bluuebunny/crossref_metadata_2025_split huggingface dataset:
EXAMINING THE EFFECTS OF SIGMA-1 RECEPTOR AGONISTS ON THE INTRACELLULAR LOCALIZATION OF THE ENDOGENOUS RECEPTOR IN NEURO2A CELLS
Authors: Yasui *Yuko , Couly Simon , Su Tsung-Ping 
Published: February 2025

Abstract

Background
Sigma-1 receptor (SIGMAR1) is a ligand-operated transmembrane protein highly expressed in the central nervous system, implicated in various psychiatric diseases such as addiction, depression and schizophrenia. Several psychostimulants and drugs for psychiatric diseases have affinity to SIGMAR1.
Pharmacological studies using animal models show that SIGMAR1 ligands have treatment effects on the disease conditions suggesting that SIGMAR1 can be a promising target for therapeutic approaches.
However, how SIGMAR1 ligands influence the molecular function of SIGMAR1 remains ambiguous. One potential aspect of SIGMAR1 ligand-mediated regulation lies on the localization of SIGMAR1. SIGMAR1 is enriched in the endoplasmic reticulum (ER), mostly at the membrane contact sites between ER and mitochondria, where SIGMAR1 associates with GRP78. Currently, there are contradicting reports on whether SIGMAR1 dissociates from GRP78 at the ER and translocates to other cellular compartments, such as the plasma membrane (PM), upon agonist stimulation. Also, many studies were conducted using overexpression of SIGMAR1 to examine the localization in cells, which may not represent the behavior of the endogenous protein.

Aims & Objectives
The aim of this study is to investigate the effects of agonist stimulation on SIGMAR1 intracellular localization at the endogenous level in the neuroblastoma cell line Neuro2a.

Methods
We utilized a novel immunocytochemistry protocol which can effectively label endogenous SIGMAR1 in cells. We fixed the cells and labeled SIGMAR1 and organelle marker proteins by using specific antibodies. Images were captured using confocal microscopy and analyzed to obtain Pearson’ s correlation co- efficiency. To test the agonist effect, we treated the cells with 10 mM of (+)-Pentazocine or PRE-084 for 30 min and performed the immunocytochemistry as described above.

Results
In untreated conditions, most of SIGMAR1 co-localizes with ER marker proteins followed by mitochondria markers, as expected. On the other hand, co-localization with other organelle markers, such as PM and ER-PM contact sites, was insignificant. The presence of SIGMAR1 in the nuclear envelope (NE) was negligible as well. With agonist stimulation, we found that SIGMAR1 co-staining with marker proteins for PM, ER-PM contact sites and NE did not increase. Nor was there any effect on the co-localization of SIGMAR1 with GRP78.

Discussion & Conclusion
In summary, our results confirm that SIGMAR1 localizes primarily in the ER in Neruo2a cells. When SIGMAR1 is stimulated with an agonist, it does not apparently translocate to PM, PM-ER contact site or NE. Nevertheless, it is possible that SIGMAR1 shows cell-type dependent dynamics. We speculate that SIGMAR1 stays in the ER and moves along within the peripheral ER structure after agonist stimulation and currently plan to study the dynamics of SIGMAR1 within the ER structures.
GLIA RESPONSES ARE ASSOCIATED WITH ABNORMAL BEHAVIORS IN AN ANIMAL MODEL OF TAU PATHOLOGIES
Authors: Liu *Yue , Mizoguchi Hiroyuki , Sobue Akira , Sahara Naruhiko , Yamanaka Koji , Yamada Kiyofumi 
Published: February 2025

