Locus coeruleus norepinephrine activity mediates sensory-evoked awakenings from sleep

Hayat, Hanna; Regev, Noa; Matosevich, Noa; Sales, Anna C; Paredes-Rodriguez, Elena; Krom, Aaron J; Bergman, Lottem; Li, Yong; Lavigne, Marina; Kremer, Eric J.; Yizhar, Ofer; Pickering, Anthony; Nir, Yuval

doi:10.1126/sciadv.aaz4232

Cited by 172 publications

(192 citation statements)

References 56 publications

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“…Although the LC is limited in size (~3mm caudorostrally) and buried deep within the brainstem [78,79], several studies have successfully recorded from single neurons in LC of the macaque [26,27,[80][81][82][83][84]. In addition, LC can be activated using optogenetics [85][86][87][88], electrical microstimulation [14,16,58], and pharmacological manipulations [17,89,90]. Thus, it should be possible to alter the course of slow drift in the cortex using some, if not all, of these methods.…”

Section: Discussionmentioning

confidence: 99%

The eyes reflect an internal cognitive state hidden in the population activity of cortical neurons

Johnston

Snyder

Khanna

et al. 2020

Preprint

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SummaryDecades of research have shown that global brain states such as arousal can be indexed by measuring the properties of the eyes. Neural signals from individual neurons, populations of neurons, and field potentials measured throughout much of the brain have been associated with the size of the pupil, small fixational eye movements, and vigor in saccadic eye movements. However, precisely because the eyes have been associated with modulation of neural activity across the brain, and many different kinds of measurements of the eyes have been made across studies, it has been difficult to clearly isolate how internal states affect the behavior of the eyes, and vice versa. Recent work in our laboratory identified a latent dimension of neural activity in macaque visual cortex on the timescale of minutes to tens of minutes. This ‘slow drift’ was associated with perceptual performance on an orientation-change detection task, as well as neural activity in visual and prefrontal cortex (PFC), suggesting it might reflect a shift in a global brain state. This motivated us to ask if the neural signature of this internal state is correlated with the action of the eyes in different behavioral tasks. We recorded from visual cortex (V4) while monkeys performed a change detection task, and the prefrontal cortex, while they performed a memory-guided saccade task. On both tasks, slow drift was associated with a pattern that is indicative of changes in arousal level over time. When pupil size was large, and the subjects were in a heighted state of arousal, microsaccade rate and reaction time decreased while saccade velocity increased. These results show that the action of the eyes is associated with a dominant mode of neural activity that is pervasive and task-independent, and can be accessed in the population activity of neurons across the cortex.

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Section: Discussionmentioning

confidence: 99%

The eyes reflect an internal cognitive state hidden in the population activity of cortical neurons

Johnston

Snyder

Khanna

et al. 2020

Preprint

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“…In human patients, invasive VNS induces markers of brain arousal that are consistent with LC-NE activity such as pupil dilation (Desbeaumes Jodoin et al, 2015) that is tightly linked with LC-NE activity (Joshi et al, 2016;Reimer et al, 2016;Gelbard-Sagiv et al, 2018;Hayat et al, 2020). VNS may also lead to EEG desynchronization, but effects are subtler than pupil dilation, at least with the clinical parameters that typically employ long (30-60s) stimulation epochs.…”

Section: Introductionmentioning

confidence: 99%

Transcutaneous vagus nerve stimulation in humans induces pupil dilation and attenuates alpha oscillations

Sharon

Fahoum

Nir

2020

Preprint

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Vagus nerve stimulation (VNS) is widely used to treat drug-resistant epilepsy and depression. While the precise mechanisms mediating its long-term therapeutic effects are not fully resolved, they likely involve Locus Coeruleus (LC) stimulation via the nucleus of the solitary tract (NTS) that receives afferent vagal inputs. In rats, VNS elevates LC firing and forebrain noradrenaline (NE) levels, whereas LC lesions suppress VNS therapeutic efficacy. Non-invasive transcutaneous VNS (tVNS) employs electrical stimulation targeting the auricular branch of the vagus nerve at the Cymba Conchae of the ear, but it remains unclear to what extent tVNS mimics VNS. Here, we investigated the short-term effects of tVNS in healthy human male volunteers (n=24) using high-density EEG and pupillometry during visual fixation at rest, comparing short (3.4s) trials of tVNS to sham electrical stimulation at the earlobe (far from the vagus nerve branch) to control for somatosensory stimulation. Although tVNS and sham stimulation did not differ in subjective intensity ratings, tVNS led to robust pupil dilation (peaking 4-5s after trial onset) that was significantly higher than following sham stimulation. We further quantified how tVNS modulates idle occipital alpha (8-13Hz) activity, identified in each participant using parallel factor analysis. We found that tVNS attenuates alpha oscillations to a greater extent than does sham stimulation. Thus, tVNS reliably induces pupillary and EEG markers of arousal beyond the effects of somatosensory stimulation, supporting the hypothesis that it elevates noradrenaline and acetylcholine signaling and mimics invasive VNS.

