The locus coeruleus (LC), as the primary source of norepinephrine (NE) in the brain, is central to modulating cognitive and behavioral processes. This review synthesizes recent findings to provide a comprehensive understanding of the LC-NE system, highlighting its molecular diversity, neurophysiological properties, and role in various brain functions. We discuss the heterogeneity of LC neurons, their differential responses to sensory stimuli, and the impact of NE on cognitive processes such as attention and memory. Furthermore, we explore the system's involvement in stress responses and pain modulation, as well as its developmental changes and susceptibility to stressors. By integrating molecular, electrophysiological, and theoretical modeling approaches, we shed light on the LC-NE system's complex role in the brain's adaptability and its potential relevance to neurological and psychiatric disorders.

People with temporal lobe epilepsy often suffer debilitating loss of consciousness during seizures. Rodent models have previously implicated the inhibition of brainstem and basal forebrain cholinergic neurons in the cortical impairment during these periods of impaired consciousness. However, there are still other subcortical pathways that remain largely unexplored. Our goal was to record multiunit activity in the locus coeruleus (LC) in an awake mouse model to help elucidate its potential role in this pathophysiology. Recordings were performed using head-fixed mice running on a wheel with chronically implanted bipolar electrodes in the right orbitofrontal cortex and bilateral dorsal hippocampi. Focal limbic seizures were induced via the application of current pulses into the HC and multiunit recordings were simultaneously obtained from the LC. We observed a significant decrease in firing of LC neurons during ictal impairment of running wheel behavior. There was also a concurrent, significant increase in power in the 1-4 Hz band in the OFC. This provides evidence of a LC noradrenergic pathway contributing to depressed arousal in focal limbic seizures. Further elucidation of these, and other pathways, will contribute better mechanistic understanding of ictal unconsciousness and may lead to novel, improved treatments for people with epilepsy.

Attention control is a fundamental cognitive function that enables individuals to sustain focus, shift attention flexibly, and filter distractions in a goal-directed manner. The locus coeruleus-norepinephrine (LC-NE) system plays a pivotal role in this process by dynamically regulating arousal, prioritizing salient stimuli, and optimizing cognitive performance. This review synthesizes evidence from molecular, cellular, systems, cognitive neuroscience, and behavioral studies to elucidate the LC-NE system's role in attention control. We first examine the neurophysiological mechanisms of the LC, highlighting its distinct firing patterns-tonic and phasic activity-and their impact on attention. Next, we integrate findings from animal models, human neuroimaging, electrophysiology, and computational modeling, demonstrating how LC-NE activity influences sensory processing, cognitive flexibility, and executive function. We interpret these findings through the lens of three major theoretical frameworks: Adaptive Gain Theory (AGT), which describes how LC activity optimizes task engagement, the Network Reset Hypothesis (NRH), which describes how optimizes network connectivity, and the Glutamate Amplifies NE Effects (GANE) model, which explains how NE enhances neural selectivity and suppresses irrelevant signals. Collectively, the evidence underscores the LC-NE system's role in modulating the signal-to-noise ratio in cortical and subcortical circuits, thereby shaping attention and behavior. We conclude by discussing implications for individual differences, age-related cognitive decline, and emphasizing the need for interdisciplinary research that integrates emerging technologies to further unravel the complexities of LC function.

Breathing is an automatic and rhythmic act primarily controlled by hindbrain neural circuits, including the pre-Bötzinger complex. While the basal ganglia are known to regulate a wide range of behaviors through downstream projections, their role in breathing control remains unclear. In this study, we demonstrate that outputs from the substantia nigra (SN) can modulate breathing rate in a cell-type specific manner. Specifically, optogenetic activation of glutamic acid decarboxylase 2 (Gad2)-expressing neurons in the SN, but not parvalbumin (Pvalb)-expressing neurons, decreased breathing rate in lightly anesthetized mice. Importantly, this effect was mediated through the inhibition of neural activity in the locus coeruleus (LC), suggesting a relationship between the decrease in breathing rate and the baseline firing rate of LC neurons. These findings provide evidence that the basal ganglia play an important role in the control of breathing rate through modulation of LC neural activity.

As the primary source of noradrenaline in the brain, the locus coeruleus (LC) regulates arousal, avoidance and stress responses1,2. However, how local neuromodulatory inputs control LC function remains unresolved. Here we identify a population of transcriptionally, spatially and functionally diverse GABAergic (γ-aminobutyric acid-producing) neurons in the LC dendritic field that receive distant inputs and modulate modes of LC firing to control global arousal levels and arousal-related processing and behaviours. We define peri-LC anatomy using viral tracing and combine single-cell RNA sequencing with spatial transcriptomics to molecularly define both LC noradrenaline-producing and peri-LC cell types. We identify several neuronal cell types that underlie peri-LC functional diversity using a series of complementary neural circuit approaches in behaving mice. Our findings indicate that LC and peri-LC neurons are transcriptionally, functionally and anatomically heterogenous neuronal populations that modulate arousal and avoidance states. Defining the molecular, cellular and functional diversity of the LC and peri-LC provides a roadmap for understanding the neurobiological basis of arousal, motivation and neuropsychiatric disorders.

