Acute skin failure (ASF) is an understudied complication in patients with septic shock, and existing predictive models lack disease-specific variables. This study aimed to investigate the characteristics of cutaneous manifestations in patients with septic shock and to identify potential biomarkers and predictive factors for cutaneous deterioration. This retrospective cohort study analysed 154 adult patients with septic shock, defined according to the Sepsis 3.0 criteria, who were admitted to a tertiary intensive care unit (ICU) between September 2020 and September 2022. Based on cutaneous manifestations observed during hospitalisation, the patients were stratified into two groups: the ASF group and the non-ASF group. Clinical characteristics, therapeutic interventions and laboratory parameters were evaluated. Significant univariate predictors were included in multivariable logistic regression. A p-value below 0.05 was considered statistically significant. This study enrolled a total of 154 patients with septic shock, among whom 49 developed ASF, yielding an incidence rate of 31.8%. In the multivariate analysis, four independent predictors were identified: maximum norepinephrine (NE) dose (odds ratio [OR] = 2.47, p = 0.051), NE duration (OR = 1.19, p = 0.054), central venous oxygen saturation (ScvO₂) (OR = 0.97, p = 0.042) and absence of oedema (OR = 0.18, p = 0.008). The model achieved an area under the curve of 0.803 (95% CI: 0.730-0.876) with 72.3% sensitivity and 72.4% specificity at the optimal cut-off. The validated prediction model identifies patients with septic shock who are at high risk for ASF using four readily available clinical parameters: maximum NE dose, NE duration, ScvO₂ and absence of oedema, helping clinicians provide early warning and thereby reduce associated skin complications. Not applicable.

Phytochemical investigation on the aerial parts of Oreomecon nudicaulis resulted in the identification of eight new benzylisoquinoline-derived secondary metabolites, including four unusual C-6-N-17 bond cleaved isopavine alkaloids oreonudines A-D (1-4), two isopavine alkaloids oreonudines E (5) and F (6), one rhoeadine alkaloid oreonudine G (7), and one morphinane alkaloid oreonudine H (8), along with 10 previously reported analogues 9-18. Their structures were determined by comprehensive spectroscopic and spectrometric analyses, single-crystal X-ray diffraction, and quantum chemical calculations of ECD spectra. In vitro studies using HT22 mouse hippocampal neuronal cells revealed that the previously reported compounds 12, 15, and 16 exhibited potent inhibition of serotonin (5-HT) and/or norepinephrine (NE) reuptake. Among them, mecoquitupline (15) showed significant inhibitory activity against 5-HT (88.0%) and NE (58.8%) reuptake, outperforming the tricyclic antidepressant amitriptyline (53.6% and 35.5%, respectively), and notably activated the neurotrophic BDNF/CREB signaling pathway. Molecular docking and drug affinity responsive target stability (DARTS) assays further confirmed the binding of 15 to both serotonin transporter (SERT) and norepinephrine transporter (NET). In contrast, 12 and 16 selectively inhibited NE and 5-HT reuptake, respectively, by targeting the corresponding transporters. These findings highlight mecoquitupline (15) as a promising dual-action antidepressant candidate with potent activity.

Repetitive stress decreases norepinephrine's dynamic range in the auditory cortex.

Impacts of aerobic exercise and whole-body vibration interventions on myokines and neurocognitive performance in postmenopausal women.

