links between locus coeruleus and Alzheimer's-related cognition

 

Lab rotation project description

You will be given the opportunity to design and collect data from a continuous, naturalistic driving simulation run, with the goal of testing a specific hypothesis about online decision making and working memory. We will provide a theoretical background on the noradrenergic system, its proposed roles in arousal, the stress response, and adaptive cognition, and its neurophysiology. You will be asked to apply the theory you have learned to formulate and test a hypothesis using the simulation approach, and will use pupillometry to estimate the activation of this system while participants perform this task. We will also provide guidance on how to analyse, interpret, and present the data you obtain from a few runs using their simulation.

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MCO

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BBSRC Doctoral Training Partnerships
 

Linked PhD Project Outline

The locus coeruleus (LC) system is a small, elongated brainstem structure containing the majority of noradrenergic (NE)-expressing neurons in the brain. This system is critical for the human stress response, but is also involved in long-term potentiation and adaptive aspects of working memory and decision-making processes. Recent studies have identified early-life occurrences of Alzheimer's disease (AD)-related tau pathology, excluded largely to the LC. Tau is a microtubule-associated protein, and misfolding of this molecule leads to the dysfunction and ultimately structural degradation of affected neurons. This and a growing body of corroborating evidence has implicated the LC/NE system in the aetiology of AD, which suggests that early changes to its function could be an indication of concomitant AD onset. 

The proposed project will utilise a continuous highway driving task, in conjunction with EEG and pupillometry, to challenge the LC/NE system in a naturalistic way. This paradigm has formerly been developed by Dr. Reid and will be customized in order to investigate the relationship of LC/NE activity to decision-making processes under varying levels of simultaneous cognitive load. Pupillometry has been strongly linked to LC firing in both animals and humans, and will be used as a proxy measure for LC function in this approach. Preliminary evidence from this approach, obtained from ~40 participants, indicates a strong, transient pupil response during decision points in the task, with stronger responses associated with more difficult decisions.

You will be involved in designing a novel implementation of the driving paradigm, in order to investigate whether working memory (WM), which declines early in AD onset, is related to pupil changes and EEG phenomena. You will use this novel task to collect data from both young and elderly (cognitively normal) participants, to characterize relationships between these variables, and how they change with age. These results will form a critical basis for future investigations into whether LC/NE function can be used to predict the onset of AD.

It is unclear how WM demands might modulate LC/NE activity. This project will test the hypothesis that WM demands result in increased LC/NE activity when WM cues are recognized and correctly utilized, but not otherwise. Decreased WM ability, and age-related differences in this ability, should therefore be reflected in decreased pupil dilation at decision points. For EEG, the methodology developed by Dr. Ison for the analysis of concurrent EEG and eye movements recordings will be applied. In particular, it is hypothesised that the LC/NE response should be reflected in the amplitude of the P300 event-related component, which has been shown to decline with age. This P300 amplitude should reflect the cortical neural activity related to decision-making events, and WM cues are expected to attenuate this association.

Altogether, this project will provide a novel way to assess cognitive-related indicators that could be used to predict early onset of AD in a non-invasive and naturalistic task.

 

Biotechnology and Biological Sciences Doctoral Training Programme

The University of Nottingham
University Park
Nottingham, NG7 2RD

Tel: +44 (0) 115 8466946
Email: bbdtp@nottingham.ac.uk