Sleep and arousal disorders are common, but the underlying physiology of wakefulness is not fully understood. The locus coeruleus promotes arousal via α1-adrenergic receptor (α1AR)-driven recruitment of wake-promoting dopamine neurons in the ventral periaqueductal gray (vPAGDA neurons). α1AR expression is enriched on vPAG astrocytes, and chemogenetic activation of astrocytic Gq signaling promotes wakefulness. Astrocytes can release extracellular gliotransmitters, such as ATP and adenosine, but the mechanism underlying how vPAG astrocytic α1ARs influence sleep/wake behavior and vPAGDA neuron physiology is unknown.

In this study, we utilized genetic manipulations with ex vivo calcium imaging in vPAGDA neurons and astrocytes, patch-clamp electrophysiology, and behavioral experiments in mice to test our hypothesis that astrocytic α1ARs mediate noradrenergic modulation of wake-promoting vPAGDA neurons via adenosine signaling.

Activation of α1ARs with phenylephrine increased calcium transients in vPAGDA neurons and vPAG astrocytes and increased vPAGDA neuron excitability ex vivo. Chemogenetic Gq-DREADD (designer receptor exclusively activated by designer drugs) activation of vPAG astrocytes similarly increased vPAGDA neuron calcium activity and intrinsic excitability. Conversely, short hairpin RNA knockdown of vPAG astrocytic α1ARs reduced the excitatory effect of phenylephrine on vPAGDA neurons and blunted arousal during the wake phase. Pharmacological blockade of adenosine A2A receptors precluded the α1AR-induced increase in vPAGDA calcium activity and excitability in brain slices, as well as the wake-promoting effects of vPAG α1AR activation in vivo.

We have identified a crucial role for vPAG astrocytic α1ARs in sustaining arousal through heightened excitability and activity of vPAGDA neurons mediated by local A2A receptors.

Subcortical neuromodulatory activity in the mammalian brain enables flexible wake behaviors, which are essential for survival in an ever-changing external environment. With the suppression of such behaviors in sleep, this activity is, on average, much reduced. Recent discoveries, enabled by unprecedented technical advancements, challenge the long-standing view that monoaminergic systems-noradrenaline (NA), dopamine (DA), and serotonin (5-HT)-remain largely inactive during sleep. This review highlights recent technological and scientific progress in this field, summarizing evidence that monoaminergic signaling in the brain supplements sleep with essential wake-related functions. Stress and/or neuropsychiatric conditions negatively impact on monoaminergic signaling, which can lead to sleep disruptions. Furthermore, subcortical neuromodulatory systems are vulnerable to neurodegenerative pathologies, which implies them in sleep disruptions at early stages of disease. We propose that future research will be well-invested in elucidating the spatiotemporal organization, cellular mechanisms, and functional relevance of neuromodulatory dynamics across species, and in identifying the molecular and physiological processes that sustain their integrity throughout the lifespan.

IntroductionThis study aims to investigate the locus coeruleus-norepinephrine system (LC-NE) function in late-life depression (LLD) patients by examining task-evoked pupil dilation in the emotional face-word Stroop task, given the recently established coupling between task-evoked pupil dilation and LC-NE activation.Materials and MethodsUsing video-based eye-tracking and principal component analysis, we explored task-evoked pupil responses and eye blinks in LLD patients (N = 25) and older healthy controls (CTRL) (N = 29) to determine whether there were alterations in pupil responses and eye blinks in LLD compared to CTRL.ResultsLLD patients exhibited significantly different pupil and eye-blink behavior compared to CTRL, with dampened task-evoked pupil dilation associated with emotional congruency and valence processing mediated by the sympathetic system compared to CTRL. Eye-blink rates associated with emotional valence were also altered in LLD compared to CTRL Moreover, Geriatric Depression Scale-15 scores in LLD correlated with emotional congruency effects revealed by task-evoked pupil dilation.ConclusionThe findings demonstrate that LLD patients display altered pupil behavior compared to CTRL. These altered responses correlated with the severity of depressive symptoms, indicating their potential as objective biomarkers for use in large at-risk populations for LLD.

Memory formation requires specific neural activity in coordination with intracellular signaling mediated by second messengers such as cyclic adenosine monophosphate (cAMP). However, the real-time dynamics of cAMP remain largely unknown. Here, using a genetically encoded cAMP sensor with high temporal resolution, we found neural-activity-dependent rapid cAMP elevation during learning. Interestingly, in slow-wave sleep, during which memory consolidation occurs, the cAMP level in mice was anti-correlated with neural activity and exhibited norepinephrine β1 receptor-dependent infra-slow oscillations that were synchronized across the hippocampus and cortex. Furthermore, the hippocampal-cortical interactions increased during the narrow time-window of the peak cAMP level; suppressing hippocampal activity specifically during this window impaired spatial memory consolidation. Thus, hippocampal-dependent memory consolidation occurs within a specific time window of high cAMP activity during slow-wave sleep.

