Integrative analysis of plasma and substantia nigra in Parkinson's disease: unraveling biomarkers and insights from the lncRNA-miRNA-mRNA ceRNA network.

Introduction: Parkinson's disease (PD) is a rapidly growing neurological disorder characterized by diverse movement symptoms. However, the underlying causes have not been clearly identified, and accurate diagnosis is challenging. This study aimed to identify potential biomarkers suitable for PD diagnosis and present an integrative perspective on the disease. Methods: We screened the GSE7621, GSE8397-GPL96, GSE8397-GPL97, GSE20163, and GSE20164 datasets in the NCBI GEO database to identify differentially expressed (DE) mRNAs in the substantia nigra (SN). We also screened the GSE160299 dataset from the NCBI GEO database to identify DE lncRNAs and miRNAs in plasma. We then constructed 2 lncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) regulatory networks based on the ceRNA hypothesis. To understand the biological function, we performed Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology analyses for each ceRNA network. The receiver operating characteristic analyses (ROC) was used to assess ceRNA results. Results: We identified 7 upregulated and 29 downregulated mRNAs as common DE mRNAs in the 5 SN datasets. In the blood dataset, we identified 31 DE miRNAs (9 upregulated and 22 downregulated) and 332 DE lncRNAs (69 upregulated and 263 downregulated). Based on the determined interactions, 5 genes (P2RX7, HSPA1, SLCO4A1, RAD52, and SIRT4) appeared to be upregulated as a result of 10 lncRNAs sponging 4 miRNAs (miR-411, miR-1193, miR-301b, and miR-514a-2/3). Competing with 9 genes (ANK1, CBLN1, RGS4, SLC6A3, SYNGR3, VSNL1, DDC, KCNJ6, and SV2C) for miR-671, a total of 26 lncRNAs seemed to function as ceRNAs, influencing genes to be downregulated. Discussion: In this study, we successfully constructed 2 novel ceRNA regulatory networks in patients with PD, including 36 lncRNAs, 5 miRNAs, and 14 mRNAs. Our results suggest that these plasma lncRNAs are involved in the pathogenesis of PD by sponging miRNAs and regulating gene expression in the SN of the brain. We propose that the upregulated and downregulated lncRNA-mediated ceRNA networks represent mechanisms of neuroinflammation and dopamine neurotransmission, respectively. Our ceRNA network, which was associated with PD, suggests the potential use of DE miRNAs and lncRNAs as body fluid diagnostic biomarkers. These findings provide an integrated view of the mechanisms underlying gene regulation and interactions in PD.

Effect of acupuncture on pain and substance P levels in middle-aged women with chronic neck pain.

Chronic neck pain is a leading health issue affecting a significant proportion of the global population. Multiple treatment options for chronic neck pain include anti-inflammatory drugs and analgesics. Acupuncture has been widely used for the treatment of chronic pain. In this study, we aimed to determine the efficacy of acupuncture for female patients with chronic neck pain. Twenty-three participants were enrolled in the study, and participants waited 4 weeks without acupuncture treatment and then received 4 weeks of treatment. One-way ANOVA with repeated measures was used to determine differences in the visual analogue scale (VAS), neck disability index (NDI), and substance P (SP) over time. The subjects' pain intensity and degree of disability due to neck pain were measured as primary outcomes. SP in the blood was also analyzed as a secondary outcome. There was no significant difference between the VAS score and NDI value of baseline and after 4 weeks waiting. However, there was an improvement in both VAS and NDI after 4 weeks treatment. SP level was decreased after 4 weeks treatment. We could conclude that acupuncture is effective in alleviating chronic neck pain. Moreover, our findings revealed the efficacy of acupuncture on chronic pain with potential underlying biological mechanisms.

The effects of acupuncture on sleep disorders and its underlying mechanism: a literature review of rodent studies.

Sleep is a set of physiological processes mainly under neurobiological regulation that affect several physiological systems, and sleep disorders are a condition where normal sleep patterns are disturbed. Clinical studies have confirmed the effects of acupuncture on sleep duration and quality. Although many studies have explored the therapeutic effects of acupuncture on sleep disorders, the mechanisms are unclear. We investigated the mechanism of acupuncture efficacy in a rodent model of sleep disorders and evaluated the therapeutic effects of acupuncture treatment. According to our results, sleep disorders are associated with several brain regions and neurotransmitters. Furthermore, this review showed that neurological processes, such as catecholamine and BDNF signaling pathways, can be regulated by acupuncture, which is a crucial aspect of the acupuncture mechanism in sleep disorders.

