EEG/ECoG/EMG publications

Many species display mating-related sleep suppression to maximize reproductive success, yet the underlying neural mechanisms in mammals remain unclear. Here, we report that male mice exhibit delayed sleep onset and reduced sleep duration in periods following successful mating, while females are unaffected. Single-cell transcriptomics identifies a group of sleep-promoting Rxfp1-expressing neurons in the preoptic area of hypothalamus (POA Rxfp1 neurons), and fiber photometry reveals selective inhibition of them during and after mating in male mice. Lifting this inhibition via chemogenetic activation reverses sleep suppression in mated males. Monosynaptic retrograde tracing from these POA Rxfp1 neurons identifies male-biased γ-aminobutyric acid–releasing inputs from the principal nucleus of the bed nucleus of the stria terminalis (BNSTpr). Notably, optogenetic activation of these neurons induces immediate wakefulness specifically in male mice, and BNSTpr → POA Rxfp1 neurons are hyperactive after mating. Together, these findings establish a BNSTpr → POA Rxfp1 circuit that integrates reproductive signals for male-specific sleep suppression in mice.

Recent work shows that the brain’s arousal system remains active during sleep, with rhythmic locus coeruleus (LC) activity shaping sleep architecture and supporting memory consolidation. The LC releases norepinephrine (NE) in infraslow (~0.02 Hz) bouts that gate NREM sleep spindles. Here, we demonstrate that heart rate (HR) fluctuations during NREM are tightly phase-locked to these NE rhythms, identifying the LC as a key driver of very-low-frequency HR variability (VLF-HRV), an understudied autonomic signal. Using optogenetics, transient LC inhibition blunts HR slowing, whereas LC activation produces rapid HR acceleration, demonstrating a direct LC-HR relationship during sleep that is maintained across a defined range of LC activity levels but breaks down when LC activity becomes excessive. We further show that infraslow HR variability is a cross-species marker of spindle-dependent memory processing. In mice, the amplitude of HR decelerations during NREM correlates with spindle activity and subsequent memory performance. Remarkably, human sleepers show the same pattern: stronger VLF-HR fluctuations during NREM correspond to increased spindle expression and better overnight memory retention. These findings reveal a mechanistic pathway through which graded changes in LC activity, up to a critical level, modulates autonomic physiology during sleep and identify infraslow HR variability as a non-invasive marker of brainstem function and memory-promoting sleep. Because LC degeneration occurs early in neurodegenerative disease, sleep-derived HR metrics may provide a scalable indicator of emerging neuromodulatory dysfunction.

Neurotransmitters and neuromodulators regulate brain states through diverse mechanisms, yet how their activities are coordinated during sleep remains unresolved. Using in vivo fiber photometry in adult mice expressing genetically encoded fluorescent biosensors, combined with EEG/EMG recordings, we investigated the temporal organization of multiple neuromodulators during sleep in barrel cortex, with norepinephrine (NE) as a reference signal. All five neuromodulators examined, acetylcholine, serotonin, dopamine, histamine, and NE, exhibited synchronized infraslow cortical oscillations during NREM sleep. Optogenetic suppression of locus coeruleus (LC) neurons abolished NE oscillations and selectively reduced acetylcholine fluctuations in barrel cortex, whereas targeted inhibition of basal forebrain cholinergic neurons attenuated REM-associated acetylcholine elevations without disrupting NREM-related oscillations or NE dynamics. The synchronized infraslow cortical oscillations spanning multiple neuromodulators reveal a previously unrecognized mechanism for organizing sleep architecture.

Background CLN3 disease, also known as juvenile Batten disease, is a recessively inherited neurodevelopmental disorder caused by mutations in the CLN3 gene. It represents the most common form of Neuronal Ceroid Lipofuscinoses (NCLs), a group of lysosomal storage disorders that impair brain function. Clinical features include progressive vision loss, language impairment, and cognitive decline. The early onset of visual deficits complicates the neurological assessment of cognitive dysfunction, while the rarity of CLN3 cases limits the study of sex-specific disease trajectories in humans. Therefore, there is a critical need for objective, translational biomarkers to monitor disease progression and support therapeutic development in preclinical animal models. Methods Building on our recent studies in individuals with CLN3 disease, we developed a parallel experimental paradigm using high-density electroencephalography (EEG) in Cln3 knockout ( Cln3-/-) mice to longitudinally assess auditory neurophysiological changes. We applied a duration-based mismatch negativity (MMN) paradigm, similar to that used in our human studies, to evaluate automatic detection of auditory pattern changes in male and female mice between 3 and 9 months of age. Results Wild-type (WT) mice of both sexes showed robust and stable duration MMN responses across this age range. In contrast, Cln3-/- mice showed marked sex- and age-dependent deficits: female mutants displayed persistent MMN deficits, whereas male mutants exhibited early MMN abnormalities that unexpectedly improved with age. Auditory brainstem responses confirmed intact peripheral hearing in Cln3-/- mice, indicating a central origin for the observed abnormalities. Further analyses revealed that MMN impairments were driven by age- and sex-specific alterations in auditory evoked potentials to both standard and deviant stimuli. Conclusions These findings demonstrate sex- and age-dependent disruptions in central auditory processing in Cln3-/- mice and support auditory duration MMN as a sensitive, translational biomarker of brain dysfunction in CLN3 disease. This approach offers a functional, cross-species measure for tracking disease progression and evaluating therapeutic interventions in Batten disease.