This study aims to investigate the antidepressant properties of Hispidulin, a flavonoid present in Scutellaria barbata D. Don. The selection of Hispidulin stems from its notable inhibitory activity against Xanthine Oxidase (XO), a parameter in the pathophysiology of depression. Mice were subjected to a rigorous evaluation using a murine model of Chronic Unpredictable Mild Stress (CUMS) to induce depression for 21 days and antidepressant properties were rigorously assessed using the Tail Suspension Test (TST), Forced Swim Test (FST), and Open Field Test (OFT). Imipramine and fluoxetine were used as standard drugs. Additionally, neurochemical analyses were conducted to quantify serotonin (5-HT), norepinephrine (NE), and dopamine (DA) levels in the cortex, hippocampus, and hypothalamus. Further mechanistic insights were sought through the estimation of monoamine oxidase (MAO) activity and assessment of antioxidant enzyme levels in the brain. Plasma nitrite and corticosterone levels were also measured to delineate the underlying mechanism of action. Hispidulin demonstrated significant antidepressant effects, as evidenced by reduced immobility time in TST and FST and increased exploratory behavior in OFT. Neurochemical analysis revealed restoration of 5-HT, NE, and DA levels in key brain regions. Furthermore, Hispidulin modulated MAO activity and enhanced antioxidant enzyme levels in the brain. Plasma nitrite levels were elevated, indicating enhanced nitric oxide synthesis, while corticosterone levels were reduced. Our findings indicate that Hispidulin exerts potent antidepressant effects, potentially mediated through its influence on monoaminergic neurotransmitters, MAO activity, and antioxidant defenses. These results provide valuable mechanistic insights into the antidepressant action of Hispidulin, supporting its potential therapeutic application in depressive disorders.

Abstract Background Rapid eye movement sleep (REMS) loss affects almost all physiological processes, while it itself is affected in disorders. REMS maintains optimum level of noradrenaline (NA) in a healthy individual, while increased NA during disturbed REMS is associated with diseases. The synthesis, release, and degradation of neurotransmitter are modulated by biomolecules, which are genetically encoded. The aim of this study is to understand the transcriptional and translational changes of those biomolecules in locus coeruleus (LC) and pedunculo‐pontine tegmentum (PPT) in association with REMS and its loss, which is expected to help us explain associated acute and chronic pathophysiological changes. Methods In this study, male inbred Wistar rats were deprived of REMS for 96 h using classical flowerpot method; free‐moving‐, large platform‐ and recovery‐control sets were also conducted ( n = 5 per group). Brain areas related to REMS regulation viz. LC, PPT as well as area unrelated to REMS regulation viz. hippocampus was dissected out for evaluation. Animals were grouped based on similar traits (age, weight, etc.) and then randomly by random table assigned within those matched sets. Dopamine β‐hydroxylase (DBH), tyrosine hydroxylase (TH), and monoamine oxidase‐A (MAO‐A) protein, their gene expressions and associated histone modifications were evaluated using western blot analysis, quantitative polymerase chain reaction (qPCR) and chromatin immunoprecipitation (ChIP) assays, respectively. One‐way analysis of variance (ANOVA) followed by Holm Sidak multiple comparison test was applied to evaluate the significance level between the experimental and control groups using GraphPad Prism (version 9.0.0; GraphPad Software, San Diego, California, USA, www.graphpad.com ) and Sigma Stat Statistical Software (version 12; Jandel Scientific Software, CA, USA). Results Upon rapid eye movement sleep deprivation (REMSD), although TH and DBH protein expressions altered significantly in all the brain areas, the latter was highest in LC (F (5,30) = 11.320, p < 0.001); MAO‐A decreased in LC (F (5,30) = 9.286, p < 0.001). In LC, DBH (F (8,44) = 7.138, p < 0.001) and TH (F (8,44) = 5.813, p < 0.001) gene expressions and histone H3 at lysine 14 (H3K14)‐acetylation of TH (F (11,59) = 25.290, p < 0.001) and DBH (F (11,59) = 11.610, p < 0.001) increased, while lysine K9 in histone H3 (H3K9)‐dimethylation tended to decrease, whereas opposite modifications were seen in MAO‐A gene expression (F (11,59) = 16.970, p < 0.001). The altered gene‐ and protein‐expressions returned or tended to return to normal levels after recovery, as in post‐REMSD prazosin treated rat brains. Conclusion The differential expressions of the genes and corresponding proteins (enzymes) responsible for synthesis and degradation of NA support sustained increase in NA upon REMSD that explains underlying causes of REMSD associated chronic effects, which may be exploited for amelioration of REMSD‐associated disorders.

