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The noradrenergiclocus coeruleus(LC) supports vital brain functions during wakefulness. In contrast, the LC has been associated with sleep-promotion and -disruption, leaving its functions for sleep uncertain. Here, we show that the LC is essential for the progression of natural, undisturbed sleep because it creates a non-reducible timeframe for the non-rapid-eye-movement (NREM) sleep-REM sleep cycle. Fiber-photometric jGCaMP8s-based LC activity measures, closed-loop optogenetics and mouse sleep-wake monitoring revealed that LC showed ∼50-s-activity fluctuations, during which high activity levels promoted a NREMS with high arousability, while low levels a NREMS with the opportunity for transitions to REMS. The NREMS-REMS cycle was shortened by LC inhibition due to precocious REMS onset. Supporting LC’s pivotal role as a gatekeeper of the NREMS-REMS cycle, REMS entries occurred on intervals no shorter than ∼50 s during REMS-restriction. A stimulus- enriched wake experience strengthened LC fluctuations, which contributed to subsequent NREMS fragmentation and delayed REMS. The LC fluctuations are hence indispensable for the NREMS-REMS cycle but they can become sleep-disruptive as a result of prior wake experience.

Closed-loop acoustic stimulation (CLAS) during sleep has shown to boost slow wave (SW) amplitude and spindle power. Moreover, sleep SW have been classified based on different processes of neuronal synchronization. Thus, different types of SW events may have distinct functional roles and be differentially affected by external stimuli. However, the SW synchronization processes affected by CLAS are not well understood. Here, we studied the effect of CLAS on the dissociation of SW events based on two features of neuronal synchronization in the electroencephalogram (topological spread and wave slope). We evaluated and classified individual SW events of 14 healthy subjects during a CLAS stimulated (STM) and a control night (CNT). Three main categories of SW events were found denoting (C1) steep slope SW with global spread, (C2) flat-slope waves with localized spread and homeostatic decline, and (C3) multipeaked flat-slope events with global spread. Comparing between conditions, we found a consistent increase of event proportion and trough amplitudes for C1 events during the time of stimulation. Furthermore, we found similar increases in post-stimulus spectral power in θ, β, and σ frequencies for CNT vs STIM condition independently of sleep stage or SW categories. However, topological analysis showed differentiated spatial dynamics in N2 and N3 for SW categories and the co-occurrence with spindle events. Our findings support the existence of multiple types of SW with differential response to external stimuli and possible distinct neuronal mechanisms.

Closed loop acoustic stimulation (CLAS) during sleep has shown to boost slow wave (SW) amplitude and spindle power. Moreover, sleep SW are suggested to be classified based on different processes of neuronal synchronization. Following this, different types of SW events may have distinct functional roles and be differentially affected by external stimuli. However, the SW synchronization processes affected by CLAS are not well understood. Here, we studied the effect of CLAS on the dissociation of SW events based on two features of neuronal synchronization in the EEG (topological spread and wave slope). We evaluated and classified individual SW events of fourteen healthy subjects during a CLAS stimulated (STM) and a control night (CNT). Three main categories of SW events were found denoting (C1) steep-slope SW with global spread, (C2) flat-slope waves with localized spread and homeostatic regulation, and (C3) multipeaked flat-slope events with global spread. Comparing between conditions, we found a consistent increase of event proportion and trough amplitudes for C1 events during the time of stimulation. Furthermore, we found similar increases in post-stimulus spectral power in θ, β and σ frequencies for CNT vs STIM condition independently of sleep stage or SW categories. However, topological analysis showed differentiated spatial dynamics in N2 and N3 for SW categories and the co-occurrence with spindle events. Our findings reveal the nature of post-stimulus SW and suggest that CLAS boosts SW amplitudes by increasing neuronal synchronization of wave troughs, leading thus the post-stimulus SW-spindle co-occurrence.

There is high interest in investigating the daily dynamics of gene expression in mammalian organs, for example, in liver. Such studies help to elucidate how and with what kinetics peripheral clocks integrate circadian signals from the suprachiasmatic nucleus, which harbors the circadian master pacemaker, with other systemic and environmental cues, such as those associated with feeding and hormones. Organ sampling around the clock, followed by the analysis of RNA and/or proteins, is the most commonly used procedure in assessing rhythmic gene expression. However, this method requires large cohorts of animals and is only applicable to behaviorally rhythmic animals whose phases are known. Real-time recording of gene expression rhythms using luciferase reporters has emerged as a powerful method to acquire continuous, high-resolution datasets from freely moving individual mice. Here, we share our experience and protocols with this technique, using the RT-Biolumicorder setup.

