Pupil fluctuations track fast switching of cortical states during quiet wakefulness

“Responses to external stimuli are strongly modulated by the brain’s internal dynamics, which are organized around characteristic states that vary with arousal, attention, and behavioral context (Harris and Thiele, 2011; Iriki et al., 1996; Kahneman, 1973; Lee and Dan, 2012).”

“Surprising and provocative stimuli produce a transient increase in pupil size (Bradley et al., 2008; Hess and Polt, 1960, 1964; Libby et al., 1973; Preuschoff et al., 2011), and pupil dilation preceding stimulus onset is correlated with faster reaction times in psychophysical tasks (Kristjansson et…”

“We found that our SOM+ Cre driver line (SST-IRES-Cre; Taniguchi et al., 2011) labeled a population of neurons that could be grouped into two distinct classes, which we call Type I and Type II.”

“For almost half a century, pupillometry has been widely used to index covert changes in attention and effort in humans and nonhuman primates (Gilzenrat et al., 2010; Hess and Polt, 1960, 1964; Iriki et al., 1996; Kahneman, 1973; Kahneman and Beatty, 1966; Kristjansson et al., 2009; Onorati et al., 2013; Wierda et al.,…”

“High-frequency oscillations in the gamma range were also enhanced during activity compared to quiet wakefulness (Figure S1B), consistent with previous reports (Niell and Stryker, 2010).”

“…century, pupillometry has been widely used to index covert changes in attention and effort in humans and nonhuman primates (Gilzenrat et al., 2010; Hess and Polt, 1960, 1964; Iriki et al., 1996; Kahneman, 1973; Kahneman and Beatty, 1966; Kristjansson et al., 2009; Onorati et al., 2013; Wierda et…”

“High-frequency oscillations in the gamma range were also enhanced during activity compared to quiet wakefulness (Figure S1B), consistent with previous reports (Niell and Stryker, 2010).”

“Given the close relationship between pupil diameter, locus coeruleus activity and sympathetic tone (Aston-Jones et al., 1999; Bradley et al., 2008; Gilzenrat et al., 2010), our data suggest a role for norepinephrine in the regulation of cortical state.”

“…century, pupillometry has been widely used to index covert changes in attention and effort in humans and nonhuman primates (Gilzenrat et al., 2010; Hess and Polt, 1960, 1964; Iriki et al., 1996; Kahneman, 1973; Kahneman and Beatty, 1966; Kristjansson et al., 2009; Onorati et al., 2013; Wierda et…”

“Responses to external stimuli are strongly modulated by the brain’s internal dynamics, which are organized around characteristic states that vary with arousal, attention, and behavioral context (Harris and Thiele, 2011; Iriki et al., 1996; Kahneman, 1973; Lee and Dan, 2012).”

“In these mice, the retinal ganglion cell layer undergoes severe degeneration by P21 (Chang et al., 2002).”

“For almost half a century, pupillometry has been widely used to index covert changes in attention and effort in humans and nonhuman primates (Gilzenrat et al., 2010; Hess and Polt, 1960, 1964; Iriki et al., 1996; Kahneman, 1973; Kahneman and Beatty, 1966; Kristjansson et al., 2009; Onorati et al.,…”

“Consistent with previous studies (Bennett et al., 2013; Crochet and Petersen, 2006; Niell and Stryker, 2010; Polack et al., 2013; Poulet and Petersen, 2008; Zagha et al., 2013), we found that during exploratory behaviors (running and/or whisking), V m in both S1 and V1 was desynchronized (red…”

“We performed whole-cell patching and two-photon calcium imaging in awake mice (Bennett et al., 2013; Niell and Stryker, 2010; Polack et al., 2013) and focused our analysis on quiet periods between epochs of running and whisking.”

“However, the potential contribution of other neuromodulators such as acetylcholine (Goard and Dan, 2009; Pinto et al., 2013) is also strongly suggested by the fact that the VIP+ activation during running has been shown to depend on cholinergic input from the diagonal band of Broca (Fu et al.”

“Specifically, recent work in awake mice has revealed that the cortex is desynchronized during bouts of exploratory behavior, such as whisking (Crochet and Petersen, 2006; Poulet and Petersen, 2008) and running (Bennett et al., 2013; Niell and Stryker, 2010; Polack et al., 2013), compared to…”

“Surprising and provocative stimuli produce a transient increase in pupil size (Bradley et al., 2008; Hess and Polt, 1960, 1964; Libby et al., 1973; Preuschoff et al., 2011), and pupil dilation preceding stimulus onset is correlated with faster reaction times in psychophysical tasks (Kristjansson et…”

“However, the potential contribution of other neuromodulators such as acetylcholine (Goard and Dan, 2009; Pinto et al., 2013) is also strongly suggested by the fact that the VIP+ activation during running has been shown to depend on cholinergic input from the diagonal band of Broca (Fu et al., 2014).”