Abstract
Tau hyperphosphorylation has been considered a major contributor to neurodegeneration in Alzheimer’ s disease and related tauopathies and has gained prominence in the development of therapies for Alzheimer’ s disease. Glia responses are key feature of AD and are associated with neuroinflammation. Numerous transgenic mouse models that recapitulate critical Alzheimer’ s disease-like pathology have been developed to examine the pathogenic mechanisms underlying Alzheimer’ s disease and evaluate therapeutic approaches targeting tau and glial reactivity, but the relevant mechanisms remain unknown. In this study, we investigated changes in gene expression related to neuroinflammation in glial cells of rTg4510 mice, an animal model of non-Alzheimer’ s disease tauopathy. We first analyzed the behaviors of rTg4510 mice at 4- and 6-month-old that mimic behavioral and psychological problems of dementia. By using a magnetic-activated cell sorting technique, we then analyzed the gene expression related to neuroinflammation, phagocytosis, and amyloid synthesis in the prefrontal cortex of rTg4510 mice. Both 4- and 6-month-old rTg4510 mice displayed significantly impaired nesting behavior compared with control mice. Paired association learning was also impaired in 4-month-old rTg4510 mice. Moreover, rTg4510 mice of both age groups exhibited abnormal exploratory behavior, and these mice spent a greater amount of time in the open arm of the plus-maze test than control mice. In rTg4510 mice, Axl, Cd11c, and CD68 expression levels were increased in the microglial cells, and H2-D1, Psmb8, and H2-T23 expression levels in astrocyte cells were also increased when mice reached 6 months compared with control mice. These results raise a possibility that glia responses in rTg4510 mice may be related to their abnormal behavior.
DIFFERENTIAL EXPRESSION AND DISTINCT ROLES OF PROTEINASE- ACTIVATED RECEPTOR 2 IN MICROGLIA AND NEURONS IN NEONATAL MOUSE BRAIN AFTER HYPOXIA-ISCHEMIC INJURY
Authors: Liu *Yicong , Ni Junjun 
Published: February 2025

Abstract
Regulation of microglial activation and neuroinflammation are critical factors in the pathogenesis of ischemic brain injury. Interest in protease-activated receptor 2 (PAR2) as a pharmaceutical target for various diseases is creasing. However, it is unclear the expression and functions of PAR2 in hypoxia- ischemic (HI) brain injury. Mice with HI and cells with oxygen– glucose deprivation and reoxygenation (OGD/R) were studied. Immunoblot and qRT-PCR were used to study the differential gene expression in cultured microglia and neurons. Immunofluorescent staining was used to study the expression pattern of PAR2 in the HI brain and phagocytotic activity of microglia after OGD/R. In neonatal mice brain after HI, we found PAR2 expression was abundant in neurons, but barely in microglia from the contralateral side of cortex and hippocampus. Conversely, PAR2 expression was barely in neurons while significantly increased in activated microglia from the ipsilateral side of cortex and hippocampus. The activations of PAR2 were increased in both microglia and neuron in a cell model of OGD/R. PAR2 activation mediated the cross-talk between microglia and neurons including the following: microglial PAR2 mediated inflammatory responses that induced neuronal damage; neuronal PAR2 regulated chemokines that recruited activated microglia to damage area; microglia PAR2 controlled the phagocytosis of degenerating neurons. These data suggested differential expression and distinct roles of PAR2 in microglia and neurons after HI injury; thereby, interventions targeting PAR2 may provide insights into the inflammatory-related diseases.
INTRA-HIPPOCAMPAL INJECTION OF ALPHA-SYNUCLEIN PRE-FORMED FIBRILS TRIGGERS COGNITIVE DEFECT AND CHANGES TRANSCRIPTOME PROFILES
Authors: Huang *Yu Ting , Chen Jin Chung , Li Yu Ying 
Published: February 2025

Abstract
Parkinson's disease (PD) constitutes a significant aspect of motor and non-motor symptoms, the latter includes cognitive defect and mood disorders. Clinically, abnormal aggregation of α-synuclein (α-Syn) was found in patient’ s brain, but the pathogenesis mechanism of synucleinopathy remains to be defined. In this study, we aimed to determine whether hippocampal synucleinopathy contributes to cognitive dysfunction and to investigate the molecular changes connecting hippocampal synucleinopathy to dementia. To understand synucleinopathy-induced dementia, mice were injected α-Syn preformed fibrils (PFFs) into the hippocampus bilaterally. After 8 months of PFF injection, there was a significant increase in amount of α-Syn/pSer129. In the behavioral test, mice displayed cognitive deficits in recognition memory, social memory, working memory, and long-term memory. In addition, RNA-sequencing analysis identified 2,585 differentially expressed genes (DEGs, p-value &lt;0.05) in the PFF-treated mice compared to the PBS control, In particular, pathway of transforming growth factor beta (TGFβ) was enriched in the PFF-injected mice. The TGFβ-related genes were increased in the hippocampus during the progress of synucleinopathy, i.e. BMPR2, BMP2, BMP5, TGFβ1 and the downstream signals of Smad1/5/8 and Smad2. Furthermore, there is a time-dependent change in the expression of GFAP, Iba1, inflammasome and the complement system, with those gene expression decreased at 8 months, while increased at 12-13 months after PFF injection. Moreover, amount of AMPA1/pSer845 of glutamate receptor increased after post- PFF injection across both time intervals. Collectively, our findings demonstrate that hippocampal synucleinopathy effectively induces cognitive impairments associated with dementia. These effects parallel with the altered BMP/TGFβ pathways, immune responses, the complement system, and glutamate systems. These molecular changes may serve as valuable biomarkers and potential therapeutic targets that bridge the link between hippocampal synucleinopathy and dementia.
ASSOCIATION BETWEEN GUT MICROBIOME AND DRINKING TYPES OF ALCOHOL USE DISORDER
Authors: Wu *Lawrence Shih Hsin , Huang Ming Chyi , Meng Shi Chun 
Published: February 2025

