Biology subjects

Nir, Y.

Publications and source records attributed to Nir, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Progressive neurodegeneration of the locus coeruleus drives rapid eye movement sleep fragmentation

Sleep disturbances are common early features of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). AD progression is also characterized by early and substantial degeneration of the noradrenergic locus coeruleus (LC), beginning with tau pathology and progressing to major neuronal loss. Although LC degeneration and sleep disruption progress in parallel, whether LC degeneration causally contributes to sleep abnormalities, and which sleep changes are associated with this process, remain unresolved. Human studies are largely correlative, while existing rodent models poorly reproduce progressive LC degeneration. Here, we employed progressive Caspase-3 (Casp3)-mediated LC ablation, with longitudinal sleep and calcium fiber photometry to monitor LC activity across defined stages of degeneration in adult female DBH-Cre mice. Histological analysis demonstrated graded, time-dependent LC degeneration, yielding mild degeneration (~25% neuronal loss) by day 8 post Casp3 injection and moderate degeneration (~50% loss) by day 18. Relative to baseline and to control mice, LC degeneration led to REM sleep fragmentation, emerging already at the mild degeneration stage. By the moderate stage, total REM sleep during light hours had significantly increased, while EEG theta power during REM sleep progressively declined across all stages of degeneration. Degeneration also blunted state-dependent LC calcium activity, significantly reducing the contrast between wakefulness and REM signal. Together, these results establish Casp3-mediated ablation as a model of progressive LC neurodegeneration and identify REM fragmentation and blunted state-dependent LC activity as its early functional signatures, providing a platform for studying how degeneration of neuromodulatory systems shapes sleep in a neurodegenerative disease-like state.

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bioRxiv2025

Auditory network persistence of stimulus representation in awake and naturally sleeping mice

Persistent neural activity often outlasts sensory stimulation, bridging perception and action. While commonly linked to working memory and decision making, its existence during passive states and sleep remains unclear. Using chronic high-density electrophysiology in freely behaving mice, we show that population spiking activity across the auditory cortical hierarchy enables decoding of past stimuli long after their offset, during both wakefulness and sleep. Time-resolved decoding revealed that in wakefulness, persistent representations decay uniformly across sensory and association cortices, whereas during sleep, persistence is prolonged in association cortex but remains brief in early auditory regions. Recurrent neural network modeling showed that higher internal noise during wakefulness reproduces this pattern, suggesting that reduced interference during sleep stabilizes sensory traces in associative areas. Our results demonstrate that persistent representation is a passive, state-dependent feature of sensory processing, supporting sensory maintenance even in the absence of active engagement.

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bioRxiv2025

Sleep Renormalizes Negative Emotional Generalization

Overgeneralization of negative experiences, in which aversive responses spread to otherwise safe stimuli, often co-occurs with sleep disruption, and both are central features of anxiety and posttraumatic stress disorder (PTSD). Here, we show that sleep shifts emotional generalization away from the negative and toward the positive. Across three experiments combining behavior, fMRI, and sleep electrophysiology, participants learned to associate three faces with positive, negative, or neutral outcomes. Participants were tested using morphed faces that blended the original stimuli in varying proportions. Immediate generalization was assessed post-learning, and delayed generalization was assessed after overnight sleep or daytime wakefulness. Behaviorally, we found that sleep selectively promotes positive generalization, whereas prolonged daytime wakefulness favors generalization of the negative face. In the fMRI scanner, amygdala and limbic activity during outcome processing predicted stronger immediate generalization of the negative face, and subsequent shift from negative to positive face generalization that occurred only after sleep. Overnight sleep spindle activity, extracted from high-density sleep EEG, positively correlated both with positive face generalization and with the shift from negative to positive generalization following sleep. These findings reveal a potential neural mechanism by which sleep attenuates negative bias and enhances positive representations, suggesting a potential method to buffer against maladaptive generalization in anxiety and PTSD.