The locus coeruleus-norepinephrine (LC-NE) system is involved in mediating a wide array of functions, including attention, arousal, cognition, and stress response. Dysregulation of the LC-NE system is strongly linked with several stress-induced neuropsychiatric disorders, highlighting the LC's pivotal role in the development of these disorders. Located in the dorsal pontine tegmental area, the LC contains noradrenergic neurons that serve as the main source of NE in the central nervous system. Activation of the LC and subsequent release of NE at different levels of the neuroaxis is adaptive, allowing the body to adjust appropriately amid a challenging stimulus. However, prolonged and repeated LC activation leads to maladaptive responses that implicate LC-NE dysfunction in stress-induced neuropsychiatric disorders. As the primary initiator of the stress response, corticotropin-releasing factor (CRF) activates the hypothalamic-pituitary-adrenal axis. Following the discovery of CRF more than four decades ago, numerous studies established that CRF also acts as a neurotransmitter that governs the activity of other neurotransmitters in the brain neurotransmitter system. The LC-NE system receives abundant CRF afferents arising from several brain nuclei. CRF afferents to LC-NE are activated and recruited in the pathogenesis of stress-induced neuropsychiatric disorders. Presented in this review are the CRF neuroanatomical connectivity and physiological characteristics that modulate LC-NE function, which may contribute to the pathogenesis of stress-induced neuropsychiatric disorders. Additionally, this review illustrates the contribution of LC-NE to the apparent sex-dependent differences in stress-induced neuropsychiatric disorders. Hence, the LC-NE system is a promising target for the development of therapeutic strategies for stress-induced neuropsychiatric disorders.

Breathing regulation depends on a highly intricate and precise network within the brainstem, requiring the identification of all neuronal elements in the brainstem respiratory circuits and a comprehensive understanding of their organization into distinct functional compartments. These compartments play a pivotal role by providing essential input to three main targets: cranial motoneurons that regulate airway control, spinal motoneurons that activate the inspiratory and expiratory muscles, and higher brain structures that influence breathing behavior and integrate it with other physiological and behavioral processes. This review offers a comprehensive examination of the phenotypes, connections, and functional roles of the major compartments within the brainstem and forebrain respiratory circuits. In addition, it summarizes the diverse neurotransmitters used by neurons in these regions, highlighting their contributions to the coordination and modulation of respiratory activity.

The locus coeruleus norepinephrine (LC-NE) system plays an important role in regulating brain function, and its neuronal loss has been well-documented in Parkinson's disease (PD). The LC-NE neurodegeneration is believed to underlie various nonmotor symptoms in people with PD, including neuropsychiatric deficits, sleep disruptions, and cognitive impairments. Of particular interest, LC-NE neurons send intensive axonal projections to the motor regions of the cerebral cortex. However, how NE depletion in the motor cortex contributes to PD pathophysiology remains poorly understood. In addition, recent studies provided increasing mechanistic insights into secondary changes in the cerebral cortex as LC-NE degenerates, which might involve its interaction with dopaminergic signaling during the chronic course of the disease. In the present article, we briefly discuss clinical and preclinical studies that support the critical roles of LC-NE neurodegeneration and motor cortical dysfunction in both motor and nonmotor deficits in Parkinsonian states. We focus our discussion on the potential impact of LC-NE neurodegeneration on motor cortical function and the subsequent symptom manifestation. Last, we propose future research directions that can advance our understanding of cortical pathophysiology in PD by integrating noradrenergic degeneration.

Pain and itch are sensations that are regulated antagonistically; painful stimulation suppresses itch, while the inhibition of pain enhances itch. However, the central neural circuit underlying this antagonistic regulation remains elusive. The noradrenaline (NA) pathway from the locus coeruleus (LC) to the spinal cord (SC) constitutes an important component of endogenous descending pain inhibitory system. While the pathway of LC:SC has been extensively studied on pain modulation, its role in itch regulation remains poorly understood. We employed behavioral assays for itch and pain, immunofluorescence, electrophysiology, and chemogenetic techniques to investigate the role of noradrenergic (NAergic) neurons of LC (LCNA neurons)and their pathways in modulating itch and pain. Our study has demonstrated that LCNA neurons encode signals for both itch and pain. Inhibition of LCNA neurons had no effect on itch but enhanced pain behaviour. Surprisingly, inhibition of the NAergic projection of LC:SC increased pain and suppressed itch. Furthermore, intrathecal injection of an α2 adrenergic receptor antagonist, but not α1 or β receptor antagonists, produced effects similar to those observed when the LC:SC pathway was inhibited. Our research suggests that the descending NAergic pathway from LC to SC exerts endogenous antagonistic regulation on itch and pain through α2 receptors.

Sleep loss is often regarded as an early manifestation of neurodegenerative diseases given its common occurrence and link to cognitive dysfunction. However, the precise mechanisms by which sleep disturbances contribute to neurodegeneration are not fully understood, nor is it clear why some individuals are more susceptible to these effects than others. This review addresses critical unanswered questions in the field, including whether sleep disturbances precede or result from neurodegenerative diseases, the functional significance of sleep changes during the preclinical disease phase, and the potential role of sleep homeostasis as an adaptive mechanism enhancing resilience against cognitive decline and neurodegeneration.

