Noradrenergic projections from the locus coeruleus (LC) to the thalamus and anterior cingulate cortex (ACC) contribute to pain-like behaviors, yet their hierarchical organization remains unclear. This article examines how locus coeruleus-derived norepinephrine inputs to the paraventricular thalamic nucleus (PVA) and ACC differentially regulate nociceptive sensitization. In adult male and female mice, complete Freund's adjuvant was used to induce pain-like behaviors. To examine functional connectivity among locus coeruleus, PVA, and ACC, targeted recombination in active populations (Fos-TRAP), in vivo recordings, and viral tracing were combined. Then optogenetic and chemogenetic tools were used to selectively manipulate locus coeruleus projections and assess their impact on neural activity and pain behaviors. Complete Freund's adjuvant led to enhanced c-Fos expression in locus coeruleus, PVA, and ACC (cells per microscopic field; locus coeruleus: 13.60 ± 2.24 vs. 44.50 ± 7.72; PVA: 8.00 ± 1.58 vs. 66.40 ± 9.45; ACC: 12.80 ± 2.28 vs. 36.70 ± 2.59; P < 0.001), alongside increased γ-band activity and single-unit firing rates. Monosynaptic LC-ACC and polysynaptic LC-PVA-ACC circuits were identified. Notably, nociception-related locus coeruleus neurons preferentially projected to PVA, which subsequently targeted hyperactive ACC neurons. Under inflammatory pain conditions, activation of the LC-PVA-ACC circuits evoked greater ACC firing (Hz; LC-PVA-ACC vs. LC-ACC: 15.75 ± 2.88 vs. 9.72 ± 2.06; P < 0.001) and tactile stimulus-evoked responses (Hz; 22.98 ± 2.60 vs. 15.34 ± 1.86; P < 0.001) than direct LC-ACC activation. Consistently, optogenetic or chemogenetic manipulation of the LC-PVA-ACC circuit produced stronger modulation of mechanical and thermal pain sensitivity than direct LC-ACC stimulation. This study identified the LC-PVA-ACC pathway as a hierarchical noradrenergic circuit that modulates nociceptive sensitization via a thalamocortical relay, thereby revealing a circuit-specific mechanism by which the locus coeruleus-norepinephrine system regulates pain processing.

Narcolepsy type 1 (NT1) is presumed to be an autoimmune disorder caused by hypothalamic loss of hypocretin (Hcrt; orexin). In postmortem NT1 brains, we observed an 11-fold increase of CD4+ T-cells in the Hcrt region compared with control hypothalami, without a corresponding rise in CD8+ T-cells. CD4+ and CD8+ T-cell numbers were unchanged in other hypothalamic regions, including the paraventricular nucleus and median eminence, and in extra-hypothalamic areas such as the substantia nigra and locus coeruleus. Hcrt-region CD4+ T-cells expressed the tissue-resident memory markers CD49a and CXCR6. These findings support the autoimmune hypothesis of NT1. ANN NEUROL 2026.

The locus coeruleus (LC) plays important roles in sleep/wake regulation and cognitive functions. LC neurons may be particularly sensitive to neural injury and serve as an early site of accumulation pathological tau in Alzheimer's disease. Obstructive sleep apnea (OSA) creates both chronic intermittent hypoxia and sleep fragmentation as potential insults to differentially sensitive neural populations including the LC. Using high field 7T imaging in cognitively normal older adults, we demonstrate that time spent with an oxygen saturation below 90% (T90), a measure of OSA's hypoxic burden, inversely correlates with LC structural integrity and explains significant variance in LC structural integrity after controlling for age, sex, and BMI. In contrast, other sleep variables such as the apnea-hypopnea index, total sleep time, and sleep efficiency did not contribute significant variance in LC structural integrity in this model. Thus, in the diagnosis of OSA, attention to hypoxic burden variables may be important in risk stratification for LC neural injury. This observation may inform future work determining whether mitigation of the hypoxemic burden from OSA can slow deterioration in LC integrity.

