With the intensification of global plastic pollution, the potential threats posed by micro- and nanoplastics (MPs/NPs) to human health have become a major concern. MPs/NPs enter the organism through ingestion, inhalation, and skin contact, subsequently accumulating in multiple organs—particularly the brain. Increasing experimental and epidemiological evidence implicates MPs/NPs in the development of Parkinson’s disease (PD). Preclinical research models indicate that MPs/NPs may accelerate both the initiation and progression of PD by facilitating α-synuclein misfolding and aggregation, triggering neuroinflammatory cascades, elevating oxidative stress, and impairing mitochondrial function. To further investigate the causal role of MPs/NPs in PD, upcoming studies should emphasize well-designed, large-scale prospective cohorts to assess individual exposure to plastic-related pollutants, elucidate the pathways of MPs/NPs into the central nervous system, establish safety thresholds for their neurotoxicity, explore the correlation between exposure levels and central nervous system accumulation, clarify the temporal relationship between MPs/NPs accumulation and PD pathology and symptom onset, and identify the neuropathological mechanisms triggered by relevant concentrations of MPs/NPs. Such data will be instrumental in informing preventive and potentially interventional strategies, while offering actionable insights into the interaction between MPs/NPs and PD.

Alzheimer’s disease (AD) is characterized by progressive neurodegeneration and neuroinflammation, with microglial dysfunction playing a pivotal role in its pathogenesis. The specific function of the immune checkpoint molecule TIM-3 (encoded by HAVCR2) in microglia remains unclear. We performed an integrated multi-omics analysis combining bulk and single-cell RNA sequencing datasets from AD patients. Bioinformatics approaches, including gene set enrichment, cell-cell communication, and pathway analysis. Furthermore, machine learning algorithms were used to stratify AD patients into molecular subtypes based on HAVCR2 expression. Finally, network pharmacology analysis was conducted to identify potential therapeutic compounds targeting TIM-3 + microglia. We identified a novel TIM-3 + microglial subset that drives pathogenesis through a dual mechanism: (i) sustained neuroinflammation via TNF-α/NF-κB and IL-6/JAK/STAT3 signaling, and (ii) impaired amyloid-β clearance linked to PI3K-AKT and FcγR pathways. TIM-3 + microglia displayed strong interactions with known AD risk genes such as INPP5D and TREM2. Clinically, machine learning classified AD patients into two molecular subtypes: a “hyper-inflammatory” subtype and a “metabolically dysregulated” subtype, revealing distinct pathological drivers. Network pharmacology predicted tretinoin (ATRA) as a candidate drug targeting the CD86–PTPRC–ITGAX axis in TIM-3 + microglia. This study reveals the immunopathological role of TIM-3 + microglia in AD and highlights their contribution to neuroinflammation and impaired protein clearance. The identification of molecular subtypes and a potential drug candidate (ATRA) provides a framework for precision medicine strategies targeting microglial heterogeneity in Alzheimer’s disease.

In the early stage of intracerebral hemorrhage (ICH), rebleeding occurs when blood from the initial hematoma permeates the surrounding brain parenchyma through the disrupted blood-brain barrier (BBB), exacerbating brain injury. Neuroinflammation is a critical driver of the pathological processes underlying this phenomenon. Research on microglia near early hematomas revealed that promoting the transition of microglia to the M2 phenotype could mitigate perihematomal inflammatory damage. Recent studies have shown that the nuclear receptor-related 1 protein (NR4A2) can regulate microglial function and inhibit inflammation. However, the functions of NR4A2 in the development of ICH are still unclear. In this study, we explored the potential protective effect and mechanism of NR4A2 in ICH models. Our results demonstrated that the expression of NR4A2 was significantly decreased in both ICH rats and cell models. Increasing NR4A2 activity could effectively decrease the hematoma volume, improve the neurological prognosis and alleviate perihematomal BBB damage. In vivo and in vitro experiments revealed that NR4A2 inhibited perihematomal inflammatory damage by driving microglial polarization toward the anti-inflammatory M2 phenotype. Mechanistically, NR4A2 targeted TLR4 and inhibited the TRAF6/NF-κB pathway, thereby promoting M2 microglial polarization, reducing inflammatory cell extravasation and maintaining the integrity of the BBB. Conversely, the protective effects of NR4A2 were negated when CRX-527 (a TLR4 agonist) was introduced. These findings suggest that NR4A2 represents a promising therapeutic target for ICH.