Since the discovery of orexin/hypocretin, numerous studies have accumulated evidence demonstrating its key role in various aspects of neuromodulation, including addiction, motivation, and arousal. This paper focuses on the projection of orexin neurons to specific target brain regions through distinct neural pathways to regulate sleep and arousal. We provide a detailed discussion of the projection mechanisms of orexin neurons to downstream neurons, particularly emphasizing their activation of monoaminergic and cholinergic neurons associated with arousal. Additionally, we briefly explore the immune response and inflammatory factors linked to the loss of orexin neurons. Our findings underscore the significance of understanding specific neural projections in the generation and maintenance of arousal, which could guide advancements in neuroscience and lead to new therapeutic opportunities for treating insomnia or narcolepsy.

Sound-evoked wakefulness from sleep is crucial in daily life, yet its neural mechanisms remain poorly understood. It is found that CaMKIIα+ neurons in the temporal association cortex (TeA) of mice are not essential for natural awakening from sleep. However, optogenetic activation of these neurons reliably induces wakefulness from non-rapid eye movement (NREM) sleep but not from rapid eye movement (REM) sleep. In vivo electrophysiological and calcium recordings further demonstrated that TeA neurons are monotonically tuned to sound intensity but not frequency. More importantly, it is found that the activity of CaMKIIα+ neurons in TeA can gate sound-evoked arousal from NREM sleep, which is further confirmed by optogenetic manipulations. Further investigation reveals that the baseline excitability of TeA CaMKIIα+ neurons and the delta oscillations in the electroencephalogram are particularly important in regulating the evoked activity of TeA neurons. Anatomical and functional screening of downstream targets of TeA reveals that excitatory projections from TeA glutamatergic neurons to glutamatergic neurons in the basolateral/lateral amygdala are critical for modulating sound-evoked arousal from NREM sleep. These findings uncover a top-down regulatory circuit that selectively governs sound-evoked arousal from NREM sleep, with the TeA functioning as a key connecting cortex to subcortical regions.

The brain builds and maintains internal models and uses them to make predictions. When predictions are violated, the current model can either be updated or replaced by a new model. The latter is accompanied by pupil dilation responses (PDRs) related to locus coeruleus activity/norepinephrine release (LC-NE). Following earlier research, we investigated PDRs associated with transitions between regular and random patterns of tones in auditory sequences. We presented these sequences to participants and instructed them to find gaps (to maintain attention). Transitions from regular to random patterns induced PDRs, suggesting that an internal model attuned to the regular pattern is reset. Transitions from one regular pattern to another regular pattern also induced PDRs, suggesting that they also led to a model reset. In contrast, transitions from random patterns to regular patterns did not induce PDRs, suggesting a gradual update of model parameters. We modelled these findings, using pupil response functions to show how ongoing PDRs and pupil event rates were sensitive to the trial-by-trial changes in the information content of the auditory sequences. Expanding on previous research, we suggest that PDRs-as biomarkers for LC-NE activation-may indicate the extent of prediction violations.

Late-life depression (LLD) is a psychiatric disorder in older adults, characterized by high prevalence and significant mortality rates. Thus, it is imperative to develop objective and cost-effective methods for detecting LLD. Individuals with depression often exhibit disrupted levels of arousal, and microsaccades, as a type of fixational eye movement that can be measured non-invasively, are known to be modulated by arousal. This makes microsaccades a promising candidate as biomarkers for LLD. In this study, we used a high-resolution, video-based eye-tracker to examine microsaccade behavior in a visual fixation task between LLD patients and age-matched healthy controls (CTRL). Our goal was to determine whether microsaccade responses are disrupted in LLD compared to CTRL. LLD patients exhibited significantly higher microsaccade peak velocities and larger amplitudes compared to CTRL. Although microsaccade rates were lower in LLD than in CTRL, these differences were not statistically significant. Additionally, while both groups displayed microsaccadic inhibition and rebound in response to changes in background luminance, this modulation was significantly blunted in LLD patients, suggesting dysfunction in the neural circuits responsible for microsaccade generation. Together, these findings, for the first time, demonstrate significant alterations in microsaccade behavior in LLD patients compared to CTRL, highlighting the potential of these disrupted responses as behavioral biomarkers for identifying individuals at risk for LLD.

Homeostatic sleep regulation is essential for optimizing the amount and timing of sleep for its revitalizing function, but the mechanism underlying sleep homeostasis remains poorly understood. Here, we show that optogenetic activation of locus coeruleus (LC) noradrenergic neurons immediately increased sleep propensity following a transient wakefulness, contrasting with many other arousal-promoting neurons whose activation induces sustained wakefulness. Fiber photometry showed that repeated optogenetic or sensory stimulation caused a rapid reduction of calcium activity in LC neurons and steep declines in noradrenaline/norepinephrine (NE) release in both the LC and medial prefrontal cortex (mPFC). Knockdown of α2A adrenergic receptors in LC neurons mitigated the decline of NE release induced by repetitive stimulation and extended wakefulness, demonstrating an important role of α2A receptor-mediated auto-suppression of NE release. Together, these results suggest that functional fatigue of LC noradrenergic neurons, which reduces their wake-promoting capacity, contributes to sleep pressure.