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bioRxiv2025

Auditory Perception Induces Cortical and Thalamic Event-Related Desynchronization in the Mouse

Studies of human perception have shown early cortical signals for primary information encoding, and later signals for higher order processing. An important late signal is the cortical event-related desynchronization (ERD) in the alpha (8-12Hz) and beta (12-30Hz) frequency band, which has been linked to human perceptual awareness. Detailed mechanistic investigation of the ERD would be greatly facilitated by availability of a suitable animal model. We conducted local field potential recordings in the mouse frontal association cortex (FrA), thalamic intralaminar centrolateral nucleus (Cl), primary auditory cortex (A1), and primary visual cortex (V1) during two auditory tasks. Fully audible brief 50 ms stimuli with both tasks produced early broadband gamma (30-100Hz) frequency activity at 0-250ms, followed by a late cortical alpha/beta ERD 250 - 750 ms after stimulus onset. The ERD was statistically significant in FrA and A1, but not in V1. Interestingly, a significant ERD was also observed in thalamic Cl. The magnitude of the ERD at full stimulus intensity, and the slope of the relationship between stimulus intensity versus ERD magnitude, were both largest in FrA, and smaller in Cl and A1. Conversely, for early broadband gamma activity the magnitude at full intensity and slopes were largest in A1, smaller in Cl and smaller still in FrA. These findings suggest that mice, like humans, process perceptual signals in hierarchically organized corticothalamic networks, and strongly support mice as a promising platform for further investigation of the ERD to better understand the origin and function of this robust yet understudied electrophysiological phenomenon. Significance StatementAuditory-induced alpha/beta event-related desynchronizations (ERDs), decreases in cortical activity between 8 and 30Hz following auditory stimulus presentation, are thought to represent systems underlying higher perception and cognition. However, fundamental mechanistic studies are difficult in humans, the dominant organism for studying this phenomenon. In this study we assess mice as a potential alternative model organism. Our results demonstrate that mice exhibit auditory-induced alpha/beta ERDs, that this response is also present in subcortical regions of the mouse brain, and that the cortical ERD is largest and most strongly related to auditory stimulus amplitude in association cortex rather than in primary auditory cortex. These results support the efficacy of mice as an ideal model organism for further examination of alpha/beta ERDs.

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bioRxiv2025

An early surge of norepinephrine along brainstem pathways drives sensory-evoked awakening

The locus coeruleus norepinephrine (LC-NE) system regulates arousal and awakening; however, it remains unclear whether the LC does this in a global or circuit specific manner. We hypothesized that sensory-evoked awakenings are predominantly regulated by specific LC-NE efferent pathways. Anatomical, physiological, and functional modularities of LC-NE pathways involving the mouse basal forebrain (BF) and pontine reticular nucleus (PRN) were tested. We found partial anatomical segregation between the LC->PRN and LC->BF circuits. Extracellular NE dynamics in BF and PRN exhibited distinct sound-evoked activation during sleep, including a fast sound-evoked NE peak specific to PRN. Causal optogenetic interrogation of LC efferent pathways, by retro-ChR2 activation or PdCO silencing of synapses in target regions, revealed a pivotal role for early LC->PRN activity in driving arousal and sound-evoked awakenings. Together, our results uncover a prominent role for early LC-NE PRN activity in connecting sensory and arousal pathways and establish LC heterogeneity in regulating arousal. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/635485v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@eb7b3eorg.highwire.dtl.DTLVardef@1e85006org.highwire.dtl.DTLVardef@ddfa7eorg.highwire.dtl.DTLVardef@1687606_HPS_FORMAT_FIGEXP M_FIG C_FIG

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bioRxiv2024

Seeing the Future: Anticipatory Eye Gaze as a Marker of Memory

Human memory is typically studied by direct questioning, and the recollection of events is investigated through verbal reports. Thus, current research confounds memory per-se with its report. Critically, the ability to investigate memory retrieval in populations with deficient verbal ability is limited. Here, using the MEGA (Memory Episode Gaze Anticipation) paradigm, we show that monitoring anticipatory gaze using eye tracking can quantify memory retrieval without verbal report. Upon repeated viewing of movie clips, eye gaze patterns anticipating salient events can quantify their memory traces seconds before these events appear on the screen. A series of five experiments with a total of 145 participants using either tailor-made animations or naturalistic movies consistently reveal that accumulated gaze proximity to the event can index memory. Machine learning-based classification can identify whether a given viewing is associated with memory for the event based on single-trial data of gaze features. Detailed comparison to verbal reports establishes that anticipatory gaze marks recollection of associative memory about the event, whereas pupil dilation captures familiarity. Finally, anticipatory gaze reveals beneficial effects of sleep on memory retrieval without verbal report, illustrating its broad applicability across cognitive research and clinical domains.

