Phasic Activation of Dorsal Raphe Serotonergic Neurons Increases Pupil Size

Abstract

Summary Transient variations in pupil size (PS) under constant luminance are coupled to rapid changes in arousal state, 1 , 2 , 3 which have been interpreted as vigilance, 4 salience, 5 or a surprise signal. 6 , 7 , 8 Neural control of such fluctuations presumably involves multiple brain regions 5 , 9 , 10 , 11 and neuromodulatory systems, 3 , 12 , 13 but it is often associated with phasic activity of the noradrenergic system. 9 , 12 , 14 , 15 Serotonin (5-HT), a neuromodulator also implicated in aspects of arousal 16 such as sleep-wake transitions, 17 motivational state regulation, 18 and signaling of unexpected events, 19 seems to affect PS, 20 , 21 , 22 , 23 , 24 but these effects have not been investigated in detail. Here we show that phasic 5-HT neuron stimulation causes transient PS changes. We used optogenetic activation of 5-HT neurons in the dorsal raphe nucleus (DRN) of head-fixed mice performing a foraging task. 5-HT-driven modulations of PS were maintained throughout the photostimulation period and sustained for a few seconds after the end of stimulation. We found no evidence that the increase in PS with activation of 5-HT neurons resulted from interactions of photostimulation with behavioral variables, such as locomotion or licking. Furthermore, we observed that the effect of 5-HT on PS depended on the level of environmental uncertainty, consistent with the idea that 5-HT could report a surprise signal. 19 These results advance our understanding of the neuromodulatory control of PS, revealing a tight relationship between phasic activation of 5-HT neurons and changes in PS.

Increasing central serotonin with 5-HTP disrupts the inhibition of social gaze in non-human primates

“…More specifically, we found that the change in pupil size was correlated with change in performance such that the more 5-HTP constricted the pupil during a session, the more it also impaired performance. In contrast to our results, SSRIs have been shown to dilate the pupil (McDougal and Gamlin, 2011), as does phasic activation of serotonergic neurons (Cazettes et al, 2020). Furthermore, serotonin syndrome, associated with pathologically high levels of serotonin, is also associated with pupil dilation (Alusik et al, 2014).…”

The Neuroscience of the Flow State: Involvement of the Locus Coeruleus Norepinephrine System

“…In addition, Ulrich et al (2016) argued that, via serotoninergic output, the dorsal raphe nucleus downregulates the medial prefrontal cortex (a key structure of the DMN) during flow. Phasic serotonin responses in this nucleus have also been found to influence pupil responses (Cazettes et al, 2021). Therefore, future research may want to try to disentangle the specific influences of the various neuromodulatory systems.…”

A unified model of the task-evoked pupil response

“…This so-called “task-evoked” pupil response is modulated in amplitude by task demands, behavioral performance, and surprise [13, 14, 15, 16, 17, 18, 19, 20, 21]. Pupil responses covary with sweating and cardiac activity [22, 23], measures of peripheral autonomic activity, as well as spiking activity in the locus coeruleus [24, 25, 26, 27], basal forebrain [24, 28, 25], and dorsal raphé [20], sources of cortical norepinephrine, acetylcholine, and serotonin, respectively. Based on these observations, many studies have used pupil size as a non-invasive measure of arousal level [29, 30, 31, 32, 33].…”