerberg, H. Mathys, L.-H. Tsai, W. Chachólski, K. Hess, S. Siegert, Nature Neuroscience 25 (2022) 1379–1393.","apa":"Colombo, G., Cubero, R. J., Kanari, L., Venturino, A., Schulz, R., Scolamiero, M., … Siegert, S. (2022). A tool for mapping microglial morphology, morphOMICs, reveals brain-region and sex-dependent phenotypes. <i>Nature Neuroscience</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41593-022-01167-6\">https://doi.org/10.1038/s41593-022-01167-6</a>","ista":"Colombo G, Cubero RJ, Kanari L, Venturino A, Schulz R, Scolamiero M, Agerberg J, Mathys H, Tsai L-H, Chachólski W, Hess K, Siegert S. 2022. A tool for mapping microglial morphology, morphOMICs, reveals brain-region and sex-dependent phenotypes. Nature Neuroscience. 25(10), 1379–1393."},"publisher":"Springer Nature","project":[{"name":"ISTplus - Postdoctoral Fellowships","call_identifier":"H2020","grant_number":"754411","_id":"260C2330-B435-11E9-9278-68D0E5697425"},{"name":"Microglia action towards neuronal circuit formation and function in health and disease","call_identifier":"H2020","grant_number":"715571","_id":"25D4A630-B435-11E9-9278-68D0E5697425"}],"ec_funded":1,"abstract":[{"lang":"eng","text":"Environmental cues influence the highly dynamic morphology of microglia. Strategies to characterize these changes usually involve user-selected morphometric features, which preclude the identification of a spectrum of context-dependent morphological phenotypes. Here we develop MorphOMICs, a topological data analysis approach, which enables semiautomatic mapping of microglial morphology into an atlas of cue-dependent phenotypes and overcomes feature-selection biases and biological variability. We extract spatially heterogeneous and sexually dimorphic morphological phenotypes for seven adult mouse brain regions. This sex-specific phenotype declines with maturation but increases over the disease trajectories in two neurodegeneration mouse models, with females showing a faster morphological shift in affected brain regions. Remarkably, microglia morphologies reflect an adaptation upon repeated exposure to ketamine anesthesia and do not recover to control morphologies. Finally, we demonstrate that both long primary processes and short terminal processes provide distinct insights to morphological phenotypes. MorphOMICs opens a new perspective to characterize microglial morphology."}],"title":"A tool for mapping microglial morphology, morphOMICs, reveals brain-region and sex-dependent phenotypes","file":[{"date_updated":"2023-01-30T08:06:56Z","creator":"dernst","file_id":"12437","relation":"main_file","success":1,"file_size":23789835,"access_level":"open_access","file_name":"2022_NatureNeuroscience_Colombo.pdf","checksum":"28431146873096f52e0107b534f178c9","content_type":"application/pdf","date_created":"2023-01-30T08:06:56Z"}],"page":"1379-1393","article_type":"original","publication_status":"published","oa":1,"language":[{"iso":"eng"}],"date_created":"2023-01-16T09:53:07Z","acknowledged_ssus":[{"_id":"PreCl"},{"_id":"Bio"},{"_id":"ScienComp"}],"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","year":"2022","_id":"12244","intvolume":"        25","ddc":["570"],"doi":"10.1038/s41593-022-01167-6","publication":"Nature Neuroscience","acknowledgement":"We thank the scientific service units at ISTA, in particular M. Schunn’s team at the preclinical facility, and especially our colony manager S. Haslinger, for excellent support. We are also grateful to the ISTA Imaging & Optics Facility, and in particular C. Sommer for helping with the data file conversions. We thank R. Erhart from the ISTA Scientific Computing Unit for improving the script performance. We thank M. Maes, B. Nagy, S. Oakeley and M. Benevento and all members of the Siegert group for constant feedback on the project and on the manuscript. This research was supported by the European Union Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Actions program (754411 to R.J.A.C.), and by the European Research Council (grant no. 715571 to S.S.). L.K. was supported by funding to the Blue Brain Project, a research center of the École polytechnique fédérale de Lausanne, from the Swiss government’s ETH Board of the Swiss Federal Institutes of Technology. L.-H.T. was supported by NIH (grant no. R37NS051874) and by the JPB Foundation. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.","type":"journal_article","file_date_updated":"2023-01-30T08:06:56Z"},{"publication_status":"published","oa":1,"file":[{"checksum":"8cd3ddfe9b53381dcf086023d8d8893a","content_type":"application/vnd.openxmlformats-officedocument.wordprocessingml.document","file_name":"Gloria_Colombo_Thesis.docx","date_created":"2023-01-25T14:31:32Z","file_id":"12379","date_updated":"2023-04-12T22:30:03Z","creator":"cchlebak","embargo_to":"open_access","file_size":23890382,"access_level":"closed","relation":"source_file"},{"file_name":"Gloria_Colombo_Thesis.pdf","checksum":"8af4319c18b516e8758e9a6cb02b103b","content_type":"application/pdf","date_created":"2023-01-25T14:31:36Z","embargo":"2023-04-11","date_updated":"2023-04-12T22:30:03Z","creator":"cchlebak","file_id":"12380","relation":"main_file","file_size":13802421,"access_level":"open_access"}],"title":"MorphOMICs, a tool for mapping microglial morphology, reveals brain region- and sex-dependent phenotypes","alternative_title":["ISTA Thesis"],"page":"142","degree_awarded":"PhD","supervisor":[{"first_name":"Sandra","full_name":"Siegert, Sandra","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-8635-0877","last_name":"Siegert"}],"abstract":[{"text":"Environmental cues influence the highly dynamic morphology of microglia. Strategies to \r\ncharacterize these changes usually involve user-selected morphometric features, which \r\npreclude the identification of a spectrum of context-dependent morphological phenotypes. \r\nHere, we develop MorphOMICs, a topological data analysis approach, which enables semi\u0002automatic mapping of microglial morphology into an atlas of cue-dependent phenotypes,\r\novercomes feature-selection bias and minimizes biological variability. \r\nFirst, with MorphOMICs we derive the morphological spectrum of microglia across seven \r\nbrain regions during postnatal development and in two distinct Alzheimer’s disease \r\ndegeneration mouse models. We uncover region-specific and sexually dimorphic\r\nmorphological trajectories, with females showing an earlier morphological shift than males in \r\nthe degenerating brain. Overall, we demonstrate that both long primary- and short terminal \r\nprocesses provide distinct insights to morphological phenotypes. Moreover, using machine \r\nlearning to map novel condition on the spectrum, we observe that microglia morphologies \r\nreflect a dose-dependent adaptation upon ketamine anesthesia and do not recover to control \r\nmorphologies.\r\nNext, we took advantage of MorphOMICs to build a high-resolution and layer-specific map of \r\nmicroglial morphological spectrum in the retina, covering postnatal development and rd10 \r\ndegeneration. Here, following photoreceptor death, microglia assume an early development\u0002like morphology. Finally, we map microglial morphology following optic nerve crush on the \r\nretinal spectrum and observe a layer- and sex-dependent response. \r\nOverall, MorphOMICs opens a new perspective to analyze microglial morphology across \r\nmultiple conditions, and provides a novel tool to characterize microglial morphology beyond \r\nthe traditionally dichotomized view of microglia.","lang":"eng"}],"project":[{"_id":"2564DBCA-B435-11E9-9278-68D0E5697425","grant_number":"665385","call_identifier":"H2020","name":"International IST Doctoral Program"}],"ec_funded":1,"file_date_updated":"2023-04-12T22:30:03Z","type":"dissertation","_id":"12378","doi":"10.15479/at:ista:12378","ddc":["570"],"language":[{"iso":"eng"}],"date_created":"2023-01-25T14:27:43Z","acknowledged_ssus":[{"_id":"PreCl"},{"_id":"Bio"},{"_id":"ScienComp"}],"user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","year":"2022","day":"11","month":"11","oa_version":"Published Version","department":[{"_id":"GradSch"},{"_id":"SaSi"}],"corr_author":"1","date_updated":"2026-04-07T14:29:41Z","publisher":"Institute of Science and Technology Austria","citation":{"short":"G. Colombo, MorphOMICs, a Tool for Mapping Microglial Morphology, Reveals Brain Region- and Sex-Dependent Phenotypes, Institute of Science and Technology Austria, 2022.","ista":"Colombo G. 2022. MorphOMICs, a tool for mapping microglial morphology, reveals brain region- and sex-dependent phenotypes. Institute of Science and Technology