Cortisol effects on pupil size and locus coeruleus activity

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

The regulation of behaviour is a higher-order cognitive function that is guided by attention.
Intrinsic and extrinsic factors, such as behavioural relevance and physical salience, as well as
the reward value of an event or stimulus can modulate behaviour by influencing attention. In
stress, attention is biased towards bottom-up salience and behaviour is modulated so that is
stimulus-driven and conducive to survival, rather than being goal-directed. The Locus
Coeruleus (LC) is a small norepinephrine (NE) nucleus residing in the dorsal pons that has an
essential role in arousal and attention, as well as strong links with the stress responsive
hypothalamic-pituitary-adrenal (HPA) axis. In a manner akin to the attentional control of
behaviour, the LC responds to both top-down and bottom-up salience in animals, so theories
have proposed a role for the LC in attentional control. However, whether this function
translates to humans is unclear due to the challenges of imaging the brainstem, which prevent
the non-invasive investigation of the LC.
The measure of pupil size provides a non-invasive index of LC activity, as stimuli with topdown and bottom-up salience evoke short bursts of firing in the LC as well as transient pupil
dilations. In addition, a change in arousal induces coincident fluctuations in baseline LC
activity and baseline pupil size. This thesis reports a series of experiments, in which human LC
function was explored in human volunteers by implementing an adapted auditory oddball
task with concurrent pupillometry. Transient pupil dilations were evoked by task relevant and
low probability events, and the effect of task relevance on the pupil was amplified by
incentive salience when a reward manipulation was added to the task. In addition to the
transient effect on pupil dilation, reward incentives evoked an increase in baseline pupil size.
This evidence indicates a role for the human LC in the processes underlying these different
types of salience.
Cortisol is the main end product of the HPA axis in humans and administering cortisol receptor
antagonists disrupted the transient effect of incentive salience on the pupil compared with
placebo. In contrast, an antagonist of the NE beta adrenoceptor enhanced the transient effect
of incentive salience on the pupil. In addition, administration of a stress-level dose of cortisol
disrupted the tonic but not the phasic effect of incentive salience on the pupil. This suggests
that cortisol and NE modulate the underlying processes of incentive salience, such as extrinsic
motivation, via the LC. Implications for a maladaptive stress system, including the LC, is
discussed in relation to the development of apathy, with disrupted attentional control and
extrinsic motivation. In addition, this technique has allowed me to demonstrate both cortisol
and NE regulation of LC activity. Therefore, this thesis demonstrates that human LC function
can be investigated with the non-invasive measure of pupillometry
Date of Award24 Jun 2021
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorIain D Gilchrist (Supervisor) & Stafford L Lightman (Supervisor)

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