Deficits and rescue of neuronal population coding in the sensory cortex of mouse models of autism spectrum disorders
Lead Research Organisation:
University of Edinburgh
Department Name: Sch of Molecular. Genetics & Pop Health
Abstract
The central aim of this project is to understand the effects of single gene mutations at the level of cortical networks activity in animal models of Autism Spectrum Disorders (ASDs) and Intellectual disabilities (ID). Cortical circuits are initially defined by genetic programmes, followed by neural plasticity initially driven by spontaneous and later by evoked sensory activity. The investigation of monogenic ASD/ID animal models at the cellular level has revealed multiple alterations in neuronal properties, including changes in excitability, synaptic transmission and neural plasticity. Yet, it remains largely unknown how such cellular changes affect the activity in neural circuits, and how this, in turn, leads to the diversity of phenotypes characterising ASD/ID. Moreover, recent work indicates that some of these changes are of secondary nature, and likely result from a developmental homeostatic compensation of primary defects. In this scenario, an initial defect leads to altered cellular and/or network activity, which, in turn, is compensated by cellular feedback processes. It is therefore possible that different primary causes, for instance defective plasticity in Fragile X Syndrome and SYNGAP haploinsufficiency, can lead to similar defects at the circuit level. This convergence may provide an opportunity for interventions targeting the resulting cellular and circuit dysfunction in adults.
Addressing this gap in knowledge requires a comprehensive understanding of the circuit-level impairments of ASD/ID in adults. Very few studies so far have investigated network activity in disease models beyond global features such as seizures, and currently no coherent picture exists. Here, we plan to use Fmr1-/y and Syngap+/- mice as two well established ASD/ID models to determine how these mutations affect the propagation of neural activity through cortical networks, focusing on sensory areas, where inputs are readily controllable.
Aims
We will examine the following three hypotheses in Fmr-/y and Syngap+/- mice in this project:
1. Cortical ensemble activity is consistently altered in ASD/ID models, compared to wild type (WT) animals, and biased towards reduced representational capabilities.
2. Cortical plasticity induced by monocular deprivation is altered in ASD/ID models.
3. Pharmacological treatments that rescue behavioural ASD/ID phenotypes in mouse models will modify cortical population activity and plasticity.
To uncover the relevant circuit defects in ASD/ID models, we will use 2-photon calcium imaging of more than one thousand neurons simultaneously in the primary visual and parietal cortex, and employ computational data analysis and modelling. Genetically labelling of different interneuron types will enable a detailed dissection of the circuit pathology. We will investigate changes in experience-dependent plasticity at the circuit level, which has so far not been attempted, and evaluate the circuit-wide effects of pharmacological rescue in adults. Together, these complementary approaches will
(i) help relate cellular and systems level pathologies in ASD/ID,
(ii) explore avenues for treatment and interventions, and
(iii) provide novel computational tools for analysis and interpretation of large neural population recordings.
Addressing this gap in knowledge requires a comprehensive understanding of the circuit-level impairments of ASD/ID in adults. Very few studies so far have investigated network activity in disease models beyond global features such as seizures, and currently no coherent picture exists. Here, we plan to use Fmr1-/y and Syngap+/- mice as two well established ASD/ID models to determine how these mutations affect the propagation of neural activity through cortical networks, focusing on sensory areas, where inputs are readily controllable.
Aims
We will examine the following three hypotheses in Fmr-/y and Syngap+/- mice in this project:
1. Cortical ensemble activity is consistently altered in ASD/ID models, compared to wild type (WT) animals, and biased towards reduced representational capabilities.
2. Cortical plasticity induced by monocular deprivation is altered in ASD/ID models.
3. Pharmacological treatments that rescue behavioural ASD/ID phenotypes in mouse models will modify cortical population activity and plasticity.
To uncover the relevant circuit defects in ASD/ID models, we will use 2-photon calcium imaging of more than one thousand neurons simultaneously in the primary visual and parietal cortex, and employ computational data analysis and modelling. Genetically labelling of different interneuron types will enable a detailed dissection of the circuit pathology. We will investigate changes in experience-dependent plasticity at the circuit level, which has so far not been attempted, and evaluate the circuit-wide effects of pharmacological rescue in adults. Together, these complementary approaches will
(i) help relate cellular and systems level pathologies in ASD/ID,
(ii) explore avenues for treatment and interventions, and
(iii) provide novel computational tools for analysis and interpretation of large neural population recordings.