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bioRxiv2024

Changes in responses of auditory cortex neurons upon falling asleep and awakening

The neural processes that change when falling asleep are only partially understood. At the cortical level, features of both spontaneous neural activity and sensory responses change between wakefulness and sleep. For example, in early auditory cortex, sleep increases the occurrence of post-onset silent (OFF) periods and elevates population synchrony. However, it remains unknown whether such changes occur abruptly or gradually around sleep onset and awakening. Here, we recorded spontaneous and sound-evoked neuronal spiking activity in early auditory cortex along with polysomnography during thousands of episodes when male rats fell asleep or woke up. We found that when falling asleep, stimulus-induced neuronal silent periods (OFF periods), characteristic of non-rapid eye movement (NREM) sleep, increased within few seconds around sleep onset. By contrast, a gradual increase in neuronal population synchrony built up over tens of seconds until reaching maximal levels. EEG auditory-evoked potentials likely representing stimulus-triggered "K complexes" changed along with post-onset neuronal firing, whereas ongoing EEG slow wave activity was associated with neuronal population synchrony. Similar effects, but with opposite direction, were observed around awakenings. The results highlight late stimulus-induced neuronal silence as a key feature changing abruptly around transitions between vigilance states, likely reflecting neuronal bistability and manifesting also in EEG evoked potentials. More generally, these findings emphasize the added value of going beyond monitoring ongoing activity and perturbing the nervous system to reveal its state - an insight that could also help guide development of more sensitive non-invasive monitors of falling asleep in humans.

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bioRxiv2023

SleepEEGpy: a Python-based package for the preprocessing, analysis, and visualization of sleep EEG data

Sleep research uses electroencephalography (EEG) to infer brain activity in health and disease. Beyond standard sleep scoring, there is increased interest in advanced EEG analysis that require extensive preprocessing to improve the signal-to-noise ratio, and dedicated analysis algorithms. While many EEG software packages exist, sleep research has specific needs that require dedicated tools (e.g. particular artifacts, event detection). Currently, sleep investigators use different libraries for specific tasks in a fragmented configuration that is inefficient, prone to errors, and requires the learning of multiple software environments. This leads to a high initial complexity, creating a crucial barrier for beginners in sleep research. Here, we present SleepEEGpy, an open-source Python software "wrapper" package to facilitate sleep EEG data preprocessing and analysis. SleepEEGpy builds upon MNE-Python, YASA, and SpecParam tools to provide an all-in-one, beginner-friendly package for comprehensive yet straightforward sleep EEG research including (i) cleaning, (ii) independent component analysis, (iii) detection of sleep events, (iv) analysis of spectral features, and associated visualization tools. A dashboard visualization tool provides an overview to evaluate data and its preprocessing, which can be useful as an initial step prior to detailed analysis. We demonstrate the SleepEEGpy pipeline and its functionalities by applying it to overnight high-density EEG data in healthy participants, revealing multiple characteristic activity signatures typical of each vigilance state. These include alpha oscillations in wakefulness, sleep spindle and slow wave activities in NREM sleep, and theta activity in REM sleep. We hope that this software will be embraced and further developed by the sleep research community, and constitute a useful entry point tool for beginners in sleep EEG research.

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bioRxiv2023

A bistable inhibitory OptoGPCR for multiplexed optogenetic control of neural circuits

Information is transmitted between brain regions through the release of neurotransmitters from long-range projecting axons. Understanding how the activity of such long-range connections contributes to behavior requires efficient methods for reversibly manipulating their function. Chemogenetic and optogenetic tools, acting through endogenous G-protein coupled receptor (GPCRs) pathways, can be used to modulate synaptic transmission, but existing tools are limited in sensitivity, spatiotemporal precision, or spectral multiplexing capabilities. Here we systematically evaluated multiple bistable opsins for optogenetic applications and found that the Platynereis dumerilii ciliary opsin (PdCO) is an efficient, versatile, light-activated bistable GPCR that can suppress synaptic transmission in mammalian neurons with high temporal precision in-vivo. PdCO has superior biophysical properties that enable spectral multiplexing with other optogenetic actuators and reporters. We demonstrate that PdCO can be used to conduct reversible loss-of-function experiments in long-range projections of behaving animals, thereby enabling detailed synapse-specific functional circuit mapping.