Abstract

Background
Alcohol use disorder (AUD) presents as a diverse condition, with clinical characteristics linked to treatment effectiveness varying among individuals. For example, distinct patterns of drinking exhibit distinct reactions to Naltrexone therapy. Individuals classified as reward drinkers tend to display a higher likelihood of positive response to Naltrexone treatment. Utilizing the gut-brain axis mechanism as a foundation, we explore disparities in gut microbiome profiles across various drinking patterns.

Methods
So far, a total of 36 patients diagnosed with AUD were included in the study, and their drinking patterns were evaluated following the guideline. DNA was extracted from the patients' stool samples, and high-throughput sequencing was employed for 16S rRNA data analysis, which was subsequently analyzed through bioinformatics methods. The AUD patients were categorized into four groups based on their reward and relief levels: low reward/low relief (4 subjects), high reward/low relief (2 subjects), low reward/high relief (9 subjects), and high reward/high relief (21 subjects).

Results
Analysis of alpha diversity in the stool samples from these groups revealed no significant differences in the microbial community richness. However, beta diversity analysis using NMDS, PCA, and PCoA indicated statistically significant distinctions in the stool microbiome patterns among the four groups.
Additionally, we conducted pairwise comparisons between low and high reward as well as relief groups using LDA. The analysis revealed a higher frequency of Bacillales and a decreased occurrence of Bacteroides species, including uniformis and fragilis, in the high relief group. Studies have linked Bacteroides uniformis and Bacteroides fragilis to depression in both human and mouse models. Moreover, Parabacteroides distasonis was more prevalent in low reward subjects compared to the high reward group and has been associated with inducing depression-like behavior in mouse models.

Conclusion
Various patterns in the gut microbiome are expected among different types of alcohol use disorder (AUD). Certain bacteria linked to specific drinking patterns have been associated with depression.
Subsequent research should explore the clinical aspects related to these drinking patterns, considering the alterations in gut bacterial composition in individuals with AUD.
DOES A DEPRESSIVE EPISODE PRECEDE PROBLEMATIC SMARTPHONE USE? : A NATIONWIDE STUDY IN KOREA
Authors: Seong *Su Jeong , Hong Jin Pyo , Hahm Bong-Jin , Chang Sung Man , Kim Byung-Soo , Lee Dong-Woo , Cho Seong-Jin , Park Jong-Ik , Park Jee Eun , Jeon Hong Jin 
Published: February 2025

Abstract

Background
Although many studies have consistently demonstrated the association between depression and problematic smartphone use (PSU), the temporal precedence and causality of this relationship remain controversial.

Aims & Objectives
This study aimed to investigate the relationship between major depressive disorder (MDD) and PSU in a sample of the general adult population by analyzing the association between present PSU and both past and current MDD.

Method
The study utilized data from the Korean Epidemiologic Catchment Area study, a nationwide epidemiologic survey that employed a multistage cluster sampling method. Participants were assessed using the Korean version of the Composite International Diagnostic Interview to diagnose MDD and the Smartphone Overuse Screening Questionnaire to identify PSU.

Results
Of the 916 subjects, 139 (15.2%) belonged to the PSU group. The prevalence of PSU in older adults was substantial, with 9.3% for the 36-50 age group and 5.4% for the over 50 age group. We found a significant association between MDD and PSU. Both current (OR 6.366, 95% CI 1.253-32.353) and previous (OR 2.826, 95% CI 1.528-5.227) MDD episodes were associated with increased risk of PSU.