Eukaryotic translation initiation factor 4G1 (eIF4G1) has been implicated in Parkinson’s disease (PD) pathogenesis. However, the contribution of EIF4G1 genetic variation to PD susceptibility remains unclear. To investigate the association between the EIF4G1 variant rs2178403 and PD risk. We analyzed EIF4G1 expression in PD and control samples using public GEO datasets (GSE54536). Additionally, we conducted a hospital-based case-control study with 541 sporadic PD patients and 401 age-/sex-matched healthy controls of Han Chinese ancestry. Genotyping of rs2178403 was performed using Sequenom MassARRAY iPLEX. GEO data revealed a non-significant trend toward elevated EIF4G1 expression in PD samples (p < 0.1). Genetic analysis identified a significant association between the rs2178403 GG genotype and increased PD risk under a recessive model (OR = 1.31, 95% CI = 1.010–1.703, p = 0.042). Stratified analysis showed a stronger effect in females. These findings suggest rs2178403 may contribute to PD susceptibility in the Han Chinese population. This study supports an association between the EIF4G1 variant rs2178403 and PD risk. Further investigation into EIF4G1 inhibition as a potential therapeutic strategy for PD is warranted.

RATIONALE Number of small airway dysfunction (SAD) assessed by impulse oscillometry (IOS) is accumulated in patients with chronic obstructive pulmonary disease (COPD), and single SAD is associated with the previous year of exacerbations. However, little is known that the associations between accumulated number of SAD and Long-term prognosis of COPD. The study aimed to explore associations between accumulated number of SAD and lung function decline and exacerbations in patients with COPD. METHODS We analyzed baseline and 2-year follow-up data from the prospective cohort study in China. We used IOS parameters greater than ULN or LLN to defined SAD, then these patients were further divided into three accumulated nubmer of SAD groups (No airway abnormalities, 1-3 airway abnormalities, and 4-5 airway abnormalities). Negative Binomial Regression was performed to analyze the associations between accumulated SAD and exacerbations, and we used multivariable linear regression model to associations between accumulated SAD and lung function decline. RESULTS 833 patients with COPD were enrolled in our study. Single SAD was associated with faster decline in lung function and severer exacerbations. As the number of SAD increased, we found that patients with 4-5 airway abnormalities had a faster decline in lung function and severer exacerbations than those with no airway abnormalities, but no differences in prognosis was found between patients with 1-3 airway abnormalities and with no airway abnormalities. CONCLUSION SAD was associated with poor outcomes, and as the number of SAD increases, the prognosis became worse.

Objective:To investigate the protective effects of luteolin on ALI induced by lipopolysaccharide (LPS) in male mice and to explore the underlying mechanisms. Methods:A two-sample Mendelian randomization (MR) analysis was conducted to assess the causal relationship between hepatocyte growth factor (HGF) and acute respiratory distress syndrome (ARDS). Network pharmacology analysis was employed to identify herbs that mitigate inflammation and apoptosis by upregulating HGF expression and to determine the hub active ingredients. These findings were subsequently validated through in vivo experiments using an LPS-induced ALI mouse model. Lung histopathological examination, enzyme-linked immunosorbent assay, and Western blot analysis were performed to evaluate relevant biomarkers of inflammation and apoptosis. Results:The MR analysis demonstrated a causal effect of HGF on ARDS (IVW: β = -1.120, OR = 0.326, 95% CI = 0.116-0.916, P = 0.033). Among herbs associated with upregulating HGF expression, Salvia miltiorrhiza Bunge is involved in the negative regulation of apoptotic process and positive regulation of cell population proliferation. Luteolin was identified as the hub active ingredient extracted from S. miltiorrhiza Bunge. In LPS-induced ALI mice, luteolin significantly alleviated histopatholocial damage, inflammation, and apoptosis in the lungs. However, these protective effects were abrogated by c-Met inhibition. Conclusion:Luteolin attenuates inflammation and apoptosis in the lungs of LPS-induced ALI mice via activation of the HGF/c-Met pathway.

