---
_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'
...