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bioRxiv2023

A visual paired associate learning (vPAL) paradigm to study memory consolidation during sleep

The hippocampus helps transform an experience into an enduring memory by associating its multiple aspects. Sleep improves the consolidation of the newly formed associations, leading to stable long-term memory. Most research on human declarative memory and its consolidation during sleep uses word-pair associations requiring exhaustive learning. Here we present the visual paired association learning (vPAL) paradigm, in which participants learn new associations between images of celebrities and animals. vPAL associations are based on a one-shot exposure that resembles learning in natural conditions. We tested if vPAL can reveal a role for sleep in memory consolidation by assessing the specificity of memory recognition, and the cued recall performance, before and after sleep. We found that a daytime nap improved the stability of recognition memory and discrimination abilities compared to identical intervals of wakefulness. By contrast, cued recall of associations did not exhibit significant sleep-dependent effects. High-density EEG during naps further revealed an association between sleep spindle density and stability of recognition memory. Thus, the vPAL paradigm opens new avenues for future research on sleep and memory consolidation across ages and heterogeneous populations in health and disease.

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bioRxiv2022

Sleep-like changes in neural processing emerge during sleep deprivation in early auditory cortex

Insufficient sleep is commonplace in modern lifestyle and can lead to grave outcomes, yet the changes in neuronal activity accumulating over hours of extended wakefulness remain poorly understood. Specifically, which aspects of cortical processing are affected by sleep deprivation (SD), and whether they also affect early sensory regions, remains unclear. Here, we recorded spiking activity in rat auditory cortex along with polysomnography while presenting sounds during SD followed by recovery sleep. We found that frequency tuning, onset responses, and spontaneous firing rates were largely unaffected by SD. By contrast, SD decreased entrainment to rapid ([≥]20 Hz) click-trains, increased population synchrony, and increased the prevalence of sleep-like stimulus-induced silent periods, even when ongoing activity was similar. Recovery NREM sleep was associated with similar effects as SD with even greater magnitude, while auditory processing during REM sleep was similar to vigilant wakefulness. Our results show that processes akin to those in NREM sleep invade the activity of cortical circuits during SD, already in early sensory cortex.

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bioRxiv2021

Claustral Projections to Anterior Cingulate Cortex Modulate Engagement with the External World

Engagement is a major determinant of performance. Hyper-engagement risks impulsivity and is fatiguing over time, while hypo-engagement could lead to missed opportunities. Even in sleep, when engagement levels are minimal, sensory responsiveness varies. Thus, maintaining an optimal engagement level with the environment is a fundamental cognitive ability. The claustrum, and in particular its reciprocal connectivity with executive regions in the frontal cortex, has been associated with salience, attention and sleep. These apparently disparate roles can be consolidated within the context of engagement. Here we describe the activity of claustro-frontal circuits in a task imposing a tradeoff between response inhibition and sensory acuity ( ENGAGE). Recording calcium fiber photometry during >80,000 trials, we characterize claustrum recruitment during salient behavioral events, and find that a moderate level of activity in claustro-cingulate projections defines optimal engagement. Low activity of this pathway is associated with impulsive actions, while high activity is associated with behavioral lapses. Chemogenetic activation of cingulate-projecting claustrum neurons suppressed impulsive behavior and reduced the engagement of mice in the task. This relationship became even clearer upon addressing individual variability in the strategy mice employed during the ENGAGE task. Furthermore, this association of claustrum activity and engagement extends into sleep. Using simultaneous EEG and photometry recordings in the claustrum, we find that cingulate projecting claustrum neurons are most active during deep unresponsive slow-wave sleep, when mice are less prone to awakening by sensory stimuli.

