By Anne Urai and Thomas Meindertsma.

Last week, we read the latest paper from Josh Gold’s lab: Joshi et al. Relationships between Pupil Diameter and Neuronal Activity in the Locus Coeruleus, Colliculi, and Cingulate Cortex. Neuron (2016).

The pupil dilates not only in response to changes in light intensity in the environment, but also reflects activity of the autonomic arousal system. In the 60s, it was already shown that pupil diameter reflects the mental effort someone’s putting in a task. For example, the pupil is larger when you’re trying to multiply two 3-digit numbers in your head, than when you’re computing 4+4. More recent research has found that the pupil dilates and constricts in response to changes in specific cognitive variables such as attention, surprise and modulation of learning rates. Many different cognitive variables thus produce changes in this single physiological measure –suggesting that all these cognitive variables share a neurobiological mechanism that also produces changes in pupil size.

One candidate for such a shared mechanism that drives fluctuations in pupil size is the release of noradrenaline (NA) by the locus coeruleus (LC). Knowing that the pupil reflects LC-NA activity would allows us to think of mechanistic interpretations of how noradrenaline might influence cortical state and behavior during our own tasks in humans. Indeed, several studies have directly investigated the effects of changes in pupil size on neural processing in the cortex, and found effects that fit very naturally with known effects of this LC-NA system. Previous work has indeed reported positive correlations between task-related pupil dilation and changes in the firing rates of LC neurons (Varazzani et al. 2015). During rest, a Society for Neuroscience Meeting abstract from 1993 reported a strong resemblance between slow fluctuations in both pupil and LC during a one hour-long recording of those two signals (Rajkowski et al, 1993). However, it is unclear to what extend pupil and LC signals co-vary at finer time scales and how this compares to the link between other brainstem regions and pupil.

Joshi et al. (2016) expand on this evidence by systematically comparing LC activity and pupil size with high temporal resolution during resting state, task-evoked responses; they further measured pupil responses to electrical micro-stimulation of the LC. They measured pupil size in five monkeys, while they simultaneously recorded from the locus coeruleus, but also other structures that have been linked to pupil size fluctuations: the superior and inferior colliculi and the anterior and posterior cingulate cortices. Using a range of recording and analysis techniques combined with microstimulation, they find compelling evidence that locus coeruleus activity co-occurs with pupil dilation on both short and longer timescales. Activity in the inferior colliculus similarly correlates with pupil size, whereas the other recorded areas showed a more variable pattern of pupil co-occurrence. Furthermore, they show a consistent difference in latency between pupil dilation and activity at these different recording sites, thereby providing a means to constrain possible mechanistic models.

Three important points must be kept in mind when interpreting the correlation between pupil and LC activity. First, average firing rates of LC neurons recorded by Joshi et al. were typically low (less then 5 spikes per second). This raises the question whether a single LC neuron fluctuates enough to account for the continuous, ongoing fluctuations in pupil size. Future recordings of multiple LC neurons simultaneously could clarify how strongly individual LC neutrons are correlated among each other, and to what extend population LC activity explains fluctuations in pupil size.

Second, although quite a lot is known about the peripheral apparatus controlling pupil dilation and constriction, there is ongoing debate about how exactly neural firing in LC relates to pupil dilations: direct projections from LC to brainstem nuclei controlling pupil size have never been found. Joshi et al. show that microstimulation of the LC causes pupil dilation, but it has been suggested that this artificial electrical stimulation causes antidromic activation (back up along the axon) of the nucleus paragigantocellularis, which has previously been suggested as the common source driving both pupil dilation and LC (Nieuwenhuis et al. 2011). Alternatively, it has been proposed that LC might drive pupil dilation via a circuit involving the superior colliculus and the mesencephalic cuneiform nucleus (Wang & Munoz, 2015), although this alternative is inconsistent with the latency differences reported in the study we discuss here. To complete a circuit diagram detailing which brain areas drive the muscles controlling pupil size, more anatomical and tracing studies are needed.

Lastly, researchers can be tempted to interpret pupil findings as reflecting noradrenaline release from the LC, but an exclusive link between pupil and LC-NE activity has not been shown. Indeed, Joshi et al. show that the inferior colliculus in many ways correlates to pupil dilation as strongly as LC. Moreover, other neuromodulatory systems that were not measured in this study, such as the dopamine and acetylcholine system, could well play a role in driving pupil dilation and constriction. In sum, Joshi et al. provide one important step on a long road towards a detailed diagram of the brain circuits driving fluctuations in pupil size.

Further reading

Costa, V.D., and Rudebeck, P.H. (2016). More than Meets the Eye: the Relationship between Pupil Size and Locus Coeruleus Activity. Neuron 89, 8–10.

Linking pupil dilation to neural activity in the locus coeruleus
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