Background: To evaluate the efficacy, safety, and adherence of oral citicoline sodium capsules in improving neurological outcomes during the recovery phase of ischemic stroke in a real-world setting. Methods: This single-arm, multicenter, real-world observational study enrolled 6496 ischemic stroke patients in the recovery phase from January 2020 through December 2024. Patients received citicoline sodium capsules (200 mg, three times daily) for three months. Outcomes were assessed using NIHSS, mRS, and Barthel Index at baseline, 1, 2, and 3 months. Treatment effectiveness was categorized based on NIHSS improvement as markedly effective (≥90% reduction), improved (60%–89%), effective (30%–59%), or ineffective (<30%). Results: Of the 6496 patients (mean age 61.9±10.6 years; 61.6% male), 85.8% had comorbidities. After three months of treatment, significant improvements were observed in all neurological function measures: NIHSS decreased from 11.6±5.5 to 9.6±6.2, mRS improved from 2.5±1.1 to 2.0±1.1, and BI increased from 51.4±24.0 to 62.8±25.7 (all P<0.001). The total effectiveness rate increased progressively from 9.9% at 1 month to 37.5% at 3 months, while the proportion of severely dependent patients decreased from 27.7% to 11.9%. Treatment adherence remained high (96%–97%) throughout the study period, with only two mild adverse events reported. Conclusions: This real-world study suggests that three-month citicoline therapy provides meaningful improvements in neurological function and daily living activities during stroke recovery, with excellent safety and adherence profiles. Further randomized controlled trials are warranted to confirm these findings and optimize treatment protocols.

Irritable Bowel Syndrome (IBS) is a common gastrointestinal disorder frequently accompanied by psychological symptoms. Bacterial microbiota plays a critical role in mediating local and systemic immunity, and alterations in these microbial communities have been linked to IBS. Emerging data indicate that other intestinal organisms, including bacteriophages, are closely interlinked with the bacterial microbiota and their host, yet their collective role remains to be elucidated. Here, we analyze the gut multi-kingdom microbiota of 360 IBS patients from a prospective cohort study in Hong Kong, with participants phenotyped through psychological assessment. Our findings reveal significantly lower intra-community correlations in IBS patients compared to healthy controls and highlight unique taxa patterns associated with IBS and mental disorders. Utilizing multi-omic data alongside machine learning techniques, we successfully predicted psychiatric comorbidities in IBS, achieving an average AUC of 0.78. Notably, gut viruses emerged as significant contributors to our predictive model, indicating a vital role for bacteriophages in the gut microbiome of IBS patients. We found that lysogenic phages in IBS displayed a broader host range, with Bilophia containing the most abundant prophages. Our analysis further indicates that IBS patients with depression exhibited a higher prevalence of viral-encoded auxiliary metabolic genes, specifically those involved in the sulfur metabolic pathway related to ubiquinone biosynthesis. The gut virome is increasingly reported to play an important role in the pathogenesis of many diseases. The study provides a systematic characterization of the drivers of the gut viral community and further expands our knowledge of the distinct interaction of gut viruses with their prokaryotic hosts, which is critical for understanding the viral–bacterial environment in IBS.

Microplastic (MP) contamination in human blood and its potential link to Parkinson's disease (PD) remain poorly understood. In this study, we collected whole blood samples from 21 PD patients and 12 age- and sex-matched healthy controls under strict anticontamination protocols. A lifestyle questionnaire was administered to assess MP exposure-related habits, revealing that PD patients reported more frequent use of disposable plastic products and bottled water consumption, suggesting greater environmental exposure. Pyrolysis-gas chromatography-mass spectrometry (Py-GC/MS), laser direct infrared imaging (LDIR) and scanning electron microscopy (SEM) were used to quantify and characterize the MPs. Five polymer types-polyethylene (PE), polystyrene (PS), polyvinyl chloride (PVC), polypropylene (PP) and nylon-66 (PA66)-were detected in the sample. The total MP burden was significantly greater in PD patients than in controls (21.36 ± 8.42 vs. 13.56 ± 5.92 μg/g; p < 0.01), with the greatest increases observed for PVC (1.49-fold), PP (2.74-fold) and PA66 (6.62-fold), whereas the PE and PS levels were not significantly different. LDIR and SEM analyses revealed diverse particle morphologies, with most polymers appearing as granular particles. In vitro assays further revealed that PVC and PP microplastics induced dopaminergic neuron apoptosis and increased the level of phosphorylated α-synuclein (p-α-syn), providing support for their potential neurotoxicity. Together, these findings indicate elevated blood MP levels in PD patients and offer preliminary evidence linking polymer exposure with PD-related neuronal vulnerability.