Norepinephrine (NE), which is also known as noradrenaline, is a catecholamine neurotransmitter that can elevate mood and cause emotional excitement. Under oxidative stress, deviation from regular metabolism can lead to several diseases, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, schizophrenia, etc. In vivo monitoring of NE may allow for earlier of these neurogenerative diseases. Current methods of NE determination mainly consider in vitro setup with no real-time sensing and require costly instruments and skilled technical hands. Aptamers could provide a better electrochemical way to determine NE. Aptamers are single-stranded DNA (ssDNA) or RNA with high specificity and affinity for various targets like proteins, drugs, small molecules, macromolecules, etc., which offer a low-cost, easy synthesis, low immunogenicity approach over more traditional antibody approaches while not compromising selectivity and specificity. Most importantly, aptamers can be separated from a large pool of ssDNA by a selection process called SELEX (Systematic Evolution of Ligands by Exponential Enrichment). Traditional SELEX processes are expensive and mainly require fluorescent-label DNA libraries. As a result, an electrochemical SELEX method has been developed to select aptamers for proteins and small molecules, effectively overcoming those challenges.This research focuses on the selection of NE aptamers through electrochemical techniques. With innate electrochemical properties, NE provided an opportunity to use square wave voltammetry (SWV), which is highly sensitive compared to other electrochemical techniques. Moreover, we can use many electrodes to achieve higher yield of DNA to move for the next cycle. In the positive selection cycle of SELEX, NE was immobilized on the gold disk electrode surface by NHS-EDC coupling for simultaneously selecting and detecting the DNA of aptamers in a single pot. In the negative cycles, dopamine (DA) was conjugated to form the self-assembled monolayer to remove the nonspecific ssDNA with affinity toward DA. After ten cycles, seven potential aptamer sequences were identified by cloning, and their efficacy towards NE and DA was studied. The progress of the study demonstrates the potential selection of a few NE aptamers along with a few effective truncated aptamer sequences of high selectivity and specificity towards NE are imminent. These aptamers would be useful for preparing in vivo aptasensor, which will be tested in live mouse brains.Keywords: Neurotransmitters, Norepinephrine, aptamers, electrochemical-SELEX, biosensing, electrochemical sensor.

The development of nonenzymatic electrochemical biosensors has been fueled by the increasing need for real-time, noninvasive bioanalyte monitoring, especially for use in neurological health. The neurochemicals, dopamine and norepinephrine, have long been proposed as biomarkers for several neurodegenerative disorders including Parkinson’s disease, schizophrenia, and PTSD. These neurochemicals can be generically referred to as catecholamines and can be oxidized to their ketone forms. Hence, electrochemical detection of these neurochemicals becomes of immense interest since it provides a method to sense these biomarkers in real time. In this presentation, we will discuss highly efficient electrocatalysts for the detection of norepinephrine (NE), dopamine (DA) and mixture of both (bifunctional electrocatalyst). Specifically, we will present the synthesis and multifunctional sensing capabilities of hydrothermally produced copper chalcogenide nanostructures. The copper chalcogenide nanostructures were synthesized via a one-pot hydrothermal method and thoroughly characterized by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and scanning electron microscopy (SEM), confirming their crystalline phase, compositional purity, and well-defined morphology. The electrochemical sensing efficiency was investigated through detailed electrochemical measurements including cyclic voltammetry (CV), differential pulse voltammetry (DPV), and square wave voltammetry (SWV). These nanostructures exhibited excellent electrocatalytic performance across multiple biomolecule targets, demonstrating their versatility as a multianalyte sensing material. The CuSe-modified electrode showed outstanding activity toward the nonenzymatic detection of norepinephrine (NE)revealing a high sensitivity of 145 μA cm⁻² μM⁻¹, an extended linear detection range of 20–2000 nM, and a low detection limit of 36 nM at an applied potential of +0.23 V vs. Ag|AgCl. The low detection limit for norepinephrine enables the possible detection of these biomolecules in peripheral physiological fluids such as tear and sweat. Simultaneously, the copper chalcogenide nanostructures also demonstrated robust capability for nonenzymatic detection of dopamine. The fabricated electrode achieved a remarkable sensitivity of 8.80 μA cm⁻² μM⁻¹, with a wide linear response range from 50 nM to 640 μM and a low detection limit of 68 nM at a significantly reduced working potential of +0.18 V vs. Ag|AgCl. These sensors showed excellent selectivity against common interfering species detecting only dopamine or norepinephrine at the respective potentials mentioned above. The multi-analyte sensing of copper chalcogenide demonstrates their exceptional electrocatalytic efficiency and versatility in a variety of sensing contexts. The low working potentials needed for both dopamine and norepinephrine detection are noteworthy because they improve signal selectivity and reduce background noise, two important factors for wearable and point-of-care diagnostic systems. These results illustrate the development of non-enzymatic biosensors for detection of neurochemicals that can be transformative for the creation of next-generation biosensors that can monitor neurochemical in real time. The results open new avenues for creating advanced electrochemical biosensors designed for real-time health monitoring and early disease diagnosis.