Stress undermines extinction learning and hinders exposure-based clinical therapies for a variety of neuropsychiatric disorders. In both animals and humans, dysfunction in the ventromedial prefrontal cortex (vmPFC) contributes to stress-impaired extinction, but the neural circuit by which stress modulates vmPFC function is not known. We hypothesize that locus coeruleus (LC) norepinephrine undermines extinction learning by recruiting projections from the basolateral amygdala (BLA) to vmPFC. Using a combination of circuit-specific chemogenetics and calcium imaging, we find that activation of LC noradrenergic neurons mimics a behavioral stressor (footshock), induces freezing behavior, reduces spontaneous neuronal activity in the vmPFC, impairs extinction learning, and alters the population dynamics of vmPFC ensembles. Activation of LC also increases shock-induced responses in BLA neurons that project to vmPFC. Selective chemogenetic activation of LC→BLA projections impairs extinction; propranolol infusions into the BLA mitigate the effects of LC activation. Together, these results indicate that the BLA serves as a critical interface between the LC and mPFC to mediate stress-induced extinction impairments.

Attention-deficit/hyperactivity disorder (ADHD) often emerges in early childhood; however, objective validated biomarkers for its early detection remain limited. In this study, we aimed to identify pupil-based candidate physiological markers (i.e., physiological correlates) associated with ADHD-related traits in preschool- and early school-aged children. To this end, we recorded the pupil diameters of typically developing children without an ADHD diagnosis during a simple fixation task. From these data, we extracted multiple features, including the mean pupil size, temporal variability, and interocular asymmetry in both magnitude and variability. ADHD-related tendencies were assessed using the ADHD Rating Scale-5. Among the features analyzed, only the temporal variability of interocular asymmetry (VarLRdiff) showed a significant positive correlation with ADHD Rating Scale-5 total and subscale scores. This association likely reflects the combined effects of immature autonomic regulation and functional asymmetry in the neural circuits involving the locus coeruleus. In contrast, other pupil-based indices showed no significant correlations, potentially because of developmental ceiling effects and the short evaluation duration. These findings suggest that VarLRdiff may serve as a promising candidate physiological marker of ADHD-related traits in young children, requiring further validation. Future studies incorporating longer recordings, advanced analytical methods, and evaluation of test–retest stability, as well as longitudinal follow-up, are warranted to evaluate its potential utility for early screening, pending clinical and longitudinal validation.

It is known that stress powerfully alters pain, but its underlying mechanisms remain elusive. Here, we identified a circuit, locus coeruleus descending noradrenergic neurons projecting to the spinal dorsal horn (LC →SDH -NA neurons), that is activated by acute exposure to restraint stress and is required for stress-induced mechanical pain hypersensitivity in mice. Interestingly, the primary target of spinal NA released from descending LC →SDH -NAergic terminals causing the stress-induced pain hypersensitivity was α 1A -adrenaline receptors (α 1A Rs) in Hes5 -positive ( Hes5 + ) astrocytes located in the SDH, an astrocyte subset that has an ability to induce pain sensitization. Furthermore, activation of Hes5 + astrocytes reduced activity of SDH-inhibitory neurons (SDH-INs) that have an inhibitory role in pain processing. This astrocytic reduction of IN activity was canceled by an A 1 -adenosine receptor (A 1 R)-knockdown in SDH-INs, and the A 1 R-knockdown suppressed pain hypersensitivity caused by acute restraint stress. Therefore, our findings suggest that LC →SDH -NA neuronal signaling to Hes5 + SDH astrocytes and subsequent astrocytic reduction of SDH-IN activity are essential for mechanical pain facilitation caused by stress.

It is known that stress powerfully alters pain, but its underlying mechanisms remain elusive. Here, we identified a circuit, locus coeruleus descending noradrenergic neurons projecting to the spinal dorsal horn (LC→SDH-NA neurons), that is activated by acute exposure to restraint stress and is required for stress-induced mechanical pain hypersensitivity in mice. Interestingly, the primary target of spinal NA released from descending LC→SDH-NAergic terminals causing the stress-induced pain hypersensitivity was α1A-adrenaline receptors (α1ARs) in Hes5-positive (Hes5+) astrocytes located in the SDH, an astrocyte subset that has an ability to induce pain sensitization. Furthermore, activation of Hes5+ astrocytes reduced activity of SDH-inhibitory neurons (SDH-INs) that have an inhibitory role in pain processing. This astrocytic reduction of IN activity was canceled by an A1-adenosine receptor (A1R)-knockdown in SDH-INs, and the A1R-knockdown suppressed pain hypersensitivity caused by acute restraint stress. Therefore, our findings suggest that LC→SDH-NA neuronal signaling to Hes5+ SDH astrocytes and subsequent astrocytic reduction of SDH-IN activity are essential for mechanical pain facilitation caused by stress.