Discussion & Conclusion
This study confirmed the association between PSU and MDD among the general adult population. Specifically, previously resolved depression was found to affect the current PSU. This study also contributes to the literature by utilizing standardized tools for diagnosing MDD, providing more robust evidence on the association between depression and PSU. Additionally, the study also highlighted that PSU is not limited to young populations.
BETAINE MITIGATES REINSTATEMENT OF METHAMPHETAMINE- INDUCED CONDITIONED PLACE PREFERENCE IN RATS: INVOLVEMENT OF CAMKK2/AMPK SIGNALING
Authors: Chen *Hwei-Hsien , Lee Mei-Yi , Chen Ching-Yi , Hung Yung-Ting 
Published: February 2025

Abstract

Background
Methamphetamine (MA) use represents a significant worldwide public health concern. Currently, no pharmacological therapy has established efficacy for treating MA use disorder. Betaine has been found to reduce MA-induced behavioral sensitization. In addition, betaine activates adenosine monophosphate (AMP)-activated protein kinase (AMPK) which has been associated with reinstatement of cocaine seeking.

Aims & Objectives
This study aimed to examine the effects of betaine on conditioning and reinstatement of MA-conditioned place preference (CPP). Additionally, it sought to explore the involvement of AMPK and its upstream activator, calcium/calmodulin-dependent protein kinase (CAMKK2), in the reducing effect of betaine on the reinstatement of MA CPP.

Method
Male Sprague-Dawley rats underwent a three-compartment CPP paradigm. Betaine or saline was administered 30 minutes prior to each MA (2 mg/kg) conditioning session or 30 minutes before MA (1 mg/kg) priming-induced reinstatement. To determine the roles of AMPK and CAMKK2 in betaine's reducing effect on the reinstatement of MA CPP, rats received bilateral intra-NAc core infusions of the AMPK inhibitor dorsomorphin or STO-609, a selective inhibitor of CAMKK2, followed by betaine (100 μ g/μ l) before MA priming-induced reinstatement.

Results
Betaine did not affect conditioning, but significantly reduced reinstatement of MA CPP at 100 mg/kg. Furthermore, acute intra-NAc core infusions of betaine effectively ameliorated the reinstatement of MA CPP, and this effect was abolished by co-treatment with dorsomorphin or STO- 609.

Discussion & Conclusions
These findings suggest that betaine may be a novel therapeutic agent for the treatment of MA use disorder, and activation of the CAMKK2-AMPK pathway might be one of the mechanisms underlying the MA relapse-preventing effect of betaine.
MICRORNA EXPRESSION IN PATIENTS WITH METHAMPHETAMINE USE DISORDER: A PILOT STUDY
Authors: Ratta-Apha *Woraphat , Bunmak Nutthaya , Saengsawang Witchuda , Chairoungdua Arthit , Zaw Thet Tun , Ranuwattananon Apichart , Kalayasiri Rasmon 
Published: February 2025

Abstract

Background
MiRNAs have the potential to use as diagnostic biomarkers for neuropsychiatric disorders However, the possibility of using the miRNAs as a biomarker for diagnosis and prognosis of substance use disorders has extensively investigated.

Aims & Objectives
In this study, we aimed to investigate miRNAs expression in the serum of patients with methamphetamine use disorder admitted at an addiction center compared with the control.

Method
We extracted the circulating miRNAs from the serum of 19 methamphetamine users and 19 controls. The expression of 800 human miRNAs from the extracted samples were quantified with NanoString analysis and differential expression analysis of miRNAs between methamphetamine users and control subjects were determined. The candidate miRNAs validated by qPCR and pathway analysis predicted target genes from miRNAs candidates were analyzed.

Results
We selected five differentially expressed miRNAs between drug users and control, i.e., has-miR- 92a-3p, has-miR-451a, has-miR-30e-5p, has-miR-630, has-miR-495-3p. We found that these selected differentially expressed miRNAs are enriched in various pathways including amphetamine addiction pathway, cholinergic synapse pathway in KEGG pathway.

Conclusion
The results from this study would provide information about potential miRNAs that could be further investigate for potential diagnostic or prognostic markers for the methamphetamine use disorder.
CHARACTERISTICS OF ANTIDEPRESSANT CLASSES FOR TREATMENT- RESISTANT DEPRESSION AS DEFINED BY THE NUMBER OF VALID PHARMACOTHERAPIES
Authors: Mori *Keisuke , Kodaka Fumitoshi , Ishii Junpei , Sakai Yoshiyuki , Kobayashi Tamayo , Saeki Chihiro , Kameyama Hiroshi , Shigeta Masahiro 
Published: February 2025

Abstract

Background
Treatment-resistant depression (TRD) is conventionally defined as depression that does not remit with two or more adequate doses of antidepressants of adequate duration (Thase, 1997). Although we have suggested that 3 or more valid pharmacotherapies may include TRD with a high probability, little is known about the characteristics of antidepressants preferred for TRD.