Anxiety disorders impose a substantial global burden, yet current pharmacotherapies often lack sustained efficacy and carry risks of dependence. Dexmedetomidine (Dex), a selective α2 adrenergic receptor agonist primarily used for sedation, demonstrates promising anxiolytic properties, but its long-term neural mechanisms remain unclear. Here, using a chronic restraint stress (CRS) mouse model, we reveal that tyrosine hydroxylase (TH)-positive neurons in the locus coeruleus (LC) are persistently hyperactivated during chronic anxiety states, driving elevated norepinephrine (NE) release in the medial prefrontal cortex (mPFC). A single low dose of Dex (50 µg/kg) produced anxiolytic effects lasting ≥3 days, evidenced by improved performance in open-field, light-dark box, and elevated plus maze tests. In vivo fiber photometry and chemogenetic approaches demonstrated that Dex suppresses LC-NE neuronal hyperactivity and normalizes mPFC NE levels. Crucially, neuron-specific knockdown of α2 receptors in the LC abolished Dex's anxiolytic effects, confirming their essential role. These findings elucidate a neural mechanism wherein Dex sustains anxiety relief via α2 receptor-mediated inhibition of the LC-NE-mPFC circuit, highlighting its potential as a novel long-acting therapeutic strategy for anxiety disorders.

Type 1 diabetes (T1D) is an autoimmune disorder marked by the injury of pancreatic β cells, during which sympathetic neurons in the endocrine region of pancreas are lost, whereas those in the exocrine regions surrounding islets remain intact. This abnormal sympathetic nervous signaling may disrupt the balance of the neuroendocrine-immune network and contribute to the development of T1D, although its underlying molecular mechanisms are still elusive. Here, single-cell omics and whole-tissue immunostaining reveal a decrease in pancreatic sympathetic nerve density in T1D patients and T1D mouse models. Surgical and chemical desensitization of the sympathetic nervous system exacerbates T1D, while macrophage depletion mitigates this effect. Mechanistically, diminished norepinephrine (NE) release impairs β2-adrenergic receptor (β2-AR)-PKA-CREB1 signaling in islet macrophages, leading to downregulation of the adaptor caspase recruitment domain family member 9 (CARD9). Loss of CARD9 decreases SLC6A8-mediated creatine uptake, shifts macrophages toward a pro-inflammatory phenotype, and promotes sympathetic axon ferroptosis driven by decreased neurotrophic factor and anti-inflammatory factor release. Conversely, β2-AR agonist formoterol restores PKA-CREB1-CARD9 activation, preserves creatine metabolism, and maintains anti-inflammatory macrophage polarization. These findings define a novel sympathetic-macrophage-creatine metabolic axis governed by CARD9 that links neural signals to immune and metabolic regulation in T1D, highlighting neuroimmune interactions as targets for therapies.