The locus coeruleus (LC) is the primary source of noradrenaline (NA) in brain and its activity is essential for learning, memory, stress, arousal, and mood. LC-NA neuron activity varies over the sleep-wake cycle, with higher activity during wakefulness, correlating with increased CSF NA levels. Whether spontaneous and burst firing of LC-NA neurons during active and inactive periods is controlled by mechanisms independent of wakefulness and natural sleep, is currently unknown. Here, using multichannel in vivo electrophysiology under anesthesia, we assessed LC-NA neuron firing in adult male Fisher 344 rats at two different times of day- ZT4- the inactive period (light phase) and ZT16-the active period (dark phase)- independent of contributions from behavioral arousal and natural sleep. In the dark phase, LC-NA neurons exhibit increased average firing rate during baseline compared to the light phase. Using a relatively weak foot shock paradigm, we observed distinct populations of LC-NA neurons with some increasing, and others decreasing, their firing rate compared to baseline. Additionally, while spike frequency during spontaneous and evoked bursts is consistent across the dark-light phase, units recorded during the dark phase have more frequent bursts with a longer duration than those during the light phase. Our findings show that independent of wake state, LC-NA neurons exhibit intrinsic diurnal activity, and that the variability of response to foot shock stimulation demonstrates a physiological heterogeneity of LC-NA neurons that is just beginning to be appreciated.

Multichannel in vivo electrophysiology assesses activity of large populations of NA neurons within an intact LC. Recording activity under anesthesia eliminates influence of behavior and sleep on LC-NA neuron physiology. Our data show that LC-NA neurons have heightened firing and burst activity during the dark phase, suggesting a hardwired diurnal rhythm. Additionally, LC-NA neurons have variable evoked firing highlighting heterogeneity, consistent with a contemporary view that LC physiology is more complex than previously appreciated.

Pupil size is a non-invasive index for autonomic arousal mediated by the locus coeruleus-norepinephrine (LC-NE) system. While pupil size and its derivative (velocity) are increasingly used as indicators of arousal, limited research has investigated the relationships between pupil size and other well-known autonomic responses. Here, we simultaneously recorded pupillometry, heart rate, skin conductance, pulse wave amplitude, and respiration signals during an emotional face-word Stroop task, in which task-evoked (phasic) pupil dilation correlates with LC-NE responsivity. We hypothesized that emotional conflict and valence would affect pupil and other autonomic responses, and trial-by-trial correlations between pupil and other autonomic responses would be observed during both tonic and phasic epochs. Larger pupil dilations, higher pupil size derivative, and lower heart rates were observed in the incongruent condition compared to the congruent condition. Additionally, following incongruent trials, the congruency effect was reduced, and arousal levels indexed by previous-trial pupil dilation were correlated with subsequent reaction times. Furthermore, linear mixed models revealed that larger pupil dilations correlated with higher heart rates, higher skin conductance responses, higher respiration amplitudes, and lower pulse wave amplitudes on a trial-by-trial basis. Similar effects were seen between positive and negative valence conditions. Moreover, tonic pupil size before stimulus presentation significantly correlated with all other tonic autonomic responses, whereas tonic pupil size derivative correlated with heart rates and skin conductance responses. These results demonstrate a trial-by-trial relationship between pupil dynamics and other autonomic responses, highlighting pupil size as an effective real-time index for autonomic arousal during emotional conflict and valence processing.

The noradrenergic locus coeruleus (LC) regulates arousal levels during wakefulness, but its role in sleep remains unclear. Here, we show in mice that fluctuating LC neuronal activity partitions non-rapid-eye-movement sleep (NREMS) into two brain-autonomic states that govern the NREMS-REMS cycle over ~50-s periods; high LC activity induces a subcortical-autonomic arousal state that facilitates cortical microarousals, whereas low LC activity is required for NREMS-to-REMS transitions. This functional alternation regulates the duration of the NREMS-REMS cycle by setting permissive windows for REMS entries during undisturbed sleep while limiting these entries to maximally one per ~50-s period during REMS restriction. A stimulus-enriched, stress-promoting wakefulness was associated with longer and shorter levels of high and low LC activity, respectively, during subsequent NREMS, resulting in more microarousal-induced NREMS fragmentation and delayed REMS onset. We conclude that LC activity fluctuations are gatekeepers of the NREMS-REMS cycle and that this role is influenced by adverse wake experiences.

The ability to prioritize among input features according to relevance enables adaptive behaviors across the human lifespan. However, relevance often remains ambiguous, and such uncertainty increases demands for dynamic control. While both cognitive stability and flexibility decline during healthy ageing, it is unknown whether aging alters how uncertainty impacts perception and decision-making, and if so, via which neural mechanisms. Here, we assess uncertainty adjustment across the adult lifespan (N = 100; cross-sectional) via behavioral modeling and a theoretically informed set of EEG-, fMRI-, and pupil-based signatures. On the group level, older adults show a broad dampening of uncertainty adjustment relative to younger adults. At the individual level, older individuals whose modulation more closely resembled that of younger adults also exhibit better maintenance of cognitive control. Our results highlight neural mechanisms whose maintenance plausibly enables flexible task-set, perception, and decision computations across the adult lifespan.