For decades, numerous seminal studies have built our understanding of the

Neuroinflammation after brain injury Traumatic brain injury affects millions of people every year and is a major cause of disability worldwide. Most of the maladaptive outcomes develop months or years later and are thought to be caused by secondary injuries that are indirect and long-term effects after the initial impact. Holden et al . found that secondary and chronic neuroinflammation and neurodegeneration are caused by the C1q molecule, a mediator of the complement pathway. C1q is responsible for chronic inflammation and secondary neuronal loss specifically in the cortico-thalamo-cortical circuit. Traumatic brain injury also leads to altered brain states that are caused by the C1q complement pathway. —PRS

SummaryOne promising approach towards understanding what makes sleep vulnerable in disease is to look at how wake-promoting mechanisms affect healthy sleep. Wake-promoting neuronal activity is inhibited during non-REM sleep (NREMS). However, many mammalian species, including humans, show recurrent moments of sleep fragility during which sensory reactivity is elevated. Wake-related neuronal activity could thus remain active in NREMS, but its roles in dynamic variations of sensory reactivity remain unknown. Here, we demonstrate that mouse NREMS is a brain state with recurrent fluctuations of the wake-promoting neurotransmitter noradrenaline on the ∼50-seconds time-scale. These fluctuations occurred around mean noradrenaline levels greater than the ones of quiet wakefulness, while they declined steeply in REMS. They coincided with a clustering of sleep spindle rhythms in the forebrain and with heart rate variations. We addressed the origins of these fluctuations by using closed-loop optogenetic locus coeruleus (LC) activation or inhibition timed to moments of low and high spindle activity during NREMS. We could suppress, lock or entrain sleep spindle clustering or heart rate variations, demonstrating that both fore- and hindbrain-projecting LC neurons show synchronized infraslow activity variations in natural NREMS. Noradrenergic modulation of thalamic but not cortical circuits was required for sleep spindle clustering and involved noradrenaline release into primary sensory and reticular thalamic nuclei that activated both α1- and β-adrenergic receptors to cause slowly decaying membrane depolarizations. Noradrenergic signaling by LC, primarily known for attention promotion in wakefulness, renders mammalian NREMS more ‘wake-like’ on the close-to-minute-time scale through sustaining thalamocortical and autonomic sensory arousability.

Chronic pain patients frequently suffer from sleep disturbances. Improvement of sleep quality alleviates pain, but neurophysiological mechanisms underlying sleep disturbances require clarification to advance therapeutic strategies. Chronic pain causes high-frequency electrical activity in pain-processing cortical areas that could disrupt the normal process of low-frequency sleep rhythm generation. We found that the spared-nerve-injury (SNI) mouse model, mimicking human neuropathic pain, had preserved sleep-wake behavior. However, when we probed spontaneous arousability based on infraslow continuity-fragility dynamics of non-rapid-eye-movement sleep (NREMS), we found more numerous local cortical arousals accompanied by heart rate increases in hindlimb primary somatosensory, but not in prelimbic, cortices of SNI mice. Closed-loop mechanovibrational stimulation revealed higher sensory arousability in SNI. Sleep in chronic pain thus looked preserved in conventional measures but showed elevated spontaneous and evoked arousability. Our findings develop a novel moment-to-moment probing of NREMS fragility and propose that chronic pain-induced sleep complaints arise from perturbed arousability.

