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(A*STAR) Mapping changes in hippocampal-prefrontal neuronal function and behaviour in the 3xTg mouse model for Alzheimer’s disease

  • Full or part time
  • Application Deadline
    Friday, January 31, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Research using mouse models of Alzheimer’s disease (AD) has focussed predominantly on deficits in hippocampal formation (HIP)-dependent behaviour and synaptic function. However, AD is much more than just a case of HIP dysfunction, with patients showing substantial deficits in executive function, such as impaired behavioural flexibility and decision making, which are normally supported by circuits involving HIP and prefrontal cortices (PFC). It is, therefore, surprising that HIP-PFC brain changes leading to executive function deficits have received sparse attention in AD models. This is a big gap in our understanding, as impaired executive cognition has a major impact on patient independence and quality of life and is a defining symptom for AD diagnosis. In particular, we do not understand how executive dysfunction develops over time in any AD strain and how this loss maps onto changes in HIP and PFC neural and synaptic function.

This project will operate between linked sites in Manchester (Division of Neuroscience and Experimental Psychology) and Singapore (Singapore Bioimaging Consortium, SBIC) as follows. Firstly, in Manchester the student will use validated mouse touchscreen operant protocols to assess executive function changes in the 3xTg mouse model for AD. This will determine how deficits in different aspects of executive cognition (e.g., attention and decision making) in 3xTgAD mice develop in relation to our previously demonstrated deficit in episodic-like, autobiographical memory and increased HIP synaptic excitability. The student will next measure how communication between HIP and PFC is compromised in these animals using in vivo electrophysiological recordings. Thirdly, in Singapore the student will use an in vitro approach in mice aged to the point at which there is a decline in executive performance (determined from Manchester studies) to reveal underlying changes in neuronal membrane characteristics and synaptic function within the 3xTgAD HIP-PFC circuit. Throughout the project the student will benefit from training in advanced techniques to address these objectives. In particular, the student will (a) measure mouse behaviour (touchscreen-enabled operant chambers), (b) use in vivo stereotaxic surgery to enable extracellular multi-electrode array recording and (c) apply in vitro electrophysiological and optogenetic approaches in 3xTgAD mouse brain slices and stem cell derived neurones from AD patients to reveal the underlying HIP-PFC cellular mechanisms for cognitive decline and network dysfunction. This project benefits from an ongoing collaboration between the Manchester and Singapore labs through a prior successful A*Star PhD studentship, so the student will be hosted between sites that are already working well together and have successfully supervised a joint PhD student under the A*Star scheme.

Entry Requirements:
Applications should be submitted online and candidates should make direct contact with the Manchester supervisor to discuss their application directly. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is available to UK/EU candidates. Funding covers fees (UK/EU rate) and stipend for four years. Overseas candidates can apply providing they can pay the difference in fees and are from an eligible country. Candidates will be required to split their time between Manchester and Singapore, as outlined on View Website.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1. Davis K., Burnett K. and Gigg J. (2017) Water and T-maze protocols are equally efficient methods to assess spatial memory in 3xTg Alzheimer’s disease mice. Behav. Brain Res. 331: 54-66.
2. Davis K., Fox S. and Gigg J. (2014) Increased hippocampal excitability in the 3xTgAD model for Alzheimer’s disease in vivo. PLoS One, DOI: 10.1371/journal.pone.0091203
3. Davis, K., Eacott, M., Easton, A. and Gigg, J. (2013) Episodic-like what-where-which occasion memory is sensitive to AD pathological accumulation and normal ageing processes in mouse. Behav. Brain Res. 254:73-82
4. Davis, K., Easton, A., Eacott, M. and Gigg, J. (2013) Episodic-like memory for What-Where-Which Occasion is selectively impaired in the 3xTgAD mouse model of Alzheimer's Disease. J. Alz. Disease 33:681-95

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