Sleep disturbances are prevalent in children with autism spectrum disorder (ASD). Strikingly, sleep problems are positively correlated with the severity of ASD symptoms, such as memory impairment. However, the neural mechanisms underlying sleep disturbances and cognitive deficits in ASD are largely unexplored. Here, we show that non-rapid eye movement sleep (NREMs) is fragmented in the 16p11.2 deletion mouse model of ASD. The degree of sleep fragmentation is reflected in an increased number of calcium transients in the activity of locus coeruleus noradrenergic (LC-NE) neurons during NREMs. In contrast, optogenetic inhibition of LC-NE neurons and pharmacological blockade of noradrenergic transmission using clonidine consolidate sleep. Furthermore, inhibiting LC-NE neurons restores memory. Finally, rabies-mediated screening of presynaptic neurons reveals altered connectivity of LC-NE neurons with sleep- and memory-regulatory regions in 16p11.2 deletion mice. Our findings identify a crucial role of the LC-NE system in regulating sleep stability and memory in ASD.

This study aimed to investigate the relationship between intraoperative sleep spindle activity and postoperative sleep disturbance (PSD) in elderly orthopedic surgery patients.

In this prospective observational cohort study, we collected intraoperative electroencephalography (EEG) data from 212 elderly patients undergoing orthopedic surgery from May 2023 to December 2023. We used the Athens Insomnia Scale to assess sleep quality on postoperative day (POD) 1 and POD 3 and analyzed the correlation between intraoperative sleep spindle activity and PSD through logistic regression.

The incidence of PSD was 65.6% on POD 1 and 41.9% on POD 3. On the first day, there were no significant differences in intraoperative sleep spindle characteristics between PSD and non-postoperative sleep disturbance (non-PSD) patients. However, by the third day, PSD patients showed lower sigma power compared to non-PSD patients, as well as lower spindle density in the bilateral frontopolar (Fp1/Fp2) and bilateral temporal (F7/F8) channels, with shorter average spindle duration (P < 0.05). Multivariate logistic regression analysis suggested that the average spindle density in F7/F8 channels (OR 0.543, 95% CI 0.375-0.786; P = 0.001) was an independent risk factor for PSD on POD 3. Furthermore, Mini-Mental State Examination (MMSE) could independently predict PSD on POD 1 (OR 0.806, 95% CI 0.656-0.991; P = 0.041) and POD 3 (OR 0.701, 95% CI 0.562-0.875; P = 0.002). Pain on movement and at rest were independently associated with PSD on POD 1 (OR 1.480, 95% CI 1.200-1.824; P < 0.001) and POD 3 (OR 1.848, 95% CI 1.166-2.927; P = 0.009), respectively.

Intraoperative mean spindle density in the F7/F8 channels was an independent risk factor for PSD on POD 3 in elderly patients undergoing orthopedic surgery. MMSE and postoperative pain also independently increased the risk of PSD.

Exercise activates the dorsal hippocampus that triggers synaptic and cellar plasticity and ultimately promotes memory formation. For decades, these benefits have been explored using demanding and stress-response-inducing exercise at moderate-to-vigorous intensities. In contrast, our translational research with animals and humans has focused on light-intensity exercise (light exercise) below the lactate threshold (LT), which almost anyone can safely perform with minimal stress. We found that even light exercise can stimulate hippocampal activity and enhance memory performance. Although the circuit mechanism of this boost remains unclear, arousal promotion even with light exercise implies the involvement of the ascending monoaminergic system that is essential to modulate hippocampal activity and impact memory. To test this hypothesis, we employed our physiological exercise model based on the LT of rats and immunohistochemically assessed the neuronal activation of the dorsal hippocampal sub-regions and brainstem monoaminergic neurons. Also, we monitored the extracellular concentration of monoamines in the dorsal hippocampus using in vivo microdialysis. We found that even light exercise increased neuronal activity in the dorsal hippocampal sub-regions and elevated the extracellular concentrations of noradrenaline and dopamine. Furthermore, we found that tyrosine hydroxylase-positive neurons in the locus coeruleus (LC) and the ventral tegmental area (VTA) were activated even by light exercise and were both positively correlated with the dorsal hippocampal activation. In conclusion, our findings demonstrate that light exercise stimulates dorsal hippocampal neurons, which are associated with LC-noradrenergic and VTA-dopaminergic activation. This shed light on the circuit mechanisms responsible for hippocampal neural activation during exercise, consequently enhancing memory function.

Cortical activity is constantly fluctuating between distinct spatiotemporal activity patterns denoted by changes in brain state. States of cortical desynchronization arise during motor generation, increased attention, and high cognitive load. Synchronized brain states comprise spatially widespread, coordinated low-frequency neural activity during rest and sleep when disengaged from the external environment or 'offline'. The claustrum is a small subcortical structure with dense reciprocal connections with the cortex suggesting modulation by, or participation in, brain state regulation. Here, we highlight recent work suggesting that neural activity in the claustrum supports cognitive processes associated with synchronized brain states characterized by increased low-frequency network activity. As an example, we outline how claustrum activity could support episodic memory consolidation during sleep.

