--- _id: '12716' abstract: - lang: eng text: "The process of detecting and evaluating sensory information to guide behaviour is termed perceptual decision-making (PDM), and is critical for the ability of an organism to interact with its external world. Individuals with autism, a neurodevelopmental condition primarily characterised by social and communication difficulties, frequently exhibit altered sensory processing and PDM difficulties are widely reported. Recent technological advancements have pushed forward our understanding of the genetic changes accompanying this condition, however our understanding of how these mutations affect the function of specific neuronal circuits and bring about the corresponding behavioural changes remains limited. Here, we use an innate PDM task, the looming avoidance response (LAR) paradigm, to identify a convergent behavioural abnormality across three molecularly distinct genetic mouse models of autism (Cul3, Setd5 and Ptchd1). Although mutant mice can rapidly detect threatening visual stimuli, their responses are consistently delayed, requiring longer to initiate an appropriate response than their wild-type siblings. Mutant animals show abnormal adaptation in both their stimulus- evoked escape responses and exploratory dynamics following repeated stimulus presentations. Similarly delayed behavioural responses are observed in wild-type animals when faced with more ambiguous threats, suggesting the mutant phenotype could arise from a dysfunction in the flexible control of this PDM process.\r\nOur knowledge of the core neuronal circuitry mediating the LAR facilitated a detailed dissection of the neuronal mechanisms underlying the behavioural impairment. In vivo extracellular recording revealed that visual responses were unaffected within a key brain region for the rapid processing of visual threats, the superior colliculus (SC), indicating that the behavioural delay was unlikely to originate from sensory impairments. Delayed behavioural responses were recapitulated in the Setd5 model following optogenetic stimulation of the excitatory output neurons of the SC, which are known to mediate escape initiation through the activation of cells in the underlying dorsal periaqueductal grey (dPAG). In vitro patch-clamp recordings of dPAG cells uncovered a stark hypoexcitability phenotype in two out of the three genetic models investigated (Setd5 and Ptchd1), that in Setd5, is mediated by the misregulation of voltage-gated potassium channels. Overall, our results show that the ability to use visual information to drive efficient escape responses is impaired in three diverse genetic mouse models of autism and that, in one of the models studied, this behavioural delay likely originates from differences in the intrinsic excitability of a key subcortical node, the dPAG. Furthermore, this work showcases the use of an innate behavioural paradigm to mechanistically dissect PDM processes in autism." acknowledged_ssus: - _id: PreCl - _id: Bio - _id: LifeSc - _id: M-Shop - _id: CampIT alternative_title: - ISTA Thesis article_processing_charge: No author: - first_name: Laura full_name: Burnett, Laura id: 3B717F68-F248-11E8-B48F-1D18A9856A87 last_name: Burnett orcid: 0000-0002-8937-410X citation: ama: Burnett L. To flee, or not to flee? Using innate defensive behaviours to investigate rapid perceptual decision-making through subcortical circuits in mouse models of autism. 