“Type I SOM+ cells, which were the majority ( n =21/30), exhibited the characteristic low V m variability described by Petersen and colleagues (Gentet et al., 2012), and these cells were inhibited during active epochs of running and whisking (−2.1±0.47 mV; P <0.001 Wilcoxon signed-rank test; Figure…”

“For example, primate cortex is more desynchronized during attentive states (Gould et al., 2011; Grent-’t-Jong et al., 2011; Rohenkohl and Nobre, 2011), and in REM sleep compared to deeper sleep stages (Colten and Altevogt, 2006).”

“For almost half a century, pupillometry has been widely used to index covert changes in attention and effort in humans and nonhuman primates (Gilzenrat et al., 2010; Hess and Polt, 1960, 1964; Iriki et al., 1996; Kahneman, 1973; Kahneman and Beatty, 1966; Kristjansson et al., 2009; Onorati et al., 2013; Wierda et al.,…”

“Surprising and provocative stimuli produce a transient increase in pupil size (Bradley et al., 2008; Hess and Polt, 1960, 1964; Libby et al., 1973; Preuschoff et al., 2011), and pupil dilation preceding stimulus onset is correlated with faster reaction times in psychophysical tasks (Kristjansson et…”

“We performed whole-cell patching and two-photon calcium imaging in awake mice (Bennett et al., 2013; Niell and Stryker, 2010; Polack et al., 2013) and focused our analysis on quiet periods between epochs of running and whisking.”

“…with previous studies (Bennett et al., 2013; Crochet and Petersen, 2006; Niell and Stryker, 2010; Polack et al., 2013; Poulet and Petersen, 2008; Zagha et al., 2013), we found that during exploratory behaviors (running and/or whisking), V m in both S1 and V1 was desynchronized (red horizontal…”

“For example, primate cortex is more desynchronized during attentive states (Gould et al., 2011; Grent-’t-Jong et al., 2011; Rohenkohl and Nobre, 2011), and in REM sleep compared to deeper sleep stages (Colten and Altevogt, 2006).”

“In mouse primary visual cortex (V1), this desynchronization is coupled with an enhancement of sensory responses (Fu et al., 2014; Froudarakis et al., 2014) and a reduction in detection thresholds (Bennett et al., 2013), and similar effects are seen in primary somatosensory cortex (area S1; Zagha et…”

“, 2011) labels subpopulations of interneurons with different in vivo functional properties has not been previously reported, a recent in vitro study using these mice found two electrophysiologically distinct populations of labeled cells in almost the same proportions that we observed here (Hu et al., 2013).”

“Approximately 90% of these epochs were accompanied by an increase in pupil size (Figure 1B,D; mean increase in pupil diameter during running periods 202±11 μm, mean ± SEM; see Methods).”

“Interestingly, theoretical work has suggested that alternating between bottom-up and top-down processing may be an efficient learning mechanism for the cortex to build a representation of the external world (Hinton, 2010).”

“Responses to external stimuli are strongly modulated by the brain’s internal dynamics, which are organized around characteristic states that vary with arousal, attention, and behavioral context (Harris and Thiele, 2011; Iriki et al., 1996; Kahneman, 1973; Lee and Dan, 2012).”

“…provocative stimuli produce a transient increase in pupil size (Bradley et al., 2008; Hess and Polt, 1960, 1964; Libby et al., 1973; Preuschoff et al., 2011), and pupil dilation preceding stimulus onset is correlated with faster reaction times in psychophysical tasks (Kristjansson et al., 2009).”

“For example, primate cortex is more desynchronized during attentive states (Gould et al., 2011; Grent-’t-Jong et al., 2011; Rohenkohl and Nobre, 2011) and in REM sleep compared to deeper sleep stages (Colten and Altevogt, 2006).”

“For almost half a century, pupillometry has been widely used to index covert changes in attention and effort in humans and nonhuman primates (Gilzenrat et al., 2010; Hess and Polt, 1960, 1964; Iriki et al., 1996; Kahneman, 1973; Kahneman and Beatty, 1966; Kristjansson et al., 2009; Onorati et al., 2013; Wierda et al.,…”

“Nonprimate mammals also display a spectrum of cortical dynamics during waking periods, from more synchronized to more desynchronized states, and this internal variability modulates responses to external stimuli (Hei et al., 2014; Zhuang et al., 2014).”