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.

Physical inactivity, which is a global issue, reduces physical and mental vitality, particularly impairing prefrontal-cortex-based mental health. This may trigger social withdrawal and depression, hindering the ability to have an active lifestyle. However, we have identified a beneficial agent, a vitamin B1 derivative called thiamine tetrahydrofurfuryl disulfide (TTFD), that enhances physical activity through dopaminergic regulation in the medial prefrontal cortex (mPFC) of rats. Since the brain dopaminergic system also regulates the sleep-wake cycle via the ascending arousal system, we postulated that TTFD may promote arousal. To test this, we performed electroencephalograms and electromyograms in rats, monitoring their physical activity and sleep-wake cycles after TTFD injection. Analysis revealed that TTFD acutely promotes arousal, reduces slow-wave sleep (SWS) and rapid eye movement (REM) sleep, and promotes increased physical activity. TTFD not only promotes physical activity but also increases arousal, thereby potentially contributing to enhanced mental health.

The advent of midazolam holds profound implications for modern clinical practice. The hypnotic and sedative effects of midazolam afford it broad clinical applicability. However, the specific mechanisms underlying the modulation of altered consciousness by midazolam remain elusive. Herein, using pharmacology, optogenetics, chemogenetics, fiber photometry, and gene knockdown, this in vivo research revealed the role of locus coeruleus (LC)-ventrolateral preoptic nucleus noradrenergic neural circuit in regulating midazolam-induced altered consciousness. This effect was mediated by α1 adrenergic receptors. Moreover, gamma-aminobutyric acid receptor type A (GABAA-R) represents a mechanistically crucial binding site in the LC for midazolam. These findings will provide novel insights into the neural circuit mechanisms underlying the recovery of consciousness after midazolam administration and will help guide the timing of clinical dosing and propose effective intervention targets for timely recovery from midazolam-induced loss of consciousness.

Peptidergic neurons often co-express fast transmitters and neuropeptides in separate vesicles with distinct release properties. However, the release dynamics of each transmitter in various contexts have not been fully understood in behaving animals. Here, we demonstrate that calcitonin gene-related peptide (CGRP) neurons in the external lateral subdivision of the parabrachial nucleus (CGRPPBel) encode opposing valence via differential release, rather than co-release, of glutamate and neuropeptides, according to firing rate. Glutamate is released preferentially at lower firing rates with minimal release at higher firing rates, whereas neuropeptides are released at higher firing rates, resulting in frequency-dependent switching of transmitters. Aversive stimuli evoke high frequency responses with accompanying neuropeptide release to encode negative valence, whereas appetitive stimuli evoke low frequency responses with glutamate release to encode positive valence. Our study reveals a previously unknown capability of single CGRPPBel neurons to bidirectionally encode valence via frequency-dependent differential release of transmitters in vivo.

The hypothalamus is a master regulator of energy balance in the body. First-order hypothalamic neurons localized in the arcuate nucleus sense systemic signals that indicate the energy stores in the body. Through distinct projections, arcuate nucleus neurons communicate with second-order neurons, which are mostly localized in the paraventricular nucleus and in the lateral hypothalamus. The signals then proceed to third- and fourth-order neurons that activate complex responses aimed at maintaining whole-body energy homeostasis. During the last 30 years, since the identification of leptin in 1994, there has been a great advance in the unveiling of the hypothalamic and extra-hypothalamic neuronal networks that control energy balance. This has contributed to the characterization of the mechanisms by which glucagon-like peptide-1 receptor agonists promote body mass reduction and has opened new windows of opportunity for the development of drugs to treat obesity. This review presents an overview of the mechanisms involved in the hypothalamic regulation of energy balance and discusses how advancements in this field are contributing to the development of new pharmacological strategies to treat obesity.

Neuromodulatory inputs to the hippocampus play pivotal roles in modulating synaptic plasticity, shaping neuronal activity, and influencing learning and memory. Recently, it has been shown that the main sources of catecholamines to the hippocampus, ventral tegmental area (VTA) and locus coeruleus (LC), may have overlapping release of neurotransmitters and effects on the hippocampus. Therefore, to dissect the impacts of both VTA and LC circuits on hippocampal function, a thorough examination of how these pathways might differentially operate during behavior and learning is necessary. We therefore utilized two-photon microscopy to functionally image the activity of VTA and LC axons within the CA1 region of the dorsal hippocampus in head-fixed male mice navigating linear paths within virtual reality (VR) environments. We found that within familiar environments some VTA axons and the vast majority of LC axons showed a correlation with the animals' running speed. However, as mice approached previously learned rewarded locations, a large majority of VTA axons exhibited a gradual ramping-up of activity, peaking at the reward location. In contrast, LC axons displayed a pre-movement signal predictive of the animal's transition from immobility to movement. Interestingly, a marked divergence emerged following a switch from the familiar to novel VR environments. Many LC axons showed large increases in activity that remained elevated for over a minute, while the previously observed VTA axon ramping-to-reward dynamics disappeared during the same period. In conclusion, these findings highlight distinct roles of VTA and LC catecholaminergic inputs in the dorsal CA1 hippocampal region. These inputs encode unique information, with reward information in VTA inputs and novelty and kinematic information in LC inputs, likely contributing to differential modulation of hippocampal activity during behavior and learning.