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bioRxiv2021

Impaired top-down auditory processing despite extensive single-neuron responses during human sleep

Sleep in all species is universally defined as a reversible, homeostatically-regulated state of a reduced behavioral responsiveness, with a high arousal threshold in response to external sensory stimulation1. However, it remains unclear whether sleep mainly gates motor output or affects responses along sensory pathways, and whether sleep primarily modulates specific aspects of the sensory response such as feedforward vs. feedback signaling2-7. Here, we simultaneously recorded polysomnography, iEEG, microwire LFPs, and neuronal spiking activity during wakefulness and sleep in 13 epilepsy patients implanted with clinical depth electrodes, while presenting auditory stimuli (e.g. click-trains, words, music). The results revealed robust spiking and induced LFP high-gamma (80-200Hz) power responses during both NREM and REM sleep across the lateral temporal lobe. The magnitude of the responses was only moderately attenuated in sleep, most notably for late responses beyond the early auditory cortex. Nonetheless, sleep responses maintained their tight locking with soundwave envelopes and their information content was only minimally affected. In contrast, a decrease in LFP alpha-beta (10-30Hz) power responses was prevalent in wakefulness but significantly disrupted in sleep. Entrainment to 40 Hz click-trains was comparable across REM sleep and wakefulness, but reduced in NREM sleep. In conclusion, our results establish the presence of extensive and robust auditory responses during sleep while LFP alpha-beta power decrease, likely reflecting top-down processes8-10, is deficient. More broadly, our findings suggest that feedback signalling is key to conscious sensory processing11-13.

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bioRxiv2020

Anesthetic Drug Concentration Rather Than Abrupt Behavioral Unresponsiveness Linearly Degrades Responses in the Rat Primary Auditory Cortex

Despite extensive knowledge of its molecular and cellular effects, how anesthesia affects sensory processing remains poorly understood. In particular, it remains unclear whether anesthesia modestly or robustly degrades activity in primary sensory regions, and whether such changes are linked to anesthesia drug concentration vs. behavioral unresponsiveness, since these are typically confounded. Here, we employed slow gradual intravenous propofol anesthesia induction together with auditory stimulation and intermittent assessment of behavioral responsiveness while recording epidural EEG, and neuronal spiking activity in the primary auditory cortex (PAC) of eight rats. We found that all main components of neuronal activity including spontaneous firing rates, onset response magnitudes, onset response latencies, post-onset neuronal silence duration, and late-locking to 40Hz click-trains, gradually deteriorated in a dose- dependent manner with increasing anesthesia levels without showing abrupt changes around loss of righting reflex or other time-points. Thus, the dominant factor affecting PAC responses is the anesthesia drug concentration rather than any sudden, dichotomous behavioral state changes. Our findings explain a wide array of seemingly conflicting results in the literature that, depending on the precise definition of wakefulness (vigilant vs. drowsy) and anesthesia (light vs. deep/surgical), report a spectrum of effects in primary regions ranging from minimal to dramatic differences.

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bioRxiv2020

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

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), which receives afferent vagal inputs. In rats, VNS elevates LC firing and forebrain noradrenaline levels, whereas LC lesions suppress VNS therapeutic efficacy. Non-invasive transcutaneous VNS (tVNS) employs electrical stimulation that targets the auricular branch of the vagus nerve at the cymba conchae of the ear. However, the extent that tVNS mimics VNS remains unclear. 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. We compared 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, using parallel factor analysis, how tVNS modulates idle occipital alpha (8-13Hz) activity identified in each participant. We found greater attenuation of alpha oscillations by tVNS than by sham stimulation. This demonstrates that tVNS reliably induces pupillary and EEG markers of arousal beyond the effects of somatosensory stimulation, thus supporting the hypothesis that tVNS elevates noradrenaline and other arousal-promoting neuromodulatory signaling, and mimics invasive VNS. Significance statementCurrent non-invasive brain stimulation techniques are mostly confined to modulating cortical activity, as is typical with transcranial magnetic or transcranial direct/alternating-current electrical stimulation. Transcutaneous vagus nerve stimulation (tVNS) has been proposed to stimulate subcortical arousal-promoting nuclei, though previous studies yielded inconsistent results. Here we show that short (3.4s) tVNS pulses in naive healthy male volunteers induced transient pupil dilation and attenuation of occipital alpha oscillations. These markers of brain arousal are in line with the established effects of invasive VNS on locus coeruleus-noradrenaline signaling, and support the notion that tVNS mimics VNS. Therefore, tVNS can be used as a tool for studying the means by which endogenous subcortical neuromodulatory signaling affects human cognition, including perception, attention, memory, and decision-making; and also for developing novel clinical applications.

