Search Results (70)

Following acute infection, herpes simplex virus type 1 (HSV-1) establishes life-long latency in neurons. Although sensory neurons in trigeminal ganglia (TG) are primary sites for latency, the brainstem is also an important site for latency. The rationale for examining the principal sensory nucleus of the spinal trigeminal tract (Pr5) receives afferent inputs from TG. Notably, the (LC) is indirectly linked to Pr5. Our previous studies revealed that senescent cells and inflammation were detected in the Pr5 and LC of aged mice and young mice that are latently infected with HSV-1. To expand our understanding of how HSV-1 influences senescence and inflammation in Pr5 and LC, NanoString studies in mice latently infected with wild-type HSV-1 or a latency-associated transcript (LAT) null mutant (dLAT2903) was compared to age-matched uninfected C57Bl/6 male and female mice. LAT is the only viral gene abundantly expressed during latency, suggesting it influences cellular gene expression during latency. Cellular genes that regulate neuron differentiation, axonal projection, and pro-inflammatory mediators were more prevalent in mice latently infected with wild-type (wt) HSV-1 and dLAT2903 versus uninfected mice. Finally, these studies revealed that latency in Pr5 and LC is a dynamic process. Full article

Unbiased stereology represents the most accurate approach for estimating the total number of neurons of specific brain regions; however, its reliability critically depends on the use of rigorously defined and anatomically appropriate sampling parameters. The brain nucleus Locus Coeruleus (LC) plays a key role in several brain functions. LC impairment has been associated with a range of disorders affecting individuals across the lifespan, from infancy to adulthood. In animal models of these conditions, precise estimation of LC neuronal number is essential. The LC analysis poses specific methodological challenges due to its small size, indistinct anatomical boundaries, and age-dependent changes in neuronal density. In this study, we present a detailed and reproducible stereological workflow for the quantification of LC neurons in the mouse brain across the lifespan. Using C57BL/6J mice at postnatal, adult, and aged stages, we optimized all key components of the Optical Fractionator method, LC neurons were identified by immunoperoxidase staining for tyrosine hydroxylase (TH) and quantified using systematic-random sampling implemented in Stereo Investigator^® software. We show that age-specific adjustment of stereological parameters is necessary to obtain reliable estimates, particularly at early postnatal stages characterized by high neuronal packing density. With the optimized protocols described here, TH+ LC neuron counts consistently met accepted precision criteria, as assessed by the Gundersen coefficient of error. Full article

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 GABA_A 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. Full article

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. Full article

Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common chronic disorder of gut–brain interaction characterized by intestinal dysmotility. Central sensitization has a proposed role in intestinal dysmotility, yet the precise neural circuits and mechanisms remain poorly understood. In this study, we established a neonatal maternal deprivation plus restraint stress (NMD + RS) mouse model that recapitulates key diarrhea-like phenotypes. Neural activation mapping revealed a significant upregulation of c-Fos expression within the medial prefrontal cortex (mPFC) and locus coeruleus (LC), which was predominantly localized to glutamatergic neurons. Chemogenetic inhibition of mPFC glutamatergic neurons suppressed intestinal dysmotility, whereas the activation of mPFC glutamatergic neurons evoked intestinal dysmotility in control mice. Furthermore, viral tracing revealed direct projections from mPFC neurons to glutamatergic neurons in the LC. Subsequent chemogenetic manipulation of these LC glutamatergic neurons receiving projection from mPFC neurons similarly regulated intestinal motility, demonstrating a functional downstream node. Critically, selective activation of the mPFC-LC glutamatergic circuit significantly induced intestinal dysmotility in CON mice. In contrast, inhibition of the mPFC-LC glutamatergic circuit significantly ameliorated intestinal dysmotility in NMD + RS mice. Our findings proved that the enhanced activity of the mPFC-LC circuit led to intestinal dysmotility in NMD + RS mice, hopefully providing new mechanistic perspectives and a potential neuromodulatory target for clinical management of IBS. Full article