Catecholamines are fundamental mediators of the stress response, regulating arousal, vigilance, and adaptive behavior. However, their dynamics under extreme real-life conditions remain insufficiently explored. Survival, Evasion, Resistance, and Escape (SERE) training provides a unique model for examining neuroendocrine mechanisms of adaptation during both the acute phase and the recovery period following intense psychological and physical stress. Serum norepinephrine (NE) and dopamine (DA) were measured in 47 special forces soldiers during peak stress in SERE and one month later, compared with 17 healthy controls. Samples were collected under standardized conditions and analyzed using validated ELISA kits. NE levels differed significantly among groups (p = 0.003), being higher during SERE training and in controls compared to the post-recovery condition. DA also showed a significant group effect (p < 0.001), with increased levels during recovery and in soldiers during SERE relative to controls. The post-recovery decline in norepinephrine suggests adaptive habituation of sympathetic activity following extreme stress exposure. Conversely, the sustained elevation of dopamine during recovery may reflect neuroadaptive mechanisms that promote motivational and cognitive restoration. Together, these findings indicate coordinated catecholaminergic regulation supporting long-term resilience in elite military personnel.

To observe the clinical effect of Tiaoshen Guben holistic therapy of acupuncture and moxibustion (holistic treatment with acupuncture and moxibustion by adjusting the mind and consolidating the root) on comorbidity of depression and insomnia. Twenty-four patients with comorbidity of depression and insomnia were included and treated with Tiaoshen Guben holistic therapy of acupuncture and moxibustion. Acupuncture was applied to Baihui (GV20), Guanyuan (CV4), bilateral Neiguan (PC6), etc. The refined moxibustion therapy was delivered at Zhongwan (CV12), Qihai (CV6), bilateral Yongquan (KI1), etc. Subcutaneous embedding therapy with thumb-tack needle was adopted at bilateral Xinshu (BL15), bilateral Pishu (BL20), etc. The intervention was operated once every other day, 3 treatments a week, and for 6 consecutive weeks. Before and after treatment completion, and in 1 month after treatment, Pittsburgh sleep quality index (PSQI) and Hamilton's depression scale (HAMD-17) were adopted to assess sleep quality and depression symptoms in the patients, respectively. Before and after treatment completion, using functional magnetic resonance imaging (fMRI), the functional connectivity (FC) of locus coeruleus (LC) in brain regions was evaluated; and the levels of serum norepinephrine (NE), cortisol (CORT), adrenocorticotropic hormone (ACTH) and corticotropin releasing hormone (CRH) were detected. Compared with the scores before treatment, PSQI and HAMD-17 scores after treatment completion and in 1 month after treatment were reduced (P<0.01); and strengthened FC was revealed between the right LC and the pars opercularis of the left inferior frontal gyrus, as well as the lateral occipital lobe region. After treatment completion, serum NE was elevated (P<0.01), the levels of CORT, ACTH and CRH were reduced (P<0.01). Before and after treatment completion, the difference in FC between the right LC and the pars opercularis of the left inferior frontal gyrus was negatively correlated with the differences in PSQI score (r = -0.484, P = 0.016) and HAMD-17 score (r = -0.233, P = 0.027). Tiaoshen Guben holistic therapy of acupuncture and moxibustion can effectively alleviate depression symptoms and improve sleep quality in the patients with comorbidity of depression and insomnia, which is obtained probably through reducing the levels of serum CORT, ACTH and CRH, increasing serum NE, strengthening the FC of the right LC with the pars opercularis of the left inferior frontal gyrus and the lateral occipital lobe region.