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bioRxiv2019

Sleep differentially affects early and late neuronal responses to sounds in auditory and perirhinal cortices

A fundamental feature of sleep is reduced behavioral responsiveness to external events, but the extent of processing along sensory pathways remains poorly understood. While responses are comparable across wakefulness and sleep in auditory cortex (AC), neuronal activity in downstream regions remains unknown. Here we recorded spiking activity in 435 neuronal clusters evoked by acoustic stimuli in the perirhinal cortex (PRC) and in AC of freely behaving male rats across wakefulness and sleep. Neuronal responses in AC showed modest (around 10%) differences in response gain across vigilance states, replicating previous studies. By contrast, PRC neuronal responses were robustly attenuated by 47% and 36% during NREM sleep and REM sleep, respectively. Beyond the separation according to cortical region, response latency in each neuronal cluster was correlated with the degree of NREM sleep attenuation, such that late (>40ms) responses in all monitored regions diminished during NREM sleep. The robust attenuation of late responses prevalent in PRC represents a novel neural correlate of sensory disconnection during sleep, opening new avenues for investigating the mediating mechanisms.\n\nSignificance StatementReduced behavioral responsiveness to sensory stimulation is at the core of sleeps definition, but it is still unclear how the sleeping brain responds differently to sensory stimuli. In the current study we recorded neuronal spiking responses to sounds along the cortical processing hierarchy of rats during wakefulness and natural sleep. Responses in auditory cortex only showed modest changes during sleep, whereas sleep robustly attenuated the responses of neurons in high-level perirhinal cortex. We also found that during NREM sleep, the response latency predicts the degree of sleep attenuation in individual neurons above and beyond their anatomical location. These results provide anatomical and temporal signatures of sensory disconnection during sleep and pave the way to understanding the underlying mechanisms.

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bioRxiv2019

Local Targeted Memory Reactivation in Human Sleep

Memory consolidation can be promoted via Targeted Memory Reactivation (TMR) that re-presents training cues or context during sleep. Whether TMR acts locally or globally on cortical sleep oscillations remains unknown. Here we exploit the unique functional neuroanatomy of olfaction with its ipsilateral stimulus processing to perform local TMR in one brain hemisphere. Participants learned associations between words and locations in left or right visual fields with contextual odor throughout. During post-learning naps, odors were presented to one nostril throughout NREM sleep. We found improved memory for specific words processed in the cued hemisphere (ipsilateral to stimulated nostril). Unilateral odor cues locally modulated slow wave activity (SWA) such that regional SWA increase in the cued hemisphere negatively correlated with select memories for cued words. Moreover, local TMR improved slow wave-spindle coupling specifically in the cued hemisphere. Thus, TMR in human sleep transcends global action by selectively promoting specific memories associated with local sleep oscillations.

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bioRxiv2019

Locus-coeruleus norepinephrine activity gates sensory-evoked awakenings from sleep

A defining feature of sleep is reduced responsiveness to external stimuli, but the mechanisms gating sensory-evoked arousal remain unclear. We hypothesized that reduced locus-coeruleus norepinephrine (LC-NE) activity during sleep mediates unresponsiveness, and its action promotes sensory-evoked awakenings. We tested this using electrophysiological, behavioral, pharmacological, and optogenetic techniques alongside auditory stimulation in freely behaving rats. We found that systemic reduction of NE signaling lowered probability of sound-evoked awakenings (SEAs). The level of tonic LC activity during sleep anticipated SEAs. Optogenetic LC activation promoted arousal as evident in sleep-wake transitions, EEG desynchronization, and pupil dilation. Importantly, liminal LC excitation before sound presentation increased SEA probability. Optogenetic LC silencing using a soma-targeted anion-conducting channelrhodopsin (stGtACR2) suppressed LC spiking and constricted pupils. Brief periods of LC opto-silencing reduced the probability of SEAs. Thus, LC-NE activity determines the likelihood of sensory-evoked awakenings and its reduction during sleep constitutes a key factor mediating behavioral unresponsiveness.

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