Background: The current biomarker classification system does not fully explain the increased prevalence of both Alzheimer’s disease (AD) and vascular risk factors for AD—such as diabetes and hypertension--among African Americans (AAs) compared to White participants. Research on cognitive aging has traditionally focused on how declines in cortical and hippocampal regions influence cognition. However, tau pathology emerges decades before amyloid pathology, initially appearing in the brainstem, particularly in the locus coeruleus (LC), the primary source of the brain’s norepinephrine (NE). Further, postmortem studies suggest that the loss of LC neurons is a better predictor of AD symptom severity than amyloid-beta/neurofibrillary tangle pathology in any other brain region. Methods: Our decade-long studies in humans using a norepinephrine transporter (NET)-selective radiotracer ([¹¹C]MRB) have demonstrated that LC is uniquely vulnerable to aging and stress. In this retrospective study, regression slopes with age (RSAs) for regional NET availability were compared across groups and tested for statistical significance. Results: In our primary analysis, higher NET availability was observed in AAs (N = 14; 7 males aged 23–49), particularly at younger ages, as compared to White (N = 16; 11 males aged 24–55) participants. Our preliminary data also suggest that the rate of decline in NET availability is faster in AAs, with a potential trend toward a more pronounced effect in AA males as compared to White males (e.g., in the left thalamus, RSA was −3.03%/year [95%CI: −5.80% to 1.19%] for AA males vs. RSA = −0.14 for White males [95%CI: −0.79% to 0.47%]. Additionally, in the right anterior cingulate cortex, RSA was −3.4%/year [95%CI: −4.6% to −1.4%] for AA males, compared to RSA = 0.3%/year [95%CI: 0.04% to 1.03%] for White males). Conclusions: This report reveals that NET availability (measured with [¹¹C]MRB) can serve as a biomarker to index the function of the LC-NE system and that the fast-decline rate of NET in AAs implicates a potential molecular mechanism underlying health disparities observed in the disproportionate AD prevalence. Full article

Background/Objectives: Migraine is a complex neurological headache disorder, and transcutaneous auricular vagus nerve stimulation (taVNS) can effectively relieve headache symptoms, but its mechanism of effect is still unclear. This study aimed to explore the regulatory effects of taVNS on the locus coeruleus (LC) and the norepinephrine (NE) system in migraine mice. Methods: C57/BL6 mice were randomly assigned to four experimental groups: the control group, model group, taVNS group, and sham taVNS group. A migraine model was established by administration of nitroglycerin. Headache behaviors were assessed using the orofacial stimulation test (OST) and the mouse grimace scale (MGS). Immunofluorescence staining was conducted to evaluate the expression of NE neurons in the LC, while Western blotting was used to determine the expression levels of α-2A adrenergic receptors in the spinal trigeminal nucleus caudalis (Sp5C). Additionally, fiber-optic recording was employed to monitor the real-time dynamics of NE release in Sp5C. Results: After taVNS intervention, the drinking time of OST in the model mice was significantly prolonged(p < 0.05), and facial expression scores were reduced (p < 0.05). TaVNS increased the number of NE neurons in the LC (p < 0.05), promoted the release of NE in Sp5C (p < 0.05), and upregulated the expression of α-2A adrenergic receptors in Sp5C (p < 0.05). Conclusions: The analgesic effects of taVNS are related to the activation of the LC-NE system and the inhibition of the decrease in Sp5C in migraine mice. Full article

Development of new therapeutic approaches and strategies for common neuropsychiatric disorders, including Major Depressive Disorder, anxiety disorders, and Post-Traumatic Stress Disorder, represent a significant global health challenge. Recent research indicates that emotional dysregulation and persistent inflammation are closely linked and serve as key pathophysiological features of these conditions. Emotional dysregulation is mechanistically coupled to locus coeruleus and norepinephrine (LC-NE) or noradrenergic system activity. Stemming from chronic stress, persistently elevated activity of the LC-NE system leads to hypervigilance, anxious states, and depressed mood. Concurrently, these symptoms are marked by systemic inflammation as indicated by elevated pro-inflammatory cytokines, and central neuroinflammation indicated by microglial activation in brain regions and networks involved in mood regulation and emotional control. In turn, chronic inflammation increases sympathetic tone and LC-NE activity resulting in a vortex of psychoneuroimmunological dysfunction that worsens mental health. Transcutaneous auricular vagus nerve stimulation (taVNS) in a non-invasive neuromodulation method uniquely positioned to address both noradrenergic dysfunction and chronic inflammation in neuropsychiatric applications. Evidence spanning the past decade demonstrates taVNS works via two complementary mechanisms. An ascending pathway engages vagal afferents projecting to the LC-NE system in the brain stem, which has been shown to modulate cortical arousal, cognitive function, mood, and stress responses. Through descending circuits, taVNS also modulates the cholinergic anti-inflammatory pathway to suppress the production of pro-inflammatory cytokines like TNF-α and IL-6 mitigating poor health outcomes caused by inflammation. By enhancing both central brain function and peripheral immune responses, taVNS has shown significant potential for recalibrating perturbed affective-cognitive processing. The present article describes and discusses recent evidence suggesting that taVNS offers a promising network-based paradigm for restoring psychoneuroimmunological homeostasis in common neuropsychiatric conditions. Full article