Effects of acupuncture on gastrointestinal diseases and its underlying mechanism: a literature review of animal studies.

Acupuncture is a non-pharmacological traditional Chinese medical technique that has been used for various types of gastrointestinal (GI) diseases in Eastern medicine. However, the specific mechanisms underlying acupuncture treatment in the GI tract have not yet been elucidated. In this study, we searched the electronic databases PUBMED, EMBASE, and MEDLINE and identified 30 eligible studies that were summarized in this review. This review demonstrates that treatments, including both manual and electroacupuncture, have therapeutic mechanisms in diverse GI diseases. The underlying mechanisms are broadly divided into the following: changes in gene expression in the gastric mucosa or nuclei of the solitary tract, metabolic change induction, regulation of anti-inflammatory substances, vagal activity increase, change in functional connectivity between brain regions, and control of the number of neurons related to GI diseases. Although this study is limited in that it does not represent all types of GI diseases with different acupuncture methods, this study identified acupuncture as effective for GI diseases through various biological mechanisms. We hope that our study will reveal various mechanisms of acupuncture in GI diseases and play an important role in the therapy and treatment of GI diseases, thus advancing the field of study.

Autonomous vehicles and street design: Exploring the role of medians in enhancing pedestrian street crossing safety using a virtual reality experiment.

As traffic lanes and on-street parking spots can potentially be downsized with the introduction of autonomous vehicles (AVs), the possibility of additional spare road space becoming available arises in future urban streets. While discussions on converting the leftover space into pedestrian-friendly alternatives exist, allocating that limited space to which alternative is foreseen to be another practical issue shared in both urban and transportation planning. However, evidence-based guidance on the issue provided from the actual verification on whether or to what extent the proposed alternatives may have an effect seems to be absent. Therefore, with an emphasis on pedestrian safety, this study focused on the "median strip" alternative as a first example and, through a VR simulation experiment aimed at empirically examining its suggested role on enhancing street crossing safety and further exploring its possible influence on pedestrians' trust toward autonomous driving. With 99 participants, perceived safety (individual assessments of safety), performance-based safety (crossing success/abandonment and collision occurrence), and trust were either questioned or recorded for nine scenarios with varying crossing conditions. A combination of multilevel models and cross-tabulation results indicate that medians seem especially significant in ensuring the performance-based safety results of pedestrians even when AVs are driving at high speeds or with smaller gaps, thus suggesting it a win-win option for both. Insights and implications on the role and management of medians in future streets are further provided.

The effect of acupuncture on pain and swelling of arthritis animal models: A systematic review and meta-analysis.

Arthritis, the inflammation of joints, attributes to the patient's pain, joint deformation, and limited range of motion. Emerging studies have shown the effects of acupuncture on different types of arthritis. We aimed to assess the effects of acupuncture on arthritis animal models and summarize the related mechanisms. We retrieved studies that met our criteria from PubMed, MEDLINE, EMBASE and the Research Information Service System. The quality assessment was evaluated by using the Systematic Review Centre for Laboratory Animal Experimentation's risk of bias tool. The pain withdrawal latency, pain withdrawal threshold, and paw volume data were digitized using Engauge Digitizer software. The meta-analysis was performed, and the figures were generated using RevMan software. The meta-analysis of data from 21 animal studies revealed that acupuncture increased tolerance to pain stimuli, and reduced swelling in arthritis animals. Although the number of included studies is insufficient, the results suggest acupuncture to be effective in improving arthritis-induced inflammation and pain by regulating the nervous and immune system.

The Effect of Acupuncture on Modulating Inflammatory Cytokines in Rodent Animal Models of Respiratory Disease: A Systematic Review and Meta-Analysis.

