Biology subjects

Regev, N.

Publications and source records attributed to Regev, N..

7 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.

neuroscience↗

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.

neuroscience↗

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

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