To observe the effect of electroacupuncture (EA) at "Hegu" (LI4) and "Taichong" (LR3) on DNA methylation of the solute carrier family 6 member 4 (SLC6A4) gene promoter region in the hippocampus of depressed rats, and to explore the potential antidepressant mechanism of EA. Thirty male Sprague-Dawley rats were randomly divided into a blank group, a model group, a medication group, a 5-Azacytidine (5-AZA) group, and an EA group, 6 rats in each group. Depression models were established in the model group, the medication group, the 5-AZA group, and the EA group using chronic unpredictable mild stress (CUMS) combined with solitary housing. The medication group was treated with intragastric administration of fluoxetine hydrochloride capsules; the 5-AZA group was treated with intraperitoneal injection of 5-AZA; the EA group was treated with EA at bilateral "Hegu" (LI4) and "Taichong" (LR3), with disperse-dense wave, frequency of 2 Hz/100 Hz, and intensity of 1-1.2 mA, 20 min each session. All the treatment was given in three groups once daily for 21 consecutive days. Behavioral changes were evaluated by sucrose preference test, open field test, and novelty-suppressed feeding test. Serum levels of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) were measured by ELISA. The expression of SLC6A4 and 5-HT1AR protein and mRNA in hippocampus was detected by Western blot and real-time quantitative PCR, respectively. DNA methylation status of the SLC6A4 promoter region in hippocampal tissue was analyzed by bisulfite sequencing PCR (BSP). Compared with the blank group, the model group showed decreased sucrose preference, reduced total locomotor distance, and prolonged latency to feeding (P<0.05), decreased serum 5-HT, DA, and NE levels (P<0.05), downregulated hippocampal SLC6A4 and 5-HT1AR protein and mRNA expression (P<0.05), and increased CpG site methylation rate of the SLC6A4 promoter region (P<0.05). Compared with the model group, the medication group, the 5-AZA group, and the EA group exhibited increased sucrose preference, increased total locomotor distance, shortened latency to feeding (P<0.05), elevated serum 5-HT, DA, and NE levels (P<0.05), upregulated hippocampal SLC6A4 and 5-HT1AR protein and mRNA expression (P<0.05), and reduced CpG site methylation rate of the SLC6A4 promoter (P<0.05). Compared with the medication group and the 5-AZA group, the EA group showed higher sucrose preference, greater total locomotor distance, shorter latency to feeding (P<0.05), and increased serum DA and NE levels (P<0.05). EA could improve depressive behaviors in depressed rat models. The underlying mechanism may involve inhibition of SLC6A4 hypermethylation in the hippocampus on the serotonergic system, upregulation of SLC6A4 and 5-HT1AR protein and mRNA expression, and elevation of monoamine neurotransmitters such as 5-HT.

Abstract H3K27M-altered diffuse midline glioma (DMG) is a highly aggressive childhood brain cancer occurring in the pons, thalamus, and spinal cord. In the DMG microenvironment, glutamatergic, GABAergic, and cholinergic neurons play critical roles in glioma progression through both neuronal activity-regulated secreted factors and direct connection via neuron-to-glioma synapses. However, the role of other subtypes of neuromodulatory neurons in glioma progression remains largely unexplored. In patients, DMGs often invade the locus coeruleus, a small pontine nucleus rich in adrenergic neurons that project axons throughout the brain and release norepinephrine (NE). Here, we used patient-derived DMG cell cultures and optogenetic techniques to investigate how adrenergic neurons and NE influence DMG proliferation and invasion. In DMG monoculture, NE treatment increased proliferation and migration in most – but not all – DMG cultures. This effect is mediated by the alpha1-adrenergic receptor (a1-AR). We found that NE induces calcium influx and membrane depolarization in DMG cells through a1-AR, promoting proliferation. Analysis of publicly available single-cell and single-nucleus RNA sequencing data revealed that the a1-AR subunit gene Adra1a is broadly expressed across CNS tumors, albeit with heterogeneity, which may explain differential NE responsiveness observed across patient-derived cultures. To further understand this heterogeneity, we co-cultured DMG cell lines with primary neurons and glial cells isolated from cortex, brainstem, and thalamus of rat brains. Remarkably, NE-nonresponsive DMG cell cultures became responsive to NE when co-cultured with brainstem neurons and glial cells, suggesting that the local microenvironment influences NE sensitivity. In vivo optogenetic stimulation of adrenergic neurons in the locus coeruleus promotes the proliferation of DMG in pons and in cortex, further supporting the role of adrenergic signaling in DMG pathobiology. Taken together, these findings highlight the importance of brain region-specific neuronal and glial interactions in shaping tumor behavior and identify adrenergic neurons as a newly appreciated neuron-glioma mechanism driving DMG growth.