Purpose: Although respiratory diseases (RD) are rapidly becoming a global health issue due to their high mortality and prevalence, there are limitations to the currently available treatments. Acupuncture has been recognized to mitigate many diseases by reducing inflammation and modulating cytokines. However, no systematic analysis has been performed to examine the effects of acupuncture on RD. We aimed to evaluate the effects of acupuncture on rodent animal models of RD. Methods: PubMed, EMBASE, MEDLINE, and the Research Information Service System were searched to retrieve studies that met our inclusion/exclusion criteria. The quality of each included study was evaluated using a 10-item checklist modified from the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies. With adequate data extracted, meta-analysis was performed using RevMan software. Results: A total of 18 studies were included, and the mean quality assessment was 5.7. The meta-analysis revealed that acupuncture had a significant effect on changing the cytokine levels, including pro-/anti-inflammatory, Th1-, Th2- and Th17- specific cytokines. Conclusion: Although there were limitations in the number of included studies, the results suggest that acupuncture can be a possible treatment for RD through its modulation of various cytokines, leading to reduced inflammation.

The Extracellular MicroRNAs on Inflammation: A Literature Review of Rodent Studies.

Inflammation is an indispensable biological process stimulated by infection and injuries. Inflammatory mechanisms related to extracellular vesicles (EVs), which are small membrane structures carrying various molecules, were summarized in this review. Emerging evidence from animal studies has highlighted the role of EVs in modulating inflammatory responses, by transporting various molecules involved in host defense. In this review, we have discussed the role of EV miRNAs in inflammation. Rodent studies associated with extracellular miRNAs in inflammatory diseases, published from 2012 to 2022, were explored from PUBMED, EMBASE, and MEDLINE. A total of 95 studies were reviewed. In summary, EV-associated miRNAs play a key role in various diseases, including organ injury, immune dysfunction, neurological disease, metabolic syndrome, vesicular disease, arthritis, cancer, and other inflammatory diseases. Diverse EV-associated miRNAs regulate inflammasome activation and pro- and anti-inflammatory cytokine levels by targeting genes.

Pedestrians safety perception and crossing behaviors in narrow urban streets: An experimental study using immersive virtual reality technology.

Virtual reality (VR) technology emerges as a promising tool for investigating human perception and behavior in highly controlled, immersive, and risk-free environments. This study proposed to apply simulated VR technology to investigate the interactions between perceived crash risk and behavior patterns in a road crossing with changes in the safety-related environmental attributes. In the context of the 8-meter-wide segment in a residential block, 35 VR environments with variations of six environmental attributes were generated. Two hundred participants were recruited for the experiment. The measured behavioral outcomes were 1) waiting and reaction time in the decision phase before crossing and 2) crossing speed and gait variability in the crossing phase. Random effect regression and multi-level structural equation models were constructed to test the study hypotheses. The results demonstrated that environmental attributes, including barriers to visibility (coefficient = 0.446), geometric patterns (coefficient = -0.625), and pavement signs (coefficient = -0.502), were associated with the pedestrians' perceived risk, but the influence varied by street types. In addition, changes in the perceived threats to pedestrians were found to mediate the environment-crossing behavior relationship (coefficient of the indirect effect = 0.679). Those who perceive higher crash risk took longer to decide to start walking at a crosswalk and tended to walk in haste while crossing the road. Using VR technology, the present study addressed an inter-relationship between environmental characteristics, cognition, and crossing behavior, contributing to better knowledge on road safety interventions to reduce the risk of pedestrian-involved crashes.

Co-Treatment with the Herbal Medicine SIP3 and Donepezil Improves Memory and Depression in the Mouse Model of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a lethal, progressive neurodegenerative disorder that has been linked to a deficiency of the neurotransmitter acetylcholine. Currently, many acetylcholinesterase inhibitors, such as donepezil, are widely used for the treatment of AD. On the other hand, the efficacy of long-term donepezil use is limited. SIP3, a mixture of three herbal extracts from Santalum album, Illicium verum, and Polygala tenuifolia, is a new formula derived from traditional Korean herbal medicine. OBJECTIVE: We assessed the synergistic effect of SIP3 and donepezil co-treatment on symptoms of AD using APP/PS1 transgenic mice. METHODS: In this study, a Drosophila AD model and SH-SY5Y clles were used to assess the toxicity of SIP3, and APPswe/PS1dE9 (APP/PS1) transgenic mice were used to evaluate the cognitive-behavioral and depression-like behavior effect of SIP3 and donepezil co-treatment on symptoms of AD. The cerebral cortex or hippocampus transcriptomes were analyzed by RNA sequencing and miRNA to investigate the molecular and cellular mechanisms underlying the positive effects of SIP3 on AD. RESULTS: In the passive avoidance test (PAT) and Morris water maze (MWM) test, the combination of SIP3 and donepezil improved the learning capabilities and memory of APP/PS1 mice in the mid-stage of AD compared to the group treated with donepezil only. In addition, co-administration of SIP3 and donepezil effectively reduced the depression-like behavior in the forced swimming and tail suspension tests. Furthermore, RNA sequencing of the cerebral cortex transcriptome and miRNA of the hippocampus showed that the gene expression profiles after a low dose SIP3 co-treatment were more similar to those of the normal phenotype mice than those obtained after the donepezil treatment alone. The Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, showed that differentially expressed genes were involved in the locomotor behavior and neuroactive ligand-receptor interactions. These results suggest that a co-treatment of low dose SIP3 and donepezil improves impaired learning, memory, and depression in the mid-stage of AD in mice. CONCLUSION: Co-treatment of low dose SIP3 and donepezil improves impaired learning, memory, and depression in the mid-stage of AD in mice.