A pesar del amplio uso de la estimulación cerebral profunda para controlar patologías neurológicas y neuropsiquiátricas, su mecanismo de acción aún no es claramente conocido, y existen pocos estudios sistemáticos que relacionen la variación de parámetros de estimulación eléctrica (frecuencia, intensidad, duración del pulso) y la ejecución comportamental. La habénula es una estructura reguladora de respuestas emocionales diana en tratamientos para dolor crónico y depresión, pero la relación entre su estimulación crónica y el desempeño animal en pruebas conductuales no se ha establecido con claridad. Con el objetivo de evaluar el efecto emocional de la estimulación habenular crónica, en este estudio se utilizaron ratas Wistar que recibieron estimulación habenular a intensidad baja (10-80 pA) o alta (120-260 pA) y frecuencia baja (80-150 Hz) o alta (240380 Hz): BIBF-AIBF-BIAF-AIAF, durante 15 minutos a lo largo de tres días consecutivos. Al cuarto día, se hizo la evaluación en un laberinto elevado en cruz y en campo abierto. Los resultados indican un efecto de tipo ansiolítico en el tratamiento BIAF, en comparación con BIBF y AIBF (aumento del número de entradas, porcentaje de tiempo en brazos abiertos y de la distancia recorrida en ellos), efecto que no se explica por cambios en la locomotricidad (distancia recorrida en los brazos cerrados y la exploración en el campo abierto). Se concluye que el parámetro frecuencia posee mayor impacto sobre el efecto comportamental que la intensidad -lo que puede explicar algunos hallazgos paradójicos previos-, que los parámetros utilizados no poseen efecto ansiogénico, y que los efectos potencialmente ansiogénicos de la estimulación a baja frecuencia y el papel de los sistemas dopaminérgicos y serotoninérgicos encontrados deben ser estudiados en futuras investigaciones. Apesar do amplo uso da estimulação cerebral profunda para controlar patologias neurológicas e neuropsiquiátricas, seu mecanismo de ação ainda não é claramente conhecido e existem poucos estudos sistemáticos que relacionem a variação de parâmetros de estimulação elétrica (frequência, intensidade, duração do pulso) e a execução comportamental. A habênula é uma estrutura reguladora de respostas emocionais específicas em tratamentos para dor crònica e depressão, mas a relação entre sua estimulação crònica e o desempenho animal em testes comportamentais não foi claramente estabelecida. Com o objetivo de avaliar o efeito emocional da estimulação habenular crònica, neste estudo foram utilizados ratos Wistar que receberam estimulação habenular de intensidade baixa (10-80 pA) ou alta (120-260 pA) e frequência baixa (80-150 Hz) ou alta (240-380 Hz): BIBF-AIBF-BIAF-AIAF, durante 15 minutos ao longo de três dias consecutivos. No quarto dia, foi feita a avaliação em um labirinto em cruz elevado e em campo aberto. Os resultados indicam um efeito de tipo ansiolítico no tratamento BIAF, em comparação com BIBF e AIBF (aumento do número de entradas, porcentagem de tempo em braços abertos e da distância percorrida neles), efeito que não se explica por mudanças na locomotividade (distância percorrida nos braços fechados e a exploração no campo aberto). Conclui-se que o parâmetro "frequência" tem mais impacto sobre o efeito comportamental do que a "intensidade" - o que pode explicar algumas descobertas paradoxais prévias -, que os parâmetros utilizados não tenham efeito ansiogênico, e que os efeitos potencialmente ansiogênicos da estimulação de baixa frequência e o papel dos sistemas dopaminérgicos e serotoninérgicos encontrados devem ser estudados em pesquisas futuras. Deep brain stimulation is a widely-used approach to the treatment of neurologic and neuropsychiatric diseases. However, its mechanisms remain unclear. There are few systematic studies relating variations on electrical stimulation parameters (frequency, intensity, pulse duration) and behavioral outcome. The habenula relates to emotional behavior and is a main target for chronic pain and depression stimulation treatment. The relation between habenular electrical stimulation and performance in behavioral tests has not been clearly defined. In order to assess the emotional effects of chronic habenular electrical stimulation, Wistar male rats were unilaterally implanted with electrodes aimed to the lateral habenula and assigned to low (10-80 pA) or high (120-260 pA) intensity and low (80-150 Hz) or high (240-380 Hz) frequency conditions: BIBF-AIBF-BIAF-AIAF. They received electrical stimulation 15 minutes/day for three consecutive days and on the fourth day were tested in the elevated plus maze and the open field. The results of these study show that BIAF stimulation has a possible anxiolytic-like effect when compared to BIBF and AIBF (increase in the percentage of open-arms time, entries into the open-arms and total-distance-run in the open-arms). This is not due to any changes in locomotion (total-distance-run and open field exploration). It is concluded that frequency is more important than intensity for behavioral modification. This could explain some previous inconsistent results. The data also suggest that these parameters of stimulation have no anxiogenic effects. The role for dopaminergic and serotonergic systems must be subsequently evaluated as well as potential anxiogenic-like effects of low frequency stimulation.