Altered locus coeruleus links to atrophy and hypometabolism in individuals with high Alzheimer's disease biomarkers.

Sex and life experience shape locus coeruleus pretangle tau pathology.

The locus coeruleus modulates acute itch via ERK-dependent neuronal excitability.

The role of resting-state functional connectivity of locus coeruleus in attention decline after acute sleep deprivation.

Excessive alcohol consumption and stress are associated with structural and functional alterations in the brain and impaired cognition. However, the persistence of long-term neural impacts after alcohol and stress is less understood. This study investigated midlife cognition and neuropathological changes following a history of alcohol and stress exposure. C57BL/6J mice acclimated to ethanol drinking (15% v/v) before exposure to four cycles of alternating chronic intermittent ethanol (CIE) vapor exposure and repeated forced swim stress (FSS), with control groups exposed to air and no stress (AIR/NS). After 3 months of abstinence, mice were evaluated at midlife (11 months old) on volitional drinking and a final CIE/FSS challenge for stress-induced drinking. Spatial learning and cognitive flexibility were assessed using the Barnes maze before brains were collected to evaluate locus coeruleus (LC) integrity at 12 months old. CIE/FSS increased volitional alcohol intake, and this drinking phenotype persisted through to midlife despite extended abstinence. CIE/FSS mice showed intact spatial learning but impaired flexibility in the Barnes maze reversal phase. Flexibility impairments were driven by decreased time in the target quadrant and increased errors during the reversal test compared with AIR/NS. Furthermore, CIE/FSS mice showed pathological measures of reduced LC integrity common to dementia-related disorders, including elevated markers of oxidative stress, apoptosis, and reduced autoinhibitory function. Our findings highlight the long-lasting impact of alcohol and stress exposure on cognition, with flexibility impairments persisting into midlife. In addition to cognitive changes, alcohol and stress history produced pathological changes in the LC, an area known to mediate cognitive flexibility via its forebrain projections. Together, these results give insight into the long-lasting impacts of chronic alcohol and stress and how they may accelerate age-related cognitive decline.

Activating the vlPAG-LC neural pathway alleviates neuropathic pain and comorbid anxiety-like behaviors through distinct projections.

Background: Posttraumatic stress disorder (PTSD) is a mental illness in which central stress-regulating regions, including locus coeruleus (LC) and paraventricular nucleus of hypothalamus (PVN), play key roles. Clonidine, a central sympatholytic drug, can inhibit LC activity and reduce PTSD-related symptoms, suggesting noradrenergic involvement. Glia-driven immune mechanisms may link LC activity to PVN responses. Since TRPA1 ion channel is implicated in both neuroinflammation and stress adaptation, we aimed to determine whether its presence modulates the function of brain structures contributing to PTSD-related alteration in central stress adaptation. Methods: Foot shock PTSD model was applied to Trpa1 wild-type (WT) and knockout (KO) mice, and outcomes were assessed four weeks later. Immunohistochemistry was used to evaluate tyrosine hydroxylase (TH) levels in the LC and glial activation in the PVN. Behavioral effects of clonidine and circulating corticosterone levels were also examined. Results: Stress increased LC/TH immunoreactivity and PVN glial activation. Trpa1 deletion exaggerated LC/TH responses but reduced PVN astrocyte activation. Clonidine increased freezing and decreased jumping (a hyperarousal marker). KO mice showed enhanced jumping and did not respond to clonidine. Corticosterone levels remained unchanged. Conclusions: TRPA1 may support stress adaptation in PTSD by regulating LC noradrenergic output and PVN neuroinflammation, independently of α2-adrenergic signaling.