Changes of local microenvironment and systemic immunity after acupuncture stimulation during inflammation: A literature review of animal studies.

An increasing number of studies have demonstrated the underlying mechanisms by which acupuncture therapy mediates both local and systemic immunomodulation. However, the connection between alterations in the local microenvironment and the resulting change in systemic immunity remains unclear. In this review, we focus on cell-specific changes in local immune responses following acupuncture stimulation and their link to systemic immune modulation. We have gathered the most recent evidence for chemo- and mechano-reactive changes in endothelial cells, neutrophils, macrophages, and mast cells in response to acupuncture. Local signaling is then related to the activation of systemic neuro-immunity including the cholinergic, adrenal, and splenic nervous systems and pain-related neuromodulation. This review aims to serve as a reference for further research in this field.

Effects of Ginsenoside Rg3 on Inhibiting Differentiation, Adipogenesis, and ER Stress-Mediated Cell Death in Brown Adipocytes.

OBJECTIVES: Ginsenoside Rg3 (Rg3), a main active component of Panax ginseng, has various therapeutic properties in literatures, and it has been studied for its potential use in obesity control due to its antiadipogenic effects in white adipocytes. However, little is known about its effects on brown adipocytes. METHODS: The mechanisms through which Rg3 inhibits differentiation, adipogenesis, and ER stress-mediated cell death in mouse primary brown adipocytes (MPBAs) are explored. RESULTS: Rg3 significantly induced cytotoxicity in differentiated MPBAs but not in undifferentiated MPBAs. Rg3 treatment downregulated the expression of differentiation and adipogenesis markers and the level of perilipin in MPBAs while upregulating the expression of lipolytic Kruppel-like factor genes. Rg3 also induced lipolysis and efflux of triglycerides from MPBAs and subsequently increased proinflammatory cytokine levels. Notably, Rg3 treatment resulted in elevation of ER stress and proapoptotic markers in MPBAs. CONCLUSIONS: Our results demonstrate that Rg3 is able to selectively exert cytotoxicity in differentiated MPBAs while leaving undifferentiated MPBAs intact, resulting in the induction of ER stress and subsequent cell death in MPBAs via regulation of various genes related to adipocyte differentiation, adipogenesis, lipolysis, and inflammation. These results indicate that further studies on the potential therapeutic applications of Rg3 are warranted.

Perceived Safety and Pedestrian Performance in Pedestrian Priority Streets (PPSs) in Seoul, Korea: A Virtual Reality Experiment and Trace Mapping.

Pedestrian Priority Street (PPS) project, launched to encourage safer and more convenient walking by improving the inferior pedestrian environment on narrow streets without sidewalks, is based on Monderman's shared space concept. Similar to the shared space approach, PPS aims for mutual consideration between pedestrians and drivers and strives to create a pedestrian-friendly environment, but the project relies on a unique road surface design. Considering the two main goals of the PPS project, this study investigated how subjective safety and pedestrians' movements differed by design types. To analyze safety perception, ordered Logit regression and post-hoc interviews were conducted with visual assessment survey using recorded VR (virtual reality) videos. Next, trace mapping and analysis were performed based on the video recordings to measure the degree of free walking. The results found that pedestrians perceived higher safety level in PPSs than in general back road. Further, the pedestrians moved more freely in the street with an integrated design. In other types, which suggested a pedestrian zone at the roadside, there was not much difference in behavior from the general back roads. Thus, the design principle of PPS, which does not set a boundary between pedestrian and vehicle area, should be observed to lead to behavioral changes in pedestrians.