“Non-primate mammals also display a spectrum of cortical dynamics during waking periods, from more synchronized to more desynchronized states; and this internal variability modulates responses to external stimuli (Hei et al., 2014; Zhuang et al., 2014).”

“Pupil diameter also can covary with neuronal activity in cortex, which is thought to reflect, at least in part, modulation by the LC-NE system (Vinck et al., 2015; Reimer et al., 2014; Ebitz and Platt, 2015; Eldar et al., 2013; McGinley et al., 2015).”

“In addition, it has been increasingly recognized that the SOM-Cre driver line (SOM-IRESCre) (31) labels a population of neurons that can be grouped into distinct types both functionally (19, 32) andmorphologically (fig.”

“In addition, levels of arousal vary during wake and correlate with pupil diameter, eyelid position, and sharp wave ripples in hippocampus (Eldar et al., 2013; McGinley et al., 2015; Reimer et al., 2014).”

“…et al., 2007; Gentet et al., 2010; Haider et al., 2013; Lee et al., 2013; McGinley et al., 2015; Nelson et al., 2013; Niell and Stryker, 2010; Polack et al., 2013; Poulet and Petersen, 2008; Reimer et al., 2014; Scholvinck et al., 2015; Vinck et al., 2015; Zagha et al., 2013; Zhou et al., 2014).”

“generated by an internal cognitive event) and its size and profile are therefore highly variable, presumably reflecting how mental effort and arousal evolve over time (e.g. Mathôt, Siebold, Donk, & Vitu, 2015a; Reimer et al., 2014).”

“…(e.g., movement) states (Bennett et al., 2013; Erisken et al., 2014; Fontanini and Katz, 2008; Polack et al., 2013; Poulet and Petersen, 2008; Reimer et al., 2014; Schneider et al., 2014; Schö lvinck et al., 2015; Vinck et al., 2015; Vyazovskiy et al., 2011; Zagha et al., 2013; Zhou et al.,…”

“For example, although in the absence of direct external stimulation the size of the pupil fluctuates in cycles of 1 – 2 s (Mathôt, Siebold, Donk, & Vitu, 2015a; Reimer et al., 2014), it does not show the slow systematic drift shown by EEG/MEG voltages (Tanner et al., 2016).”

“…of waking mice reveals that they are strongly activated by facial movements, locomotion, and arousal (Eggermann et al. 2014, Lee et al. 2014, Reimer et al. 2016), suggesting that these transmitter pathways may participate in the network dynamics associated with the sustained…”

“Phasic versus tonic arousal effects A number of recent studies have characterized the relationship between tonic arousal levels (measured through baseline pupil diameter) and cortical state (McGinley et al., 2015a; Reimer et al., 2014; Vinck et al., 2015; Warren et al., 2016).”

“The authors distinguished two populations of SST interneurons (see Supplementary Figure 5C of Reimer et al., 2014): Type I cells were inhibited by running while Type II cells were depolarized.”

“In mice, pupil dilation is associated with periods of whisking and increases in locomotion (Reimer et al., 2014; McGinley et al., 2015).”

“(C) Schematics of various neuromodulatory signaling mechanisms in neurons, from rapid (top) to persistent (bottom). as neurohormones (Kravitz, 2000; Reiter et al., 2014; White et al., 1986).”

“Pupil size fluctuates in waves of several seconds that reflect the waxing and waning of arousal (Mathôt, Siebold, et al., 2015b; Reimer et al., 2014), and in slower waves that reflect more prolonged states of fatigue and wakefulness (Geacin-tov & Peavler, 1974; Lowenstein et al., 1963).”

“Cortical membrane potential recordings show that the transitions between these states occur on the order of seconds and are precisely correlated with pupil fluctuations (Reimer et al., 2014).”

“Moreover, because pupil size has been shown to tightly co-vary with level of arousal (McGinley et al., 2015a; Nassar et al., 2012; Reimer et al., 2014; Vinck et al., 2015), which involves both the sympathetic andparasympathetic nervous systems, we wanted to further tease apart the contribution of…”

“…imaging sessions, we recorded the movement of the running disk via a custom-built infra-red optical mouse apparatus to distinguish between movement and stationary epochs as this is known to modulate V1 neurons (Fu et al., 2014, Polack et al., 2013, Reimer et al., 2014, Vinck et al., 2015).”

“, 2013), only some of which are suppressed during locomotion (Fu et al., 2014; Reimer et al., 2014).”

“During awake 356 experiments, the mouse was placed on a treadmill with its head restrained beneath the 357 microscope objective (Reimer et al., 2014).”