The sympathetic nervous system modulates immune responses through the release of norepinephrine (NE), yet the dynamics of this signaling differ across lymphoid organs. In this study, we investigated how NE release and α2-adrenergic receptor (α2AR) modulation influence neuroimmune interactions in the spleen and mesenteric lymph nodes (MLNs), 2 secondary lymphoid tissues with distinct innervation patterns. Using fast-scan cyclic voltammetry (FSCV), we found that the spleen exhibited more frequent and higher-amplitude NE events than the MLNs, consistent with its denser sympathetic innervation. Pharmacological manipulation of α2ARs revealed that yohimbine hydrochloride, an α2AR antagonist, increased NE release in both organs, while dexmedetomidine hydrochloride, an α2AR agonist, suppressed it, often below detection thresholds. Complementary 3D immunohistochemistry demonstrated tissue- and cell type-specific changes in immune cell proximity to neuronal structures following adrenergic modulation, with T cells and B cells displaying distinct spatial reorganization. These findings highlight that α2AR signaling fine-tunes NE release and immune cell localization in a context-dependent manner, influenced by organ-specific architecture and innervation. Our results underscore the importance of dynamic local neuroimmune interactions in immune regulation and suggest potential therapeutic opportunities for targeting adrenergic signaling in inflammatory and autoimmune diseases.

Sympathetic sprouting in dorsal root ganglia (DRG) is a feature of sympathetically maintained pain (SMP) following peripheral nerve injury, yet the factors determining its occurrence remain unclear. Here, we compare transection and crush injury models to determine if injury type or site influence sympathetic remodeling and pain. Using TH-IR immunostaining and Phox2b reporter mice to selectively label sympathetic fibers, we found that an L5 spinal nerve transection (SpNT) triggered robust sympathetic fiber sprouting and elevated norepinephrine (NE) levels in the DRG, correlating with a mechanical hypersensitivity reversed by chemical sympathectomy. In contrast, a partial sciatic nerve crush injury (PCI) produced long-lasting mechanical hypersensitivity without sympathetic sprouting or NE elevation and was unaffected by sympathectomy. Importantly, sympathetic sprouting was consistently more pronounced after transection injuries at both spinal and sciatic nerve sites, suggesting that injury type, rather than location, is a dominant factor shaping sympathetic remodeling. These findings establish nerve transection as a key driver of sympathetic sprouting and SMP, whereas crush-induced pain likely involves distinct non-sympathetic mechanisms. This distinction has important implications for pain subtype identification and treatment strategies.