Peripheral ERK modulates acupuncture-induced brain neural activity and its functional connectivity.

Acupuncture has been widely used as a therapeutic intervention, and the brain network plays a crucial role in its neural mechanism. This study aimed to investigate the acupuncture mechanism from peripheral to central by identifying how the peripheral molecular signals induced by acupuncture affect the brain neural responses and its functional connectivity. We confirmed that peripheral ERK activation by acupuncture plays a role in initiating acupuncture-induced peripheral proteomic changes in mice. The brain neural activities in the neocortex, hippocampus, thalamus, hypothalamus, periaqueductal grey, and nucleus of the solitary tract (Sol) were significantly changed after acupuncture, and these were altered by peripheral MEK/MAPK inhibition. The arcuate nucleus and lateral hypothalamus were the most affected by acupuncture and peripheral MEK/MAPK inhibition. The hypothalamic area was the most contributing brain region in contrast task PLS analysis. Acupuncture provoked extensive changes in brain functional connectivity, and the posterior hypothalamus showed the highest betweenness centrality after acupuncture. After brain hub identification, the Sol and cingulate cortex were selected as hub regions that reflect both degree and betweenness centrality after acupuncture. These results suggest that acupuncture activates brain functional connectivity and that peripheral ERK induced by acupuncture plays a role in initiating brain neural activation and its functional connectivity.

Co-Administration of Gagam-Sipjeondaebo-Tang and Ibuprofen Alleviates the Inflammatory Response in MPTP-Induced Parkinson's Disease Mouse Model and RAW264.7 Macrophages.

Parkinson's disease (PD), a common neurodegenerative disease, is characterized by degeneration of dopaminergic neurons with neuroinflammation. Gagam-Sipjeondaebo-Tang (GST), a traditional herbal formula made of twelve medicinal herbs, is known to be effective in PD, and the use of ibuprofen has been associated with a lower risk of PD. The aim of this study was to evaluate whether the combined administration of GST and ibuprofen affects the inflammatory response of Parkinson's disease. MPTP-induced parkinsonian mouse models were treated with GST or ibuprofen using oral gavage once a day for 5 days. The effects of GST were examined by measuring the TH level and expression of CD68 in the mice brain in addition to behavioral tests. The anti-inflammatory effect of GST on the LPS-treated RAW264.7 murine macrophages was examined using the NO assay. Inflammatory cytokines were analyzed using quantitative-PCR and flow cytometry. In the results, GST significantly improved the loss of dopaminergic neurons and alleviated PD-induced behavioral deficits. GST also decreased macrophage activation in the MPTP-induced PD mouse model. Interestingly, co-administration of GST and ibuprofen showed a synergistic effect in improving the loss of dopaminergic neurons and decreasing the activation of macrophages. Moreover, the NO level decreased in LPS-stimulated macrophages with this combined treatment. GST reduced iNOS, COX-2, IL-1ß, and IL-6 levels, and co-administration with ibuprofen showed a synergistic effect. Furthermore, pretreatment of GST reduced the expression levels of MCP-1 and IL-12 p70 in LPS-stimulated RAW264.7 cells. These results can possibly suggest a future therapeutic approach for PD patients.

Anti-Inflammatory Effects of Acupuncture at ST36 Point: A Literature Review in Animal Studies.

So far, a number of acupuncture studies have shown anti-inflammatory effects of acupuncture treatment, mostly known at specific point ST36. However, there is no literature that oversaw the inflammation-regulatory effects of acupuncture in each tissue. Therefore, we investigated how acupuncture at specific acupoint ST36 regulates inflammation and its underlying mechanisms. We searched literatures on PubMed until July 2021 using the keywords "animal, acupuncture, ST36, inflammation, immune," and 292 literatures were searched. We ultimately selected 69 studies to determine the anti-inflammatory actions of acupuncture at ST36 and classified the changes of inflammatory mediators according to target regions. Forty-three studies were included in body fluids, 27 studies in the digestive system, 17 studies in the nervous system, and 30 studies in other tissues or organs. In this review, we found that acupuncture at ST36 has clinical benefits in relieving inflammation through several mechanisms such as vagus nerve activation, toll-like receptor 4 (TLR4)/NF-κB signaling, macrophage polarization, mitogen-activated protein kinase (MAPK) signaling pathway, and cholinergic anti-inflammatory pathway. We expect that these data will inform further studies related to ST36 acupuncture on inflammation.