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“…Not only LC, the parameters of micro-stimulations and time lag of modulatory effects may also apply to other neuromodulatory nuclei. Although there is growing studies that activated LC optogenetically (Carter et al, 2010;Breton-Provencher & Sur, 2019;Hayat et al, 2020), future studies could selectively activate LC and record from sensory cortices to confirm the specificity of the observed modulations both in spontaneous and evoked activities. Locus Coeruleus (LC).…”

Section: Discussionmentioning

confidence: 99%

“…The role of LC-NE system in changing cortical state is implicated in several studies (Lee & Dan, 2012;Marzo et al, 2014;Zagha & McCormick, 2014;Fazlali et al, 2016;Hayat et al, 2020;Ranjbar-Slamloo & Fazlali, 2020). The change in cortical state can be quantified using a low-to-high (LH) EEG power ratio (Fazlali et al 2016).…”

Section: Lc Activity and Cortical Statementioning

confidence: 99%

“…Locus Coeruleus-norepinephrine (LC-NE) system has widespread projections throughout the brain and affects neuronal activity, network dynamics, and task-relevant perceptual behavior (Berridge & Waterhouse, 2003;Sara, 2009;Sara & Bouret, 2012;Waterhouse & Navarra, 2019). Previous studies have revealed a prominent role of LC-NE system in controlling behavioral and brain states (Aston-Jones & Bloom, 1981a;Berridge & Waterhouse, 2003;Aston-Jones & Cohen, 2005;Carter et al, 2010;Fazlali et al, 2016;Hayat et al, 2020) as well as modulation of sensory processing (Waterhouse et al, 1998;Berridge & Waterhouse, 2003;Lecas, 2004;Manunta & Edeline, 2004a;Devilbiss & Waterhouse, 2004Edeline et al, 2011;Vazey et al, 2018;Rodenkirch et al, 2019). Inhibition of both spontaneous and sensory-evoked cortical activity is well documented in classic experiments that used either LC electrical micro-stimulation or local application of norepinephrine (NE) (Foote et al, 1975;Phillis & Kostopoulos, 1977).…”

Section: Introductionmentioning

confidence: 99%

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Stimulation of Locus Coeruleus Noradrenergic System Modulates Sensory Processing and Brain State in two Different Time Scales

Fazlali

Ranjbar-Slamloo

Arabzadeh

2020

Preprint

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AbstractLocus Coeruleus (LC) noradrenergic system has widespread projections throughout the brain and affects sensory processing in various modalities. Inhibition of both spontaneous and sensory-evoked cortical activity is well-documented in early experiments by either LC electrical micro-stimulation or local application of norepinephrine (NE). However, the temporal profile of LC modulation of sensory response is not well-established. Here, we recorded neuronal activity from the rat barrel cortex under urethane anesthesia and coupled LC micro-stimulation with brief mechanical deflection of whiskers at 10 different time lags (50-500 ms). LC micro-stimulation exhibited a biphasic effect on BC spontaneous activity: a period of suppression (~100 ms) followed by a period of excitation (~200 ms). This profile was highly consistent across BC units: 82% of BC units showed early suppression and 91% of BC units showed late excitation. We observed a similar effect on the sensory-evoked response: at 50-ms lag, the evoked response (1-75 ms after deflection onset) decreased in 77% of units and at 150-ms lag, the early evoked response was facilitated in 85% of units. At 150 to 350-ms time lags, LC micro-stimulation caused a combined facilitation followed by suppression on the evoked response. For lags of 400-ms and higher, the effect was pure facilitation. Additionally, response latency was significantly decreased at 250 ms time lag. In summary, we found that LC modulation affects the cortical processing of sensory inputs in a complex manner which critically depends on the time lag between LC activation and sensory input. These results have clear implications for temporal integration of sensory input and its noradrenergic modulation in a behavioral setting.

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Locus coeruleus norepinephrine activity mediates sensory-evoked awakenings from sleep

Cited by 172 publications

References 56 publications

The eyes reflect an internal cognitive state hidden in the population activity of cortical neurons

The eyes reflect an internal cognitive state hidden in the population activity of cortical neurons

Transcutaneous vagus nerve stimulation in humans induces pupil dilation and attenuates alpha oscillations

Stimulation of Locus Coeruleus Noradrenergic System Modulates Sensory Processing and Brain State in two Different Time Scales

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