ABSTRACT This study examined the impact of cold-induced stress on cognitive and motor performance. Thirteen males (19.7 ± 0.23 yr) trained on a computer-based visuomotor task once daily for six consecutive days. The task (19 min per trial; joystick-controlled falling blocks) included brief rest/training intervals. After the first three trials, participants were allocated to control (CON, n = 5) or cold stress (CS, n = 8). On days 4–6, CS completed a 60-min head-out cold-water immersion immediately before the task, producing a ~ 0.5°C drop in core temperature, whereas CON remained stable. Heart rate, ventilation, respiratory frequency (R f), inspiratory drive (I d), oxygen consumption, epinephrine, norepinephrine (NEP), cortisol, and subjective measures (thermal comfort, TC; temporal judgment, TJ) were recorded pre-, during, and end-of-trial. CON improved performance by 84%, whereas CS performance was attenuated;(p < 0.01). CON showed no significant physiological or subjective changes. In CS, performance correlated inversely with R f (r = −0.56, p = 0.004), and regression indicated I d, NEP, Rf, TC, and TJ predicted performance;(p < 0.0001; R2 = 0.87). Thus, repeated pre-task cold exposure impaired performance, consistent with a complex interaction between physiological and subjective responses.

The corticotrophin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus critically regulate neuroendocrine and autonomic nervous system function. Primary hypertension patients display an increase in hypothalamic CRH levels. However, the role of PVN-CRH neurons in the pathogenesis of primary hypertension remains unclear. Here, we showed that the PVN-CRH neurons were juxtaposed to neurons projecting to the rostral ventrolateral medulla (RVLM), a brain stem region crucial for regulating cardiovascular functions. Optical stimulation of PVN-CRH neurons with selective expression of light-sensitive channel channelrhodopsin-2 (ChR2) on these neurons increased blood pressure (BP) in conscious Wistar-Kyoto (WKY) rats and the activity of PVN-RVLM neurons, an effect abolished by blocking CRHRs with astressin. Optical stimulation of PVN-CRH neurons also significantly increased plasma levels of norepinephrine (NE) and copeptin, a stable surrogate marker for vasopressin. Compared to Wistar-Kyoto rats, PVN-CRH neurons in spontaneously hypertensive rats (SHRs) display a significantly high firing activity, increased glutamatergic synaptic inputs and NMDA receptor activity. Optical inhibition of PVN-CRH neurons by expressing inhibitory light-sensitive channel stGtACR2s on these neurons decreased BP in SHRs and suppressed PVN-RVLM neurons. The plasma NE and adrenocorticotropic hormone (ACTH) levels were significantly lower after inhibiting PVN-CRH neurons. Furthermore, the ablation of PVN-CRH neurons by selective expression of Casp3 decreased BP in adult SHRs and suppressed hypertension development in young SHRs. These findings suggest that the PVN-CRH neurons play a pivotal role in the pathogenesis of hypertension through interacting with PVN-RVLM neurons and that the hyperactivity of PVN-CRH neurons contribute to high vasopressin levels and the onset and maintenance of primary hypertension.

Norepinephrine (NE) is released in cortex by axons arising from the locus coeruleus (LC). The cortical innervation patterns from LC have been mapped previously using antibodies directed against the vesicular synthetic enzyme for NE, dopamine β-hydroxylase (DBH), which provides information about putative release sites. We sought to quantify putative NE reuptake sites by immunolabeling the norepinephrine transporter (NET), focusing on the primary (V1) and secondary (V2) visual cortex of macaque monkeys. We used stereological methods to determine the density of axon segments immunoreactive for NET (NET+ segments) in V1 and V2, and non-stereological methods to compare the laminar distribution of NET+ segments and to compare the distribution of NET+ segments in V1 with segments immunoreactive for DBH (DBH+). We also developed a novel analysis approach on the basis of Bayesian statistics that allowed us to combine these quantitative data with qualitative data from previously published studies to generate and compare updated estimates of LC axon density. In line with prior reports based on DBH immunoreactivity, we find that LC axon density is higher in V2 than in V1 and has a similar laminar pattern across both areas. We also find that densities of DBH+ and NET+ segments differ across the layers of V1. This indicates that sites of NE release and reuptake may not be colocated and suggests a role for differing scales of diffusion in cortical modulatory effects mediated by NE.

Research note: Peripheral administration of Met-enkephalin: Novel attenuation of the adrenal medullary and thyroidal stress responses in young female chickens.