Locus coeruleus (LC) noradrenergic neurons project their axons to the cerebellar cortex and modulate cerebellar circuit function via distinct adrenergic receptor (AR) subtypes. The present study investigated the mechanism by which optogenetic activation of LC noradrenergic neurons modulates facial stimulation-evoked long-term synaptic plasticity at cerebellar mossy fiber-granule cell (MF-GrC) synapses in urethane-anesthetized DBH-Cre mice. Blockade of GABAA receptors, 20 Hz facial stimulation induced MF-GrC long-term potentiation (LTP) in the control group, and this LTP was impaired by optogenetic activation of LC noradrenergic neurons via α2-ARs. Meanwhile, facial stimulation induced LTP of glutamate sensor fluorescence in the granular layer, which was abolished by chemogenetic activation of LC noradrenergic neurons. Following NMDA receptor blockade, optogenetic activation of LC noradrenergic neurons triggered facial stimulation-induced MF-GrC long-term depression (LTD) via α2A-ARs. Optogenetically activated LC noradrenergic neuron-induced MF-GrC LTD was abolished by protein kinase A (PKA) inhibition but not by protein kinase C inhibition. Immunofluorescence results revealed abundant α2A-AR expression in the granular layer, with particularly high levels in glomeruli, and no colocalization with the glutamate sensor. These results indicate that optogenetic activation of LC noradrenergic neurons impairs facial stimulation-induced MF-GrC LTP by triggering presynaptic LTD via the α2A-AR/PKA signaling cascade.

To investigate the fiber connections between the claustrum (CLA)/insular cortex (IC) and the locus coeruleus (LC), as well as the role of this neural pathway in neuropathic pain, morphological techniques, patch-clamp recording, and chemogenetics were used in this study, to observe the CLA/IC-LC neural pathway in mice, the effects of neuropathic pain stimuli on the electrophysiological properties of CLA/IC neurons, and the impact of regulating the pathway on pain behaviors, respectively. The results showed that: (1) After injecting anterograde tracing virus into the CLA/IC, anterogradely labeled fibers and terminals were observed in the ipsilateral LC. When retrograde tracers were injected into the LC, retrogradely labeled neurons were observed in both the ipsilateral CLA/IC, whereas fewer labeled neurons were observed in the contralateral side; (2) In the neuropathic pain state, the presynaptic release of neurotransmitters from CLA/IC-LC projection neurons was increased, postsynaptic receptor responses were enhanced, and the number of action potential discharges was elevated; (3) Specific inhibition of the CLA/IC-LC neural pathway induced pain responses in sham-operated mice; specific activation of this pathway alleviated pain-related behaviors in neuropathic pain mice. The present results indicate the existence of functional projection from the CLA/IC to the LC. Under neuropathic pain condition, the CLA/IC-LC pathway exhibits enhanced neuronal activity, and selective activation of this pathway produces significant analgesic effects against neuropathic pain.

Central to the linkage of pain circuitry with the limbic system is its initial NAα2-mediated antinociceptive effect in acute pain models, followed by contradictory pronociceptive activation by the locus coeruleus seen in chronic pain models. Rats with a stable, long-term (>10 weeks) inflammatory compression of the trigeminal infraorbital nerve (FRICT-ION) preclinical model were given daily doxazosin, a slow-release NAα1 receptor antagonist, in weeks 8-10. Facial hypersensitivity was reversed back to baseline in male and female rats, but anxiety was only reduced in male animals. Doxazosin-decreased astrocytic activation was indicated by a decrease in both intracranial cathepsin B imaging in vivo and GFAP immunostaining in the somatosensory cortex and hippocampus. Doxazosin reduction in NAα1 receptor activation diminished glial-neuronal interactions, resulting in downstream reduction in pain-related behaviors. Other significant differences by sex included improved elevated zero maze anxiety measures only in males, and improved novel recognition scores only in females. Elevated thymus chemokine CXCL7 levels were reduced by doxazosin but only in male rats. These sexually dimorphic contradictions further complicate the understanding of the noradrenergic system's involvement in nociception. The findings indicate that by reducing NAα1 receptor drive with doxazosin, the role of the locus coeruleus can be shifted back to NAα2-receptor-mediated pain inhibition.