Austria.","apa":"Colombo, G. (2022). <i>MorphOMICs, a tool for mapping microglial morphology, reveals brain region- and sex-dependent phenotypes</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/at:ista:12378\">https://doi.org/10.15479/at:ista:12378</a>","mla":"Colombo, Gloria. <i>MorphOMICs, a Tool for Mapping Microglial Morphology, Reveals Brain Region- and Sex-Dependent Phenotypes</i>. Institute of Science and Technology Austria, 2022, doi:<a href=\"https://doi.org/10.15479/at:ista:12378\">10.15479/at:ista:12378</a>.","chicago":"Colombo, Gloria. “MorphOMICs, a Tool for Mapping Microglial Morphology, Reveals Brain Region- and Sex-Dependent Phenotypes.” Institute of Science and Technology Austria, 2022. <a href=\"https://doi.org/10.15479/at:ista:12378\">https://doi.org/10.15479/at:ista:12378</a>.","ieee":"G. Colombo, “MorphOMICs, a tool for mapping microglial morphology, reveals brain region- and sex-dependent phenotypes,” Institute of Science and Technology Austria, 2022.","ama":"Colombo G. MorphOMICs, a tool for mapping microglial morphology, reveals brain region- and sex-dependent phenotypes. 2022. doi:<a href=\"https://doi.org/10.15479/at:ista:12378\">10.15479/at:ista:12378</a>"},"status":"public","publication_identifier":{"issn":["2663-337X"]},"has_accepted_license":"1","article_processing_charge":"No","author":[{"orcid":"0000-0001-9434-8902","last_name":"Colombo","full_name":"Colombo, Gloria","id":"3483CF6C-F248-11E8-B48F-1D18A9856A87","first_name":"Gloria"}],"OA_place":"publisher","related_material":{"record":[{"status":"public","id":"12244","relation":"part_of_dissertation"}]},"tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"date_published":"2022-11-11T00:00:00Z"},{"_id":"10565","intvolume":"         2","ddc":["573"],"doi":"10.1016/j.xpro.2021.101012","language":[{"iso":"eng"}],"date_created":"2021-12-19T23:01:32Z","year":"2021","acknowledged_ssus":[{"_id":"Bio"}],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","file_date_updated":"2021-12-20T08:58:40Z","publication":"STAR Protocols","acknowledgement":"This research was supported by the European Research Council (grant 715571 to S.S.). We thank Rouven Schulz, Michael Schunn, Claudia Gold, Gabriel Krens, Sarah Gorkiewicz, Margaret Maes, Jürgen Siegert, Marco Benevento, and Sara Oakeley for comments on the manuscript and the IST Austria Bioimaging Facility for the technical support.","type":"journal_article","abstract":[{"lang":"eng","text":"Enzymatic digestion of the extracellular matrix with chondroitinase-ABC reinstates juvenile-like plasticity in the adult cortex as it also disassembles the perineuronal nets (PNNs). The disadvantage of the enzyme is that it must be applied intracerebrally and it degrades the ECM for several weeks. Here, we provide two minimally invasive and transient protocols for microglia-enabled PNN disassembly in mouse cortex: repeated treatment with ketamine-xylazine-acepromazine (KXA) anesthesia and 60-Hz light entrainment. We also discuss how to analyze PNNs within microglial endosomes-lysosomes. For complete details on the use and execution of this protocol, please refer to Venturino et al. (2021)."}],"project":[{"name":"Microglia action towards neuronal circuit formation and function in health and disease","grant_number":"715571","call_identifier":"H2020","_id":"25D4A630-B435-11E9-9278-68D0E5697425"}],"ec_funded":1,"article_type":"original","publication_status":"published","oa":1,"article_number":"101012","title":"Minimally invasive protocols and quantification for microglia-mediated perineuronal net disassembly in mouse brain","file":[{"creator":"cchlebak","date_updated":"2021-12-20T08:58:40Z","file_id":"10570","success":1,"relation":"main_file","access_level":"open_access","file_size":6207060,"file_name":"2021_STARProt_Venturino.pdf","checksum":"9ea2501056c5df99e84726b845e9b976","content_type":"application/pdf","date_created":"2021-12-20T08:58:40Z"}],"article_processing_charge":"Yes","has_accepted_license":"1","author":[{"id":"41CB84B2-F248-11E8-B48F-1D18A9856A87","full_name":"Venturino, Alessandro","last_name":"Venturino","orcid":"0000-0003-2356-9403","first_name":"Alessandro"},{"orcid":"0000-0001-8635-0877","last_name":"Siegert","full_name":"Siegert, Sandra","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","first_name":"Sandra"}],"tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"volume":2,"date_published":"2021-12-17T00:00:00Z","department":[{"_id":"SaSi"}],"date_updated":"2025-05-14T11:26:30Z","publisher":"Elsevier","citation":{"short":"A. Venturino, S. Siegert, STAR