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  Study of the neural mechanisms underlying cognitive flexibility and their alterations in rat models of autism


   Simons Initiative for the Developing Brain

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  Dr Marino Pagan  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

Applications are invited for one 3.5 year full-time fully funded PhD studentship in the lab of Dr Marino Pagan within the Simons Initiative for the Developing Brain at the University of Edinburgh. SIDB (www.sidb.org.uk) is a philanthropic Centre funded by the Simons Foundation Autism Research Initiative (www.sfari.org).

Title: Study of the neural mechanisms underlying cognitive flexibility and their alterations in rat models of autism

Background: A common feature of autism and other neurodevelopmental disorders consists of an impairment of fundamental cognitive skills, like the ability to make appropriate decisions, to memorize and use new information, and to quickly switch between different tasks (Uddin, 2021). Little is known about the neural circuits underlying such key cognitive abilities, and how these circuits are altered by genetic mutations associated with neurodevelopmental disorders. Recently, we developed new techniques to train rats to perform sophisticated behavioural tasks requiring flexible decision-making, and to record and analyse neural activity while rats solve these tasks, allowing us to uncover some of the neural mechanisms underlying decision-making, working memory and task-switching (Duan, Pagan et al., 2021; Pagan et al., 2022).

Aims: In this project we will combine a rat behavioural task requiring flexible decision-making (Pagan et al., 2022) with electrophysiology recordings and optogenetics to address 3 main aims:

  1. Study of the brain-wide circuits supporting flexible decision-making
  2. Study of the behavioural roles for autism-associated genes in cognitive function
  3. Study of the neural mechanisms linking genetic mutations to cognitive dysfunction

Training outcomes: By the end of the project, the PhD student will be trained to build and maintain operant chambers for rat decision-making tasks, design behavioural tasks and experiments, use wireless electrophysiology methods to record neural activity during behaviour, use wireless optogenetics methods to perturb neural activity during behaviour, analyse behavioural and neural recording data, and write and review scientific manuscripts.

Rationale & hypothesis: Analysis of behaviour and neural activity while rats solve complex decision-making tasks allows the study of the neural mechanisms underlying cognitive function. In combination with the recent introduction of several lines of rat genetic models of autism, this approach provides us with an unprecedented opportunity to systematically characterize cognitive deficits induced by different mutations, and to dissect the mechanisms linking neural circuit abnormalities to cognitive dysfunction. Our hypothesis is that different single-gene mutations impair specific sets of cognitive skills (e.g. decision-making, working memory, task-switching), and that such cognitive impairments can be traced back to altered neural activity in high-order brain regions, such as prefrontal cortex. Finally, we hypothesize that it will be possible to ameliorate some of these cognitive deficits by precisely manipulating neural activity in these brain areas using optogenetics or pharmacology approaches.

Eligibility: Applicants should meet the academic and English language entry requirements for admission to postgraduate programmes at the University of Edinburgh.

Applicants should also have a good (2:1 or higher) undergraduate degree in a relevant subject (including, not limited to, neuroscience, biomedical sciences, molecular biology, genetics, or computational biology).

Funding: This is a SIDB-funded award. It will provide an annual stipend for 3.5 years of £21,080 per annum, plus tuition fees (including international).

How to Apply: Please email [Email Address Removed] to request an application form. Once you have completed the form you should return it direct, along with two references at the same email address. Please contact Marino Pagan ([Email Address Removed]) to discuss questions and the nature of your interest in the project. In the application form you should indicate why you are interested in the project and why you would be a good fit for the project.

Deadline: The deadline for applications is 15th March 2024.

Start time: The start time for the studentship is 9th September 2024.

Enquiries: Please email [Email Address Removed] to request an application form. Once you have completed the form you should return it direct, along with two references at the same email address. Please contact Marino Pagan ([Email Address Removed]) to discuss questions and the nature of your interest in the project. In the application form you should indicate why you are interested in the project and why you would be a good fit for the project.

Biological Sciences (4) Computer Science (8) Mathematics (25)

Funding Notes

This is a SIDB-funded award. It will provide an annual stipend for 3.5 years of £21,080 per annum, plus tuition fees (including international).

References

Uddin, L.Q. (2021) Cognitive and Behavioural Flexibility: Neural Mechanisms and Clinical Considerations. Nature Reviews Neuroscience 22 (3): 167–79.
Duan, C.A.*, Pagan, M.*, Piet, A.T.*, Kopec, C.D., Akrami, A., Riordan, A.J., Erlich, J.C., Brody, C.D. (2021) Collicular circuits for flexible sensorimotor routing, Nature Neuroscience. 24 (8), 1110-1120
Pagan, M., Tang, V., Aoi, M.C., Pillow, J.W., Mante, V., Sussillo, D., Brody, C.D. (2022) A new theoretical framework jointly explains behavioral and neural variability across subjects performing flexible decision-making, bioRxiv. https://doi.org/10.1101/2022.11.28.518207

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