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
MR/N013166/1 | 01/10/2016 | 30/09/2025 | |||
1937978 | Studentship | MR/N013166/1 | 01/09/2017 | 31/08/2021 | Theoklitos Amvrosiadis |
Description | MRC Flexible Supplement Funding |
Amount | £5,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2020 |
End | 10/2021 |
Description | Dr Arno Onken |
Organisation | University of Edinburgh |
Department | School of Informatics Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I am a named collaborator (Dr Nathalie Rochefort) on the New Investigator Award to Dr Arno Onken, Novel techniques for stochastic modelling of time-dependent multivariate relationships with application to primary visual cortex, 3 years, 289728.05 pounds. I have provided data sets and we have been meeting around 5-6 times in 2019 to discuss data analysis and progression of the project |
Collaborator Contribution | Dr Arno Onken team (post-doctoral researcher Nina KUDRYASHOVA) is developing copula-based models and apply them to our data set. |
Impact | Poster Bernstein conference 2019, Parametric copula models reveal neuronal and behavioral time-dependent relationships in primary visual cortex Nina Kudryashova, Theoklitos Amvrosiadis, Nathalie Dupuy, Nathalie Rochefort, Arno Onken Poster selected for Cosyne meeting, feb. 2020, Parametric Copula-GP model reveals tuning of neuronal and behavioral relationships to visual stimuli Nina Kudryashova, Arno Onken, School of Informatics, University of Edinburgh; Theoklitos Amvrosiadis, Nathalie Dupuy, Nathalie Rochefort, CDBS, Biomedical Sciences, University of Edinburgh. Three articles: https://doi.org/10.1371/journal.pcbi.1009799 https://arxiv.org/abs/2111.13073 https://arxiv.org/abs/2009.02707 |
Start Year | 2019 |
Description | Prof. Máté Lengyel |
Organisation | University of Cambridge |
Department | Department of Engineering |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Scientific discussions and Analysis of data set acquired by Theoklitos Amvrosiadis in my research group. |
Collaborator Contribution | Analysis of data set, writing of abstract and poster presentation for Cosyne conference 2022 https://www.cosyne.org/poster-session-2 Diverse covariates modulate neural variability: a widespread (sub)cortical phenomenon David Liu, Theoklitos Amvrosiadis, Nathalie Rochefort, Máté Lengyel |
Impact | Poster, Cosyne conference 2022 https://www.cosyne.org/poster-session-2 Diverse covariates modulate neural variability: a widespread (sub)cortical phenomenon David Liu, Theoklitos Amvrosiadis, Nathalie Rochefort, Máté Lengyel |
Start Year | 2021 |
Description | Poster co-author at Bernstein Conference 2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Title: Parametric copula models reveal modulations of neuronal and behavioural relationships in visual cortex neuronal networks Authors: Nina Kudryashova, Theoklitos Amvrosiadis, Nathalie Dupuy, Nathalie Rochefort, Arno Onken |
Year(s) Of Engagement Activity | 2019 |
Description | Poster co-author at Bernstein Conference 2020 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Title: Copula-GP method for conditioning on behavioral and contextual variables reveals navigation task structure Authors: Nina Kudryashova, Theoklitos Amvrosiadis, Nathalie Dupuy, Nathalie Rochefort, Arno Onken |
Year(s) Of Engagement Activity | 2020 |
URL | https://abstracts.g-node.org/abstracts/d5279094-9a7b-4457-b860-36a5402030da |
Description | Poster co-author at COSYNE 2020 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Title: Parametric Copula-GP model reveals tuning of neuronal and behavioral relationships to visual stimuli Authors: Nina Kudryashova, Theoklitos Amvrosiadis, Nathalie Dupuy, Nathalie Rochefort, Arno Onken |
Year(s) Of Engagement Activity | 2020 |
Description | Poster co-author at COSYNE conference 2021 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Title: Behavioral modulation of information processing in visual cortex analysed with Copula-GP model Authors: Nina Kudryashova, Theoklitos Amvrosiadis, Nathalie Dupuy, Nathalie Rochefort, Arno Onken |
Year(s) Of Engagement Activity | 2021 |
Description | Poster co-author at COSYNE conference 2022 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Poster presentation at an international conference, in person. Cosyne 2022: Poster II-067 Diverse covariates modulate neural variability: a widespread (sub)cortical phenomenon David Liu, Theoklitos Amvrosiadis, Nathalie Rochefort, Máté Lengyel |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.cosyne.org/poster-session-2 |
Description | Poster co-author at European Visual Cortex Meeting 2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Title: Task engagement and visuomotor feedback facilitate stimulus encoding in visual cortex Authors: Julia U. Henschke*, Evelyn Dylda*, Danai Katsanevaki, Theoklitos Amvrosiadis, Nathalie Dupuy, Stephen P. Currie, Janelle M.P. Pakan*, and Nathalie L. Rochefort* |
Year(s) Of Engagement Activity | 2019 |
Description | Poster presentation at Precision Medicine DTP event |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | Presentation of a poster during the induction week for the MRC Precision Medicine DTP. |
Year(s) Of Engagement Activity | 2019 |
Description | Talk at Precision Medicine DTP event |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Postgraduate students |
Results and Impact | This was a 15-min talk at the annual Precision Medicine DTP event where 3rd-year PhD students present their research. All 3rd-year students attended (plus students from other cohorts). Questions and discussion followed the presentation. |
Year(s) Of Engagement Activity | 2020 |
Description | University of Edinburgh Student Stories (blogging) |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Postgraduate students |
Results and Impact | I am part of the student bloggers for the University's "Student Stories" blog. In this blog, I write monthly about my experiences as a PhD student and try to present them as advice to students who might be considering taking the same path. |
Year(s) Of Engagement Activity | 2019,2020 |
URL | https://studentstories.ed.ac.uk |