Time-resolved resonant elastic soft x-ray scattering at Pohang Accelerator Laboratory X-ray Free Electron Laser.

Resonant elastic x-ray scattering has been widely employed for exploring complex electronic ordering phenomena, such as charge, spin, and orbital order, in particular, in strongly correlated electronic systems. In addition, recent developments in pump-probe x-ray scattering allow us to expand the investigation of the temporal dynamics of such orders. Here, we introduce a new time-resolved Resonant Soft X-ray Scattering (tr-RSXS) endstation developed at the Pohang Accelerator Laboratory X-ray Free Electron Laser (PAL-XFEL). This endstation has an optical laser (wavelength of 800 nm plus harmonics) as the pump source. Based on the commissioning results, the tr-RSXS at PAL-XFEL can deliver a soft x-ray probe (400 eV-1300 eV) with a time resolution of ∼100 fs without jitter correction. As an example, the temporal dynamics of a charge density wave on a high-temperature cuprate superconductor is demonstrated.

Serum MicroRNA on inflammation: a literature review of mouse model studies.

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate target gene expression by binding to sequences in messenger RNA processing. Inflammation is a protective reaction from harmful stimuli. MiRNAs can be biomarkers of diseases related to inflammation and are widely expressed in serum. However, overall changes in serum miRNA levels during inflammation have yet to be observed. Here, we selected studies published until 20 January 2020 that examined miRNAs in mouse models of inflammation. Serum microRNA, inflammation, inflammatory and mouse were used as search terms to select articles from PubMed and MEDLINE. Among the articles, sepsis and 18 related miRNAs were mainly examined. Eleven miRNAs were related to brain disease and 10 with fibrosis. Seventeen injury-induced inflammatory disease studies were included, as well as other inflammatory diseases, such as metabolic disease, vascular disease, arthritis, asthma, autoimmune disease, inflammatory bowel disease, and thyroiditis. The data described miRNA-associated downstream pathways associated with inflammation as well as mitochondrial responses, oxidative responses, apoptosis, cell signalling, and cell differentiation. We expect that the data will inform future animal inflammation-related miRNA studies.

The Impact of PM10 Levels on Pedestrian Volume: Findings from Streets in Seoul, South Korea.

Although many studies have revealed that both air quality and walking activity are dominant contributors to public health, little is known about the relationship between them. Moreover, previous studies on this subject have given little consideration to the day-to-day atmospheric conditions and floating populations of surrounding areas even though most pedestrian count surveys are not conducted on a single day. Against this backdrop, using the 2015 Pedestrian Volume Survey data and quasi-real-time weather, air quality, and transit ridership data in Seoul, this study investigates the relationship between particulate matter (PM)10 and pedestrian street volumes empirically. The regression results suggest that PM10 concentration determines people's intention to walk and affects the volume of street-level pedestrians. The three regression models, which adopted different spatial aggregation units of air quality, demonstrated that PM10 elasticity of pedestrian volume is the largest in the borough-level (the smallest spatial unit of air quality alert) model. This means that people react to the most accurate information they can access, implying that air quality information should be provided in smaller spatial units for public health. Thus, strengthening air quality warning standards of PM is an effective measure for enhancing public health.

Acupuncture attenuates alcohol dependence through activation of endorphinergic input to the nucleus accumbens from the arcuate nucleus.

A withdrawal-associated impairment in ß-endorphin neurotransmission in the arcuate nucleus (ARC) of the hypothalamus is associated with alcohol dependence characterized by a chronic relapsing disorder. Although acupuncture activates ß-endorphin neurons in the ARC projecting to the nucleus accumbens (NAc), a role for ARC ß-endorphin neurons in alcohol dependence and acupuncture effects has not been examined. Here, we show that acupuncture at Shenmen (HT7) points attenuates behavioral manifestation of alcohol dependence by activating endorphinergic input to the NAc from the ARC. Acupuncture attenuated ethanol withdrawal tremor, anxiety-like behaviors, and ethanol self-administration in ethanol-dependent rats, which are mimicked by local injection of ß-endorphin into the NAc. Acupuncture also reversed the decreased ß-endorphin levels in the NAc and a reduction of neuronal activity in the ARC during ethanol withdrawal. These results suggest that acupuncture may provide a novel, potential treatment strategy for alcohol use disorder by direct activation of the brain pathway.