Brain function is reliant upon maintaining a constant internal environment; however, the methods employed to maintain this environment have historically been viewed as largely passive in nature, relying on diffusion and vascular pulsations to create the conditions necessary for continued brain activity. This review seeks to provide an overview of current data suggesting that brain clearance is in fact an active process that is dependent upon both the current regulatory state of the brain and the presence of noradrenergic slow vasomotion, which is generated by rhythmic output from the locus coeruleus (LC). The LC-generated output has been found to influence the degree of contraction exhibited by pericytes, the geometric shape of astrocytic end-feet, and vascular tone, ultimately impacting the rate of exchange between cerebrospinal fluid (CSF), interstitial fluid (ISF), and the blood–brain barrier through aquaporin-4 (AQP4) channels. These LC-generated rhythmic changes are thought to provide the mechanical forces necessary for sustaining the metabolic clearance of waste products within the parenchyma. This review seeks to synthesize several recent studies which indicate that LC-generated vasomotion correlates with both the structure and progression of sleep states, neuronal oscillation patterns, and metabolic states, and that dysfunction of this LC-generated rhythm may contribute to pathological features associated with Alzheimer’s disease, Parkinson’s disease, and small-vessel disease. Understanding the mechanisms of clearance within the brain as a physiologically tunable system will allow researchers to view brain clearance as an adaptive neuro-modulatory function rather than merely as a passive event. Therefore, the focus of this review is on identifying the potential applications of advancements in the field of physiological imaging, molecular biomarkers, and neuro-modulatory or vascular-based therapies for early detection and therapeutic manipulation of clearance processes. Understanding these mechanisms will potentially lead to enhanced cognitive resilience and immune regulation, and promote healthy brain aging. Full article

The locus coeruleus-norepinephrine (LC-NE) system is a phylogenetically conserved neuromodulatory hub that regulates fundamental brain states and behaviors, including arousal, cognition, emotion, and pain. This review integrates two critical perspectives to provide a unified framework for understanding this system. First, we synthesize the evolutionary trajectory of the LC from non-mammalian to mammalian vertebrates, highlighting conserved properties and changes in cell number, anatomical projections, and physiological functions. Second, we detail the intricate connectivity of its afferent and efferent circuits, explaining how specific inputs and outputs modulate LC activity and govern diverse behaviors under physiological and disease conditions. Together, we aim to highlight the central role of the LC in brain function and disease through an evolutionary and circuit-based lens. Full article

Background: Royal jelly is a protein-rich honeybee secretion that is used in the nutrition of larvae and adult queens. Previous studies have reported that royal jelly had induced pro-cognitive, anxiolytic, and antidepressant-like effects in laboratory rats. Since serotonin (5-HT), noradrenaline, and dopamine play an important role in the control of several mental functions, changes in the excitability of monoaminergic neurons may be involved in the mechanisms of the behavioral and neurochemical effects of royal jelly. The present study aimed to test this hypothesis. Methods: Adult male Wistar rats were treated with royal jelly for two weeks. Thereafter, their cognitive performance was evaluated using the novel object recognition (NOR) test. The excitability of monoaminergic neurons was assessed using in vivo single-unit extracellular electrophysiology. Results: We found that rats treated with royal jelly had a higher recognition index in the NOR test and a higher burst activity of dopaminergic neurons of the ventral tegmental area (VTA) compared to the vehicle-treated controls. The firing activities of 5-HT neurons of the dorsal raphe nucleus (DRN) and the noradrenergic neurons of the locus coeruleus (LC) were not altered. Conclusions: We conclude that the pro-cognitive effect of royal jelly is mediated, at least in part, by mechanisms involving the excitability of mesolimbic dopaminergic neurons. The present findings encourage further research towards the improvement of the safety and efficacy of currently available therapies for cognitive dysfunction. Full article