Excess cholesterol is positively correlated with colorectal cancer (CRC). Current therapeutic strategies for modulating cholesterol levels in CRC are limited and often come with complications. Here, we demonstrated that microbiome shunting of intestinal cholesterol to anticancer metabolites is a safe and applicable therapeutic approach for CRC. By screening major microbial metabolic products of cholesterol, we found that 4-cholesten-3-one (4-C-3) was selectively depleted in fecal samples and tumor tissues of patients with CRC. 4-C-3 exhibits strong antitumor effects on human CRC cell lines, patient-derived organoids, and patient-derived xenograft (PDX) models. Mechanistically, 4-C-3 suppresses CRC tumorigenesis by dually targeting the epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homologue (KRAS). 4-C-3 directly binds to EGFR, blocking its signal transduction by inhibiting the binding of EGFR ligands. Additionally, 4-C-3 inhibits oncogenic KRAS variants, such as KRASG12D, by suppressing nucleotide exchange activity and effector engagement. By targeting both EGFR and KRAS, 4-C-3 reduces primary resistance to anti-EGFR therapies caused by KRAS mutations in CRC. As a proof-of-concept study, we showed that delivery of 4-C-3 by Oscillibacter ruminantium , a 4-C-3- producing commensal bacterium that is reduced in CRC patients, or a nonpathogenic Escherichia coli strain engineered to specifically convert intestinal cholesterol into 4-C-3, removed intratumoral cholesterol and led to rapid tumor regression in multiple models of CRC. These results suggest that microbial therapies for restoring intestinal cholesterol homeostasis represent a new therapeutic avenue for CRC. ### Competing Interest Statement The authors have declared no competing interest.

Obesity has been linked to an increased risk of cognitive impairment and dementia in later life. Although aging and obesity are both associated with cognitive decline, it remains unclear how they interact to affect cognitive function across the lifespan and how brain function might mediate their relationship with cognition. Our previous findings and other studies have shown that membrane type 1-matrix metalloproteinase (MT1-MMP/MMP14), which increases with age, regulates energy homeostasis. Inhibiting MT1-MMP improves insulin sensitivity, reduces body fat, and lowers serum cholesterol. Here, we demonstrate that MT1-MMP links neuroinflammation to cognitive decline in aging and obesity. Inflammatory responses in the brain increase MT1-MMP activation in the hippocampus of both mice and humans. Activation of hippocampal MT1-MMP alone can trigger cognitive decline and synaptic impairment independently of neuroinflammation. Conversely, ablation of MT1-MMP in the hippocampus reverses cognitive decline and improves synaptic plasticity in aging and obesity. Pharmacological inhibition of MT1-MMP, through an orally administered brain-penetrant inhibitor or targeted delivery of a neutralizing antibody to the hippocampus, improves memory and learning in aged and obese mice without toxicity. Mechanistically, MT1-MMP proteolytically inactivates G-protein-coupled receptor 158 (GPR158), a hippocampal receptor for osteocalcin (OCN) that is important for the maintenance of cognitive integrity, thus suppressing the ability of the OCN-GPR158 axis to promote cognition in aging and obesity. These findings suggest a new mechanism underlying hippocampal dysfunction and reveal the potential for treating multiple age-related diseases, including neurodegenerative disorders, obesity, diabetes, and atherosclerosis, with a single MT1-MMP-blocking agent.

The function of astrocytes in response to gut microbiota-derived signals has an important role in the pathophysiological processes of central nervous system (CNS) diseases. However, the specific effects of microbiota-derived metabolites on astrocyte activation have not been elucidated yet. Experimental autoimmune encephalomyelitis (EAE) was induced in female C57BL/6 mice as a classical MS model. The alterations of gut microbiota and the levels of short-chain fatty acids (SCFAs) were assessed after EAE induction. We observed that EAE mice exhibit low levels of Allobaculum, Clostridium_IV, Clostridium_XlVb, Lactobacillus genera, and microbial-derived SCFAs metabolites. SCFAs supplementation suppressed astrocyte activation by increasing the level of tryptophan (Trp)-derived AhR ligands that activating the AhR. The beneficial effects of SCFAs supplementation on the clinical scores, histopathological alterations, and the blood brain barrier (BBB)-glymphatic function were abolished by intracisterna magna injection of AAV-GFAP-shAhR. Moreover, SCFAs supplementation suppressed the loss of AQP4 polarity within astrocytes in an AhR-dependent manner. Together, SCFAs potentially suppresses astrocyte activation by amplifying Trp-AhR-AQP4 signaling in EAE mice. Our study demonstrates that SCFAs supplementation may serve as a viable therapy for inflammatory disorders of the CNS.