Protocols 2 (2021).","apa":"Venturino, A., &#38; Siegert, S. (2021). Minimally invasive protocols and quantification for microglia-mediated perineuronal net disassembly in mouse brain. <i>STAR Protocols</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.xpro.2021.101012\">https://doi.org/10.1016/j.xpro.2021.101012</a>","ista":"Venturino A, Siegert S. 2021. Minimally invasive protocols and quantification for microglia-mediated perineuronal net disassembly in mouse brain. STAR Protocols. 2(4), 101012.","ieee":"A. Venturino and S. Siegert, “Minimally invasive protocols and quantification for microglia-mediated perineuronal net disassembly in mouse brain,” <i>STAR Protocols</i>, vol. 2, no. 4. Elsevier, 2021.","mla":"Venturino, Alessandro, and Sandra Siegert. “Minimally Invasive Protocols and Quantification for Microglia-Mediated Perineuronal Net Disassembly in Mouse Brain.” <i>STAR Protocols</i>, vol. 2, no. 4, 101012, Elsevier, 2021, doi:<a href=\"https://doi.org/10.1016/j.xpro.2021.101012\">10.1016/j.xpro.2021.101012</a>.","chicago":"Venturino, Alessandro, and Sandra Siegert. “Minimally Invasive Protocols and Quantification for Microglia-Mediated Perineuronal Net Disassembly in Mouse Brain.” <i>STAR Protocols</i>. Elsevier, 2021. <a href=\"https://doi.org/10.1016/j.xpro.2021.101012\">https://doi.org/10.1016/j.xpro.2021.101012</a>.","ama":"Venturino A, Siegert S. Minimally invasive protocols and quantification for microglia-mediated perineuronal net disassembly in mouse brain. <i>STAR Protocols</i>. 2021;2(4). doi:<a href=\"https://doi.org/10.1016/j.xpro.2021.101012\">10.1016/j.xpro.2021.101012</a>"},"status":"public","publication_identifier":{"eissn":["2666-1667"]},"scopus_import":"1","oa_version":"Published Version","quality_controlled":"1","issue":"4","day":"17","month":"12"},{"tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"date_published":"2021-12-10T00:00:00Z","volume":23,"has_accepted_license":"1","external_id":{"isi":["000748748500019"]},"article_processing_charge":"Yes","author":[{"last_name":"Maes","orcid":"0000-0001-9642-1085","id":"3838F452-F248-11E8-B48F-1D18A9856A87","full_name":"Maes, Margaret E","first_name":"Margaret E"},{"full_name":"Wögenstein, Gabriele M.","last_name":"Wögenstein","first_name":"Gabriele M."},{"orcid":"0000-0001-9434-8902","last_name":"Colombo","id":"3483CF6C-F248-11E8-B48F-1D18A9856A87","full_name":"Colombo, Gloria","first_name":"Gloria"},{"orcid":"0000-0001-8293-4568","last_name":"Casado Polanco","id":"15240fc1-dbcd-11ea-9d1d-ac5a786425fd","full_name":"Casado Polanco, Raquel","first_name":"Raquel"},{"first_name":"Sandra","last_name":"Siegert","orcid":"0000-0001-8635-0877","full_name":"Siegert, Sandra","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87"}],"status":"public","isi":1,"publication_identifier":{"eissn":["2329-0501"]},"department":[{"_id":"SaSi"},{"_id":"SiHi"}],"corr_author":"1","date_updated":"2025-04-14T07:41:46Z","citation":{"ista":"Maes ME, Wögenstein GM, Colombo G, Casado Polanco R, Siegert S. 2021. Optimizing AAV2/6 microglial targeting identified enhanced efficiency in the photoreceptor degenerative environment. Molecular Therapy - Methods and Clinical Development. 23, 210–224.","apa":"Maes, M. E., Wögenstein, G. M., Colombo, G., Casado Polanco, R., &#38; Siegert, S. (2021). Optimizing AAV2/6 microglial targeting identified enhanced efficiency in the photoreceptor degenerative environment. <i>Molecular Therapy - Methods and Clinical Development</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.omtm.2021.09.006\">https://doi.org/10.1016/j.omtm.2021.09.006</a>","short":"M.E. Maes, G.M. Wögenstein, G. Colombo, R. Casado Polanco, S. Siegert, Molecular Therapy - Methods and Clinical Development 23 (2021) 210–224.","ama":"Maes ME, Wögenstein GM, Colombo G, Casado Polanco R, Siegert S. Optimizing AAV2/6 microglial targeting identified enhanced efficiency in the photoreceptor degenerative environment. <i>Molecular Therapy - Methods and Clinical Development</i>. 