Locus Coeruleus (LC) is a brain nucleus that is involved in a variety of key functions (ranging from attention modulation to sleep–wake cycle regulation, to memory encoding); its proper function is necessary both during brain development and for brain integrity maintenance, and both at the microscale and macroscale level. Due to their specific intrinsic and extrinsic features, LC cells are considered particularly susceptible to damage concerning a variety of insults. This explains LC involvement in degenerative diseases not only in adults (in the context of neurodegenerative disease, mainly), but also in children (in relation to early hypoxic damage and Down’s Syndrome, among others). In this narrative review, we dissect the potential mechanisms through which LC is affected in different diseases, with a special emphasis on the high rate of activity it is subjected to and the oxidative stress associated with it. Further research aimed at deepening our understanding of these mechanisms is needed to enable the development of potential strategies in the future that could slow down LC degeneration in subjects predisposed to specific brain disorders. Full article

The gut–brain axis represents an important bidirectional communication network, with the vagus nerve acting as a central conduit for peripheral signals from the various gut organs to the central nervous system. Among the molecular mediators involved, serotonin (5-HT), synthesized predominantly by enterochromaffin cells in the gut, plays a pivotal role. Gut-derived serotonin activates vagal afferent fibers, transmitting signals to the nucleus tractus solitarius (NTS) and modulating serotonergic neurons in the dorsal raphe nucleus (DRN) as well as the norepinephrinergic neurons in the locus coeruleus (LC). This interaction influences emotional regulation, stress responses, and immune modulation. Emerging evidence also highlights the role of microbial metabolites, particularly short-chain fatty acids (SCFAs), in enhancing serotonin synthesis and vagal activity, thereby shaping gut–brain communication. This review synthesizes the current knowledge on serotonin signaling, vagal nerve pathways, and central autonomic regulation, with an emphasis on their implications for neuropsychiatric and gastrointestinal disorders. By elucidating these pathways, novel therapeutic strategies targeting the gut–brain axis may be developed to improve mental and physical health outcomes. Full article

Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation technique that modulates the noradrenergic activity of the locus coeruleus (LC). Yet, there is still uncertainty about the most effective stimulation and reliable outcome parameters. In a double blind, sham-controlled study including a sample of healthy young individuals (N = 29), we compared a shorter (3.4 s) and a longer (30 s) stimulation duration and investigated the effects of taVNS (real vs. sham) on saliva samples (alpha amylase and cortisol concentration), pupil (pupillary light reflex and pupil size at rest) and EEG data (alpha and theta activity at rest, ERPs for No-Go signals), and cognitive tasks (Go/No-Go and Stop Signal Tasks). Salivary alpha amylase concentration was significantly increased in the real as compared to sham stimulation for the 30 s stimulation condition. In the 3.4 s stimulation condition, we found prolonged reaction times and increased error rates in the Go/No-Go task and increased maximum acceleration in the pupillary light reflex. For the other outcomes, no significant differences were found. Our results show that prolonged stimulation increases salivary alpha-amylase, which was expected from the functional properties of the LC. The finding of longer response times to short taVNS stimulation was not expected and cannot be explained by an increase in LC activity. We also discuss the difficulties in assessing pupil size as an expression of taVNS-mediated LC functional changes. Full article

The insular cortex is an important hub for sensory and emotional integration. It is one of the areas consistently found activated during pain. While the insular’s connections to the limbic system might play a role in the aversive and emotional component of pain, its connections to the descending pain system might be involved in pain intensity coding. Here, we used anterograde tracing with viral expression of mCherry fluorescent protein, to examine the connectivity of insular axons to different brainstem nuclei involved in the descending modulation of pain in detail. We found extensive connections to the main areas of descending pain control, namely, the periaqueductal gray (PAG) and the raphe magnus (RMg). In addition, we also identified an extensive insular connection to the parabrachial nucleus (PBN). Although not as extensive, we found a consistent axonal input from the insula to different noradrenergic nuclei, the locus coeruleus (LC), the subcoereuleus (SubCD) and the A5 nucleus. These connections emphasize a prominent relation of the insula with the descending pain modulatory system, which reveals an important role of the insula in pain processing through descending pathways. Full article