BACKGROUND:Chronic heart failure (CHF) has always posed a significant threat to human survival and health. The efficacy of thiamine supplementation in CHF patients remains uncertain. HYPOTHESIS:Receiving supplementary thiamine may not confer benefits to patients with CHF. METHODS:A comprehensive search was conducted across the Cochrane Library, PubMed, EMBASE, ClinicalTrials.gov, and Web of Science databases up until May 2023 to identify articles investigating the effects of thiamine supplementation in CHF patients. Predefined criteria were utilized for selecting data on study characteristics and results. RESULTS:Seven randomized, double-blind, controlled trials (five parallel trials and two crossover trials) involving a total of 274 patients were enrolled. The results of the meta-analysis pooling these studies did not reveal any significant effect of thiamine treatment compared with placebo on left ventricular ejection fraction (WMD = 1.653%, 95% CI:  -1.098 to 4.405, p = 0.239, I2 = 61.8%), left ventricular end-diastolic volume (WMD = -6.831 mL, 95% CI:  -26.367 to 12.704, p = 0.493, I2 = 0.0%), 6-min walking test (WMD = 16.526 m, 95% CI:  -36.582 to 69.634, p = 0.542, I2 = 66.3%), N-terminal pro-B type natriuretic peptide (WMD = 258.150 pg/mL, 95% CI:  -236.406 to 752.707, p = 0.306, I2 = 21.6%), or New York Heart Association class (WMD = -0.223, 95% CI:  -0.781 to 0.335, p = 0.434, I2 = 87.1%). However, it effectively improved the status of thiamine deficiency (TD). CONCLUSIONS:Our meta-analysis indicates that thiamine supplementation does not have a direct therapeutic effect on CHF, except for correcting TD.

As a respiratory tract-transmitted disease, coronavirus disease 2019 (COVID-19) exerts a profound immune injury effect, leading not only to pulmonary impairment but also to cardiac complications. We present a case of a 79-year-old woman, who had previously contracted COVID-19 and subsequently developed sinus arrest (SA) following her second infection. The longest asystole time detected by Holter monitoring was 7.2 seconds. Although the patient met criteria for permanent pacemaker implantation, her family declined this intervention and conservative management was pursued instead. However, after a period of observation, the patient’s SA resolved. The present case study describes a patient who experienced SA upon reinfection with COVID-19, which was not present during the initial infection. It emphasizes the impact of COVID-19 on cardiac health, particularly its potential to induce arrhythmias. In addition, it is worth noting that the arrhythmia induced by a COVID-19 infection may show reversibility, suggesting that a permanent pacemaker might not be the priority option if further pacing therapy is being considered.

Ubiquitin-proteasome system dysfunction triggers alpha-synuclein aggregation, a hallmark of neurodegenerative diseases, such as Parkinson's disease (PD). However, the crosstalk between deubiquitinating enzyme (DUBs) and alpha-synuclein pathology remains unclear. In this study, we observed a decrease in the level of ubiquitin-specific protease 14 (USP14), a DUB, in the cerebrospinal fluid (CSF) of PD patients, particularly females. Moreover, CSF USP14 exhibited a dual correlation with alpha-synuclein in male and female PD patients. To investigate the impact of USP14 deficiency, we crossed USP14 heterozygous mouse (USP14+/-) with transgenic A53T PD mouse (A53T-Tg) or injected adeno-associated virus (AAV) carrying human alpha-synuclein (AAV-h alpha-Syn) in USP14+/- mice. We found that Usp14 deficiency improved the behavioral abnormities and pathological alpha-synuclein deposition in female A53T-Tg or AAV-h alpha-Syn mice. Additionally, Usp14 inactivation attenuates the pro-inflammatory response in female AAV-h alpha-Syn mice, whereas Usp14 inactivation demonstrated opposite effects in male AAV-h alpha-Syn mice. Mechanistically, the heterodimeric protein S100A8/A9 may be the downstream target of Usp14 deficiency in female mouse models of alpha-synucleinopathies. Furthermore, upregulated S100A8/A9 was responsible for alpha-synuclein degradation by autophagy and the suppression of the pro-inflammatory response in microglia after Usp14 knockdown. Consequently, our study suggests that USP14 could serve as a novel therapeutic target in PD.