2023. doi:10.15479/at:ista:12716 apa: Burnett, L. (2023). To flee, or not to flee? Using innate defensive behaviours to investigate rapid perceptual decision-making through subcortical circuits in mouse models of autism. Institute of Science and Technology Austria. https://doi.org/10.15479/at:ista:12716 chicago: Burnett, Laura. “To Flee, or Not to Flee? Using Innate Defensive Behaviours to Investigate Rapid Perceptual Decision-Making through Subcortical Circuits in Mouse Models of Autism.” Institute of Science and Technology Austria, 2023. https://doi.org/10.15479/at:ista:12716. ieee: L. Burnett, “To flee, or not to flee? Using innate defensive behaviours to investigate rapid perceptual decision-making through subcortical circuits in mouse models of autism,” Institute of Science and Technology Austria, 2023. ista: Burnett L. 2023. To flee, or not to flee? Using innate defensive behaviours to investigate rapid perceptual decision-making through subcortical circuits in mouse models of autism. Institute of Science and Technology Austria. mla: Burnett, Laura. To Flee, or Not to Flee? Using Innate Defensive Behaviours to Investigate Rapid Perceptual Decision-Making through Subcortical Circuits in Mouse Models of Autism. Institute of Science and Technology Austria, 2023, doi:10.15479/at:ista:12716. short: L. Burnett, To Flee, or Not to Flee? Using Innate Defensive Behaviours to Investigate Rapid Perceptual Decision-Making through Subcortical Circuits in Mouse Models of Autism, Institute of Science and Technology Austria, 2023. date_created: 2023-03-08T15:19:45Z date_published: 2023-03-10T00:00:00Z date_updated: 2023-04-05T10:59:04Z day: '10' ddc: - '599' - '573' degree_awarded: PhD department: - _id: GradSch - _id: MaJö doi: 10.15479/at:ista:12716 ec_funded: 1 file: - access_level: closed checksum: 6c6d9cc2c4cdacb74e6b1047a34d7332 content_type: application/vnd.openxmlformats-officedocument.wordprocessingml.document creator: lburnett date_created: 2023-03-08T15:08:46Z date_updated: 2023-03-08T15:08:46Z file_id: '12717' file_name: Burnett_Thesis_2023.docx file_size: 23029260 relation: source_file - access_level: open_access checksum: cebc77705288bf4382db9b3541483cd0 content_type: application/pdf creator: lburnett date_created: 2023-03-08T15:08:46Z date_updated: 2023-03-08T15:08:46Z file_id: '12718' file_name: Burnett_Thesis_2023_pdfA.pdf file_size: 11959869 relation: main_file success: 1 file_date_updated: 2023-03-08T15:08:46Z has_accepted_license: '1' language: - iso: eng month: '03' oa: 1 oa_version: Published Version page: '178' project: - _id: 2634E9D2-B435-11E9-9278-68D0E5697425 call_identifier: H2020 grant_number: '756502' name: Circuits of Visual Attention publication_identifier: issn: - 2663-337X publication_status: published publisher: Institute of Science and Technology Austria status: public supervisor: - first_name: Maximilian A full_name: Jösch, Maximilian A id: 2BD278E6-F248-11E8-B48F-1D18A9856A87 last_name: Jösch orcid: 0000-0002-3937-1330 title: To flee, or not to flee? Using innate defensive behaviours to investigate rapid perceptual decision-making through subcortical circuits in mouse models of autism type: dissertation user_id: 8b945eb4-e2f2-11eb-945a-df72226e66a9 year: '2023' ... --- _id: '944' abstract: - lang: eng text: The concerted production of neurons and glia by neural stem cells (NSCs) is essential for neural circuit assembly. In the developing cerebral cortex, radial glia progenitors (RGPs) generate nearly all neocortical neurons and certain glia lineages. RGP proliferation behavior shows a high degree of non-stochasticity, thus a deterministic characteristic of neuron and glia production. However, the cellular and molecular mechanisms controlling RGP behavior and proliferation dynamics in neurogenesis and glia generation remain unknown. By using mosaic analysis with double markers (MADM)-based genetic paradigms enabling the sparse and global knockout with unprecedented single-cell resolution, we identified Lgl1 as a critical regulatory component. We uncover Lgl1-dependent tissue-wide community effects required for embryonic cortical neurogenesis and novel cell-autonomous Lgl1 functions controlling RGP-mediated glia genesis and postnatal NSC behavior. These results suggest that NSC-mediated neuron and glia production is tightly regulated through the concerted interplay of sequential Lgl1-dependent global and cell intrinsic mechanisms. acknowledged_ssus: - _id: Bio - _id: PreCl article_processing_charge: No author: - first_name: Robert J full_name: Beattie, Robert J id: 2E26DF60-F248-11E8-B48F-1D18A9856A87 last_name: Beattie orcid: 0000-0002-8483-8753 - first_name: Maria P full_name: Postiglione, Maria P id: 2C67902A-F248-11E8-B48F-1D18A9856A87 last_name: Postiglione - first_name: Laura full_name: Burnett, Laura id: 3B717F68-F248-11E8-B48F-1D18A9856A87 last_name: Burnett orcid: 0000-0002-8937-410X - first_name: Susanne full_name: Laukoter, Susanne id: 2D6B7A9A-F248-11E8-B48F-1D18A9856A87 last_name: Laukoter orcid: 0000-0002-7903-3010 - first_name: Carmen full_name: Streicher, Carmen id: 36BCB99C-F248-11E8-B48F-1D18A9856A87 last_name: Streicher - first_name: Florian full_name: Pauler, Florian id: 48EA0138-F248-11E8-B48F-1D18A9856A87 last_name: Pauler orcid: 0000-0002-7462-0048 - first_name: Guanxi full_name: Xiao, Guanxi last_name: Xiao - first_name: Olga full_name: Klezovitch, Olga last_name: Klezovitch - first_name: Valeri full_name: Vasioukhin, Valeri last_name: Vasioukhin - first_name: Troy full_name: Ghashghaei, Troy last_name: Ghashghaei - first_name: Simon full_name: Hippenmeyer, Simon id: 37B36620-F248-11E8-B48F-1D18A9856A87 last_name: Hippenmeyer orcid: 0000-0003-2279-1061 citation: ama: Beattie RJ, Postiglione MP, Burnett L, et al. Mosaic analysis with double markers reveals distinct sequential functions of Lgl1 in neural stem cells. Neuron. 2017;94(3):517-533.e3. doi:10.1016/j.neuron.2017.04.012 apa: Beattie, R. J., Postiglione, M. P., Burnett, L., Laukoter, S., Streicher, C., Pauler, F., … Hippenmeyer, S. (2017). Mosaic analysis with double markers reveals distinct sequential functions of Lgl1 in neural stem cells. Neuron. Cell Press. https://doi.org/10.1016/j.neuron.2017.04.012 chicago: Beattie, Robert J, Maria P Postiglione, Laura Burnett, Susanne Laukoter, Carmen Streicher, Florian Pauler, Guanxi Xiao, et al. “Mosaic Analysis with Double Markers Reveals Distinct Sequential Functions of Lgl1 in Neural Stem Cells.” Neuron. Cell Press, 2017. https://doi.org/10.1016/j.neuron.2017.04.012. ieee: R. J. Beattie et al., “Mosaic analysis with double markers reveals distinct sequential functions of Lgl1 in neural stem cells,” Neuron, vol. 94, no. 3. Cell Press, p. 517–533.e3, 2017. ista: Beattie RJ, Postiglione MP, Burnett L, Laukoter S, Streicher C, Pauler F, Xiao G, Klezovitch O, Vasioukhin V, Ghashghaei T, Hippenmeyer S. 2017. Mosaic analysis with double markers reveals distinct sequential functions of Lgl1 in neural stem cells. Neuron. 94(3), 517–533.e3. mla: Beattie, Robert J., et al. “Mosaic Analysis with Double Markers Reveals Distinct Sequential Functions of Lgl1 in Neural Stem Cells.” Neuron, vol. 94, no. 3, Cell Press, 2017, p. 517–533.e3, doi:10.1016/j.neuron.2017.04.012. short: R.J. Beattie, M.P. Postiglione, L. Burnett, S. Laukoter, C. Streicher, F. Pauler, G. Xiao, O. Klezovitch, V. Vasioukhin, T. Ghashghaei, S. Hippenmeyer, Neuron 94 (2017) 517–533.e3. date_created: 2018-12-11T11:49:20Z date_published: 2017-05-03T00:00:00Z date_updated: 2023-09-26T15:37:02Z day: '03' department: - _id: SiHi - _id: MaJö doi: 10.1016/j.neuron.2017.04.012 ec_funded: 1 external_id: isi: - '000400466700011' intvolume: ' 94' isi: 1 issue: '3' language: - iso: eng month: '05' oa_version: None page: 517 - 533.e3 project: - _id: 25D61E48-B435-11E9-9278-68D0E5697425 call_identifier: FP7 grant_number: '618444' name: Molecular Mechanisms of Cerebral Cortex Development - _id: 25D7962E-B435-11E9-9278-68D0E5697425 grant_number: RGP0053/2014 name: Quantitative Structure-Function Analysis of Cerebral Cortex Assembly at Clonal Level publication: Neuron publication_identifier: issn: - '08966273' publication_status: published publisher: Cell Press publist_id: '6473' quality_controlled: '1' scopus_import: '1' status: public title: Mosaic analysis with double markers reveals distinct sequential functions of Lgl1 in neural stem cells type: journal_article user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 volume: 94 year: '2017' ...