2021;23:210-224. doi:<a href=\"https://doi.org/10.1016/j.omtm.2021.09.006\">10.1016/j.omtm.2021.09.006</a>","mla":"Maes, Margaret E., et al. “Optimizing AAV2/6 Microglial Targeting Identified Enhanced Efficiency in the Photoreceptor Degenerative Environment.” <i>Molecular Therapy - Methods and Clinical Development</i>, vol. 23, Elsevier, 2021, pp. 210–24, doi:<a href=\"https://doi.org/10.1016/j.omtm.2021.09.006\">10.1016/j.omtm.2021.09.006</a>.","chicago":"Maes, Margaret E, Gabriele M. Wögenstein, Gloria Colombo, Raquel Casado Polanco, and Sandra Siegert. “Optimizing AAV2/6 Microglial Targeting Identified Enhanced Efficiency in the Photoreceptor Degenerative Environment.” <i>Molecular Therapy - Methods and Clinical Development</i>. Elsevier, 2021. <a href=\"https://doi.org/10.1016/j.omtm.2021.09.006\">https://doi.org/10.1016/j.omtm.2021.09.006</a>.","ieee":"M. E. Maes, G. M. Wögenstein, G. Colombo, R. Casado Polanco, and S. Siegert, “Optimizing AAV2/6 microglial targeting identified enhanced efficiency in the photoreceptor degenerative environment,” <i>Molecular Therapy - Methods and Clinical Development</i>, vol. 23. Elsevier, pp. 210–224, 2021."},"publisher":"Elsevier","oa_version":"Published Version","scopus_import":"1","quality_controlled":"1","month":"12","day":"10","language":[{"iso":"eng"}],"date_created":"2022-01-23T23:01:28Z","user_id":"3E5EF7F0-F248-11E8-B48F-1D18A9856A87","acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"},{"_id":"PreCl"}],"year":"2021","_id":"10655","doi":"10.1016/j.omtm.2021.09.006","intvolume":"        23","ddc":["570"],"publication":"Molecular Therapy - Methods and Clinical Development","type":"journal_article","acknowledgement":"This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 715571). The research was supported by the Scientific Service Units (SSU) of IST Austria through resources provided by the Bioimaging Facility, the Life Science Facility, and the Pre-Clinical Facility, namely Sonja Haslinger and Michael Schunn for their animal colony management and support. We would also like to thank Chakrabarty Lab for sharing the plasmids for AAV2/6 production. Finally, we would like to thank the Siegert team members for discussion about the manuscript.","file_date_updated":"2022-01-24T07:43:09Z","project":[{"call_identifier":"H2020","_id":"25D4A630-B435-11E9-9278-68D0E5697425","grant_number":"715571","name":"Microglia action towards neuronal circuit formation and function in health and disease"}],"ec_funded":1,"abstract":[{"text":"Adeno-associated viruses (AAVs) are widely used to deliver genetic material in vivo to distinct cell types such as neurons or glial cells, allowing for targeted manipulation. Transduction of microglia is mostly excluded from this strategy, likely due to the cells’ heterogeneous state upon environmental changes, which makes AAV design challenging. Here, we established the retina as a model system for microglial AAV validation and optimization. First, we show that AAV2/6 transduced microglia in both synaptic layers, where layer preference corresponds to the intravitreal or subretinal delivery method. Surprisingly, we observed significantly enhanced microglial transduction during photoreceptor degeneration. Thus, we modified the AAV6 capsid to reduce heparin binding by introducing four point mutations (K531E, R576Q, K493S, and K459S), resulting in increased microglial transduction in the outer plexiform layer. Finally, to improve microglial-specific transduction, we validated a Cre-dependent transgene delivery cassette for use in combination with the Cx3cr1CreERT2 mouse line. Together, our results provide a foundation for future studies optimizing AAV-mediated microglia transduction and highlight that environmental conditions influence microglial transduction efficiency.\r\n","lang":"eng"}],"title":"Optimizing AAV2/6 microglial targeting identified enhanced efficiency in the photoreceptor degenerative environment","file":[{"date_created":"2022-01-24T07:43:09Z","file_name":"2021_MolTherMethodsClinDev_Maes.pdf","content_type":"application/pdf","checksum":"77dc540e8011c5475031bdf6ccef20a6","relation":"main_file","success":1,"access_level":"open_access","file_size":4794147,"creator":"cchlebak","date_updated":"2022-01-24T07:43:09Z","file_id":"10657"}],"page":"210-224","article_type":"original","publication_status":"published","oa":1}]