Seed amplification assays (SAA) enable the amplification of pathological misfolded proteins, including α-synuclein (αSyn), in both tissue homogenates and body fluids of Parkinson’s disease (PD) patients. SAA involves repeated cycles of shaking or sonication coupled with incubation periods. However, this amplification scheme has limitations in tracking protein propagation due to repeated fragmentation. We introduced a modified form of SAA, known as Quiescent SAA (QSAA), and evaluated biopsy and autopsy samples from individuals clinically diagnosed with PD and those without synucleinopathies (control group). Brain biopsy samples were obtained from 14 PD patients and 6 controls without synucleinopathies. Additionally, skin samples were collected from 214 PD patients and 208 control subjects. Data were analyzed from April 2019 to May 2023. QSAA successfully amplified αSyn aggregates in brain tissue sections from mice inoculated with pre-formed fibrils. In the skin samples from 214 PD cases and 208 non-PD cases, QSAA demonstrated high sensitivity (90.2

INTRODUCTION:Recent advances have highlighted the relationships between gut dysbiosis and Parkinson's disease (PD). Microbiota transplantation from PD patients to mice can induce increased alpha-synuclein-mediated motor deficits. Human studies have identified differences in the gut microbiota of PD patients compared to healthy controls. We undertook a systematic review to evaluate the available evidence for the involvement of gut bacteria in the etiology of PD. METHODS:The PubMed databank, the China National Knowledge Infrastructure databank, and Wanfang Data were searched from inception until June 2021 to identify human case-control studies that investigated relationships between PD and microbiota quantified from feces. We evaluated the resulting studies focusing on bacterial taxa that were different between PD patients and healthy controls. RESULTS:Twenty-six studies were found in which 53 microbial families and 98 genera exhibited differences between patients with PD and healthy controls. The genera identified by more than two studies as increased in PD were Bifidobacterium, Alistipes, Christensenella, Enterococcus, Oscillospira, Bilophila, Desulfovibrio, Escherichia/Shigella, and Akkermansia, while Prevotella, Blautia, Faecalibacterium, Fusicatenibacter, and Haemophilus had three or more reports of being lower in PD patients. More than one report demonstrated that Bacteroides, Odoribacter, Parabacteroides, Butyricicoccus, Butyrivibrio, Clostridium, Coprococcus, Lachnospira, Lactobacillus, Megasphaera, Phascolarctobacterium, Roseburia, Ruminococcus, Streptococcus, and Klebsiella were altered in both directions. CONCLUSION:Our review shows that the involvement of the gut microbiome in the etiology of PD may involve alterations of short-chain fatty acids (SCFAs)-producing bacteria and an increase in putative gut pathobionts. SCFAs-producing bacteria may vary above or below an "optimal range," causing imbalances. Considering that Bifidobacterium, Lactobacillus, and Akkermansia are beneficial for human health, increased Bifidobacterium and Lactobacillus in the PD gut microbiome may be associated with PD medications, especially COMT inhibitors, while a high level of Akkermansia may be associated with aging.

Parkinson's disease (PD) is a multi-system neurodegenerative disorder. Patients with PD often suffer chronic pain. In the present study, we investigated motor, sensory and emotional changes in three different PD mice models. We found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treatment caused significant changes in all measurements. Mechanical hypersensitivity of PD model induced by MPTP peaked at 3 days and persisted for at least 14 days. Using Fos transgenic mice, we found that neurons in the anterior cingulate cortex (ACC) were activated after MPTP treatment. Inhibiting ACC by bilateral microinjection of muscimol significantly reduced mechanical hypersensitivity and anxiety-like responses. By contrast, MPTP induced motor deficit was not affected, indicating ACC activity is mostly responsible for sensory and emotional changes. We also investigated excitatory synaptic transmission and plasticity using brain slices of MPTP treated animals. While L-LTP was blocked or significantly reduced. E-LTP was not significantly affected in slices of MPTP treated animals. LTD induced by repetitive stimulation was not affected. Furthermore, we found that paired-pulse facilitation and spontaneous release of glutamate were also altered in MPTP treated animals, suggesting presynaptic enhancement of excitatory transmission in PD. Our results suggest that ACC synaptic transmission is enhanced in the animal model of PD, and cortical excitation may play important roles in PD related pain and anxiety.