Classical neuromodulators regulate arousal states, spanning deep sleep to vigilant wakefulness, primarily by activating cortical neurons. However, cortical astrocytes also express neuromodulatory G-protein-coupled receptors (GPCRs). While astrocytic noradrenergic receptors have been shown to modulate two critical regulators of arousal—cortical synchrony and extracellular adenosine levels—how other neuromodulatory signaling pathways similarly shape arousal remains unclear. Astrocytes in mammalian cortex express particularly high levels of the wake-promoting, Gq-coupled histamine-1-receptor (H1R), yet little is known about how astrocytic H1R contributes to regulation of arousal. To address this gap, we used pharmacological and genetic approaches in murine cortex to test how astrocyte-H1R signaling affects astrocyte calcium (Ca 2+ ), cortical neural activity across sleep/wake, and extracellular adenosine—an astrocytic output that regulates cortical arousal. Using ex vivo two-photon Ca 2+ imaging in acute cortical slices, we show that H1R mediates cell-autonomous astrocyte Ca 2+ responses to histamine (HA) and attenuates responses to norepinephrine (NE). Next, in vivo fiber photometry and electrophysiology results show that H1R deletion in cortical astrocytes disrupts local astrocyte Ca 2+ during wake and extracellular adenosine dynamics specifically around REM sleep transitions, when HA release is minimal. Further, astrocyte-specific H1R deletion in cortex promotes wakefulness and reduces REM sleep time. Our results indicate that H1R activity modulates astrocyte responses to non-histaminergic inputs by inducing lasting changes in astrocyte physiology that modulate extracellular adenosine and REM sleep. Our findings contribute to an emerging model in which neuromodulator GPCRs synergistically shape astrocyte physiology to regulate arousal behavior and adenosine signaling in the cortex.

Impaired sleep is a common aspect of aging and often precedes the onset of Alzheimer's disease. Here, we compare the effects of sleep deprivation in young wild-type mice and their APP/PS1 littermates, a murine model of Alzheimer's disease. After 7 h of sleep deprivation, both genotypes exhibit an increase in EEG slow-wave activity. However, only the wild-type mice demonstrate an increase in the power of infraslow norepinephrine oscillations, which are characteristic of healthy non-rapid eye movement sleep. Notably, the APP/PS1 mice fail to enhance norepinephrine oscillations 24 h after sleep deprivation, coinciding with an accumulation of cerebral amyloid-β protein. Proteome analysis of cerebrospinal fluid and extracellular fluid further supports these findings by showing altered protein clearance in APP/PS1 mice. We propose that the suppression of infraslow norepinephrine oscillations following sleep deprivation contributes to increased vulnerability to sleep loss and heightens the risk of developing amyloid pathology in early stages of Alzheimer's disease.

Information transfer within neuronal circuits depends on the balance and recurrent activity of excitatory and inhibitory neurotransmission. Chloride (Cl − ) is the major central nervous system (CNS) anion mediating inhibitory neurotransmission. Astrocytes are key homoeostatic glial cells populating the CNS, although the role of these cells in regulating excitatory-inhibitory balance remains unexplored. Here we show that astrocytes act as a dynamic Cl − reservoir regulating Cl − homoeostasis in the CNS. We found that intracellular chloride concentration ([Cl − ] i ) in astrocytes is high and stable during sleep. In awake mice astrocytic [Cl − ] i is lower and exhibits large fluctuation in response to both sensory input and motor activity. Optogenetic manipulation of astrocytic [Cl − ] i directly modulates neuronal activity during locomotion or whisker stimulation. Astrocytes thus serve as a dynamic source of extracellular Cl − available for GABAergic transmission in awake mice, which represents a mechanism for modulation of the inhibitory tone during sustained neuronal activity.

Sleep is not homogenous but contains a highly diverse microstructural composition influenced by neuromodulators. Prior methods used to measure neuromodulator levels in vivo have been limited by low time resolution or technical difficulties in achieving recordings in a freely moving setting, which is essential for natural sleep. In this protocol, we demonstrate the combination of electroencephalographic (EEG)/electromyographic (EMG) recordings with fiber photometric measurements of fluorescent biosensors for neuromodulators in freely moving mice. This allows for real-time assessment of extracellular neuromodulator levels during distinct phases of sleep with a high temporal resolution.