Vestibulo-ocular reflex (VOR) impairment has been reported in Parkinson's disease (PD). However, the clinical implications, particularly for cognition remains unclear. We investigated canal-specific VOR changes and their associations with cognitive function, motor symptoms, gaits, and dopamine transporter (DAT) uptake in de-novo PD. We prospectively enrolled 127 patients with de- novo PD who underwent video head-impulse tests (video-HITs), comprehensive neuropsychological assessment, gait analysis, and FP-CIT PET. Associations between VOR gains and clinical characteristics of PD were evaluated using general linear models adjusted for age, sex, and education. Cognitive analyses were performed after stratifying patients into PD with normal cognition (PD-NC) and PD with mild cognitive impairment (PD-MCI). Partial correlation analyses assessed relationships between VOR gains and regional DAT uptake. Decreased VOR gain in at least one canal was observed in 22 patients (17.3%). Horizontal canal (HC) gain was positively associated with the Montreal Cognitive Assessment (p=0.040), anterior canal (AC) gain had negative association with the base of support (p=0.018). Patterns of association between VOR gains and neuropsychological measures differed between PD-NC and PD-MCI. In addition, VOR-cognition relationships were canal-specific: HC gain was positively related to visuospatial function, whereas AC and posterior canal gains were negatively related to language and frontal-executive functions. DAT uptake in the locus coeruleus was positively correlated with HC gain (p=0.020). Conclusion: VOR integrity is associated with cognitive and gait function in patients with PD. Video-HITs may serve as a potential biomarker for disease monitoring in PD.

Transcutaneous vagus nerve stimulation (tVNS) has emerged as a method for interrogating the role of the locus coeruleus (LC) norepinephrine system in human behavior. Tuning of excitability in the corticospinal tract is central to many cognitive and motor processes, but little is known about how the LC contributes to this tuning. In particular, no existing studies have examined the effect of tVNS on corticospinal excitability "online" during active stimulation, where the largest effects on pupil size are observed. To address this question, we delivered repeated 4-second trains of tVNS and sham stimulation and elicited motor evoked potentials (MEPs) during stimulation trains (online) and shortly after train offset (offline). Pupil size was concurrently recorded throughout each train. We discovered that tVNS significantly increases corticospinal excitability compared to sham stimulation, but only when measured online and not offline. The excitatory effects on corticospinal excitability were greater in the latter half of tVNS trains. Pupil size was also significantly increased by tVNS compared to sham; however, the effect on pupil size peaked earlier during the tVNS trains compared to corticospinal excitability. In line with these distinct temporal profiles, changes in corticospinal excitability and pupil size were not significantly correlated, likely reflecting differences in the anatomical circuits underpinning each effect. This work demonstrates for the first time that tVNS increases corticospinal excitability at rest, but the effect only emerges when corticospinal excitability is measured online during active tVNS. Implications for basic and clinical neuroscientific research are discussed.

Neuromelanin-sensitive imaging visualizes degeneration of the substantia nigra pars compacta (SNc) and locus coeruleus (LC), characteristic features of Parkinson's disease (PD). Spectral presaturation with inversion recovery (SPIR), using fat-selective radiofrequency pulses, has been reported to provide superior delineation of the SNc and LC in healthy individuals and offers shorter acquisition times than conventional magnetization transfer (MT) imaging. This study evaluated the clinical utility of SPIR imaging for assessing PD compared with MT imaging. Neuromelanin-sensitive images were acquired from 24 patients with PD and 24 healthy controls using MT and SPIR sequences, each with an acquisition time of approximately five minutes. Signal ratios (SRs) of the SNc and LC were automatically quantified using established brain atlases. For each sequence and brain region, diagnostic performance in distinguishing PD from controls was assessed using receiver operating characteristic curve analysis. In patients with PD, associations between SRs and nigrostriatal degeneration, as measured by dopamine transporter SPECT imaging, were investigated. SPIR images yielded higher SRs in the SNc than MT images. Diagnostic accuracy for PD with SPIR imaging (87.50%) was significantly greater than that with MT imaging (77.08%). SRs of the SNc and LC on SPIR images were correlated with nigrostriatal degeneration on dopamine transporter SPECT, unlike MT images. SPIR imaging demonstrated superior visualization of the SNc and LC, and outperformed MT imaging in the evaluation of PD. With shorter acquisition time and stronger correlation with nigrostriatal degeneration, SPIR represents a promising and practical tool for diagnosing and monitoring PD.