Aims & Objectives
The purpose of this study was to characterize antidepressant classes for TRD by comparing prescriptions for TRD and non-treatment-resistant depression (non-TRD), classified by the number of valid pharmacotherapies. The study was approved by the Ethics Committee of the Jikei University School of Medicine.

Method
A longitudinal prescription data set of 494 patients who visited the Department of Psychiatry, The Jikei University Hospital between January 1, 2018 and December 31, 2021 was analyzed. The patients diagnosed with ICD-10 codes F32 (depressive episode) and F33 (recurrent depressive disorder) and treated with antidepressants for 30 days or more were extracted.Patients treated with 3 or more valid pharmacotherapies were included in the TRD group (58 patients) and those treated with 2 or less pharmacotherapies were included in the non-TRD group (436 patients).The presence or absence of antidepressant prescriptions for each group at the last visit during the period was compared using the chi-square test for each class. The significance level was set at 5%.

Results
The TRD group had significantly higher prescription rates for tricyclic antidepressants and serotonin- noradrenaline reuptake inhibitors (p=3.73×10-5 and 3.22×10-5, respectively), while the non-TRD group had significantly higher prescription rates for selective serotonin reuptake inhibitors (p=1.28×10-2). Prescription rates for noradrenergic and specific serotonergic antidepressants and tetracyclic antidepressants were not significantly different between the two groups (p= 6.14×10-1 and 1.61×10-1, respectively).

Discussion & Conclusion
It was suggested that in the real-world setting, psychiatrists choose antidepressant classes based on tolerability.

References
1. Thase, M. E. and Rush A. J. (1997), “When at first you don't succeed: sequential strategies for antidepressant nonresponders”, J Clin Psychiatry 58: 23–29.
ROLE OF MICROSOMAL PROSTAGLANDIN E SYNTHASE-1 IN MOUSE MODELS OF STRESS
Authors: Ikeda-Matsuo *Yuri , Takagi Hina , Kawabata Yuta , Iwato Saki , Doumae Asumi , Akira Shizuo , Uematsu Satoshi , Takahashi Tatsuo 
Published: February 2025

Abstract

Although there are many antidepressants available, most of which are drugs based on the monoamine hypothesis, and about one third of patients experience treatment-resistant depression. Thus, new therapeutic targets for antidepressants need to be discovered. We have previously reported that microsomal prostaglandin E synthase-1 (mPGES-1), a terminal inducible enzyme for PGE2 synthesis, induced at lesion sites in animal models and patients with Parkinson's disease and cerebral infarction contributes to the brain inflammation and deterioration of the pathology through PGE2 production1,2). Recently, brain inflammation has been reported to be involved in not only stroke or neurodegenerative diseases, but also psychiatric disorders. In this study, to elucidate the contribution of mPGES-1 to stress-induced brain inflammation and functions, we used two mouse models of stress, acute restraint stress (RS: 6 h) and social defeat stress (SDS). mPGES-1 mRNA was significantly increased after RS. Induction of mPGES-1 protein was observed in neurons in the frontal cortex (FC). PGE2 in FC was also significantly upregulated in wild-type (WT) mice, but not in mPGES-1 knockout (ES1KO) mice. The inflammatory responses, such as increases in GFAP and TNF-α, observed after RS in ES1KO were significantly less than those in WT. In sucrose preference test (SPT), the ratio of sucrose intake after RS in WT was significantly less than that in ES1KO. In SDS model, upregulation of mPGES-1 mRNA was also observed in FC, amygdala and ventral tegmental area at Day1 and 4. Induction of mPGES-1 protein was observed in neurons in the FC at Day4. PGE2 in FC was significantly upregulated at Day4 in WT mice, but not in ES1KO mice. The inflammatory responses, such as increases in Iba-1, GFAP and IL-1β, observed at Day10 of SDS in ES1KO were significantly less than those in WT. The ratio of sucrose intake at Day8 of SDS in WT was significantly less than that in ES1KO. Taken together, these results suggest that mPGES- 1 is induced by both RS and SDS stress in FC neurons, and then contributes to brain inflammation and anhedonia through PGE2 production. Thus, mPGSE-1 may be a promising novel therapeutic target for treatment of depression.

References
1)Ikeda-Matsuo Y, et al., Proc Natl Acad Sci U S A. 2006; 103(31): 11790-