Perception can be refined by experience, up to certain limits. It is unclear whether perceptual limits are absolute or could be partially overcome via enhanced neuromodulation and/or plasticity. Recent studies suggest that peripheral nerve stimulation, specifically vagus nerve stimulation (VNS), can alter neural activity and augment experience-dependent plasticity, although little is known about central mechanisms recruited by VNS. Here we developed an auditory discrimination task for mice implanted with a VNS electrode. VNS applied during behavior gradually improved discrimination abilities beyond the level achieved by training alone. Two-photon imaging revealed VNS induced changes to auditory cortical responses and activated cortically projecting cholinergic axons. Anatomical and optogenetic experiments indicated that VNS can enhance task performance through activation of the central cholinergic system. These results highlight the importance of cholinergic modulation for the efficacy of VNS and may contribute to further refinement of VNS methodology for clinical conditions.

Adverse childhood experiences have been associated with many neurodevelopmental and affective disorders including attention deficit hyperactivity disorder and generalized anxiety disorder, with more exposures increasing negative risk. Sex and genetic background are biological variables involved in adverse psychiatric outcomes due to early life trauma. Females in general have an increased prevalence of stress-related psychopathologies beginning after adolescence, indicative of adolescence being a female-specific sensitive period. To understand the underlying neuronal mechanisms potentially responsible for this relationship between genetic background, sex, stress/trauma, and cognitive/affective behaviors, we assessed behavioral and neuronal changes in a novel animal model of early life stress exposure. Male and female BALB/cJ mice that express elevated basal anxiety-like behaviors and differences in monoamine signaling-associated genes, were exposed to an early life variable stress protocol that combined deprivation in early life with unpredictability in adolescence. Stress exposure produced hyperlocomotion and attention deficits (5-choice serial reaction time task) in male and female mice along with female-specific increased anxiety-like behavior. These behavioral changes were paralleled by reduced excitability of locus coeruleus (LC) neurons, due to resting membrane potential hyperpolarization in males and a female-specific increase in action potential delay time. These data describe a novel interaction between sex, genetic background, and early life stress that results in behavioral changes in clinically relevant domains and potential underlying mechanistic lasting changes in physiological properties of neurons in the LC.

Noradrenaline (NA) release from the locus coeruleus (LC) changes activity and connectivity in neuronal networks across the brain, modulating multiple behavioral states. NA release is mediated by both tonic and burst-like LC activity. However, it is unknown whether the functional changes in target areas depend on these firing patterns. Using optogenetics, photometry, electrophysiology and functional magnetic resonance imaging in mice, we show that tonic and burst-like LC firing patterns elicit brain responses that hinge on their distinct NA release dynamics. During moderate tonic LC activation, NA release engages regions associated with associative processing, while burst-like stimulation biases the brain toward sensory processing. These activation patterns locally couple with increased astrocytic and inhibitory activity and change the brain's topological configuration in line with the hierarchical organization of the cerebral cortex. Together, these findings reveal how the LC-NA system achieves a nuanced regulation of global circuit operations.

Sleeping animals can be woken up rapidly by external threat signals, which is an essential defense mechanism for survival. However, neuronal circuits underlying the fast transmission of sensory signals for this process remain unclear. Here, we report in mice that alerting sound can induce rapid awakening within hundreds of milliseconds and that glutamatergic neurons in the pontine central gray (PCG) play an important role in this process. These neurons exhibit higher sensitivity to auditory stimuli in sleep than wakefulness. Suppressing these neurons results in reduced sound-induced awakening and increased sleep in intrinsic sleep/wake cycles, whereas their activation induces ultra-fast awakening from sleep and accelerates awakening from anesthesia. Additionally, the sound-induced awakening can be attributed to the propagation of auditory signals from the PCG to multiple arousal-related regions, including the mediodorsal thalamus, lateral hypothalamus, and ventral tegmental area. Thus, the PCG serves as an essential distribution center to orchestrate a global auditory network to promote rapid awakening.

Compared to traditional bio-mimic robots, animal robots show superior locomotion, energy efficiency, and adaptability to complex environments but most remained in laboratory stage, needing further development for practical applications like exploration and inspection. Our pigeon robots validated in both laboratory and field, tested with an electrical stimulus unit (2-s duration, 0.5 ms pulse width, 80 Hz frequency). In a fixed stimulus procedure, hovering flight was conducted with 8 stimulus units applied every 2 s after flew over the trigger boundary. In a flexible procedure, stimulus was applied whenever they deviated from a virtual circle, with pulse width gains of 0.1 ms or 0.2 ms according to the trajectory angle. These optimized protocols achieved a success hovering rate of 87.5% and circle curvatures of 0.008 m-1-0.024 m-1, largely advancing the practical application of animal robots.