“…the estimated modulator signals against other neural or physiological signals (e.g. neurotransmitter concentrations, or pupil dilation (McGinley et al., 2015; Reimer et al., 2014), and by comparing the weights with detailed anatomical and functional properties of the neurons in the population.”

“To meet this goal, we took advantage of changes in cortical state that occur naturally [15,18] without experimental control and we also imposed changes in cortical state by tuning cortical inhibitory interactions [19].”

“changes in the gain of neural interactions in the cerebral cortex (Eldar et al., 2013; Reimer et al., 2014).”

“First, we tested the effect of pupil size on visual response magnitude, as has been demonstrated previously [63,64].”

“In addition to movement, many studies measuring neural activity in primary sensory areas have also found correlates of other non-sensory variables, including arousal [20,42,43], reward [44], and thirst [45].”

“Indeed, since themouse pupil dilates during locomotion (Erisken et al., 2014; McGinley et al., 2015a, 2015b; Reimer et al., 2014; Vinck et al., 2015), and since narrowband gamma power depends on light intensity (Figure 3F), it remains possible that the correlation between locomotion and narrowband gamma reflects a gre…”

“Changes in pupil diameter occur on the order of seconds and are associated with alterations in brain activity measured at levels ranging from cellular membrane potential [1,34] to circuit-level synaptic and firing rate synchronization [35] and to brain-wide network coupling [36,37], all of which comprise or reflect br…”

“Even in the awake state, levels of attention and alertness fluctuate over time (Reimer et al., 2014).”

“However, recent results based on population recordings (Reimer et al., 2014; Rabinowitz et al., 2015; Schölvinck et al., 2015) that highlight the extent of brain-state dependent modulation of sensory processing, the discovery of substantial modulation of sensory activity with locomotion (Niell and Stryker, 2010; Polac…”

“Previous studies in head-restrained mice have also reported that the frequency of whisking is increased in the active compared to the quiescent behavioral state (Moore, 2004; Poulet and Petersen, 2008; Reimer et al., 2014).”

“performance and sensory neuron activity (Reimer et al., 2014; McGinley et al., 2015a, 2015b; Vinck et al., 2015; Lee and Margolis, 2016; Schriver et al., 2018).”

“Specifically, the transition from stillness to locomotion was accompanied by a transient increase in PS that remained elevated until locomotion offset (Figure 1D), and locomotion offset was followed by a gradual decrease in PS (Figure 1E).(1,2,27) PS also varied spontaneously during stillness epochs (Figure 1C, event…”

“Indeed, recent work has shown that pupil diameter closely tracks several established measures of cortical arousal state (Larsen and Waters, 2018; McGinley et al., 2015a; McGinley et al., 2015b; Reimer et al., 2014; Vinck et al., 2015).”

“…cells in response to visual stimulation is enhanced (Niell and Stryker, 2010; Polack et al., 2013; Saleem et al., 2013; Reimer et al., 2014), which is accompanied by an increase in the firing frequency of local VIP+ interneurons as well (Fu et al., 2014; Reimer et al., 2014; Jackson et al., 2016).”

“Recent recordings from VIP interneurons found that they also increase their firing rate during locomotion [52–54], while the firing rate of SOMs decreases [52,53].”

“Thus, when animals transition from quiet to active wakefulness, this correlates with suppression of delta oscillations and a concomitant enhancement of gamma oscillations (Niell and Stryker, 2010; Rasmussen et al., 2019; Reimer et al., 2014; Vinck et al., 2015).”

“non-invasive readout of cortical and hippocampal signatures of brain state, in mice (McGinley et al., 2015a; McGinley et al., 2015b; Reimer et al., 2014; Vinck et al., 2015).”

“Because changes in pupil diameter are thought to reflect changes in the balance between sympathetic and parasympathetic tone, one idea is that ascending neuromodulatory inputs alter the global brain state to affect movement and auditory cortical responsiveness in parallel (Reimer et al. 2014).”

“Our findings are consistent with previously reported links between both locomotion-related and pupil-related changes in arousal and LFP recordings in sensory cortices of rodents ( McGinley et al., 2015a ; Reimer et al., 2014 ; Reimer et al., 2016 ).”

“certain types of stimuli may engage feedback connections) [100, 101].”

“However, a more thorough study needs to be performed, because locomotion can be accompanied by whisking (Reimer et al., 2014), which decreases responses to passive whisker touch (Ferezou et al., 2007); in our study, we cannot distinguish these two effects.”

“(Fu et al., 2014; Reimer et al., 2014), are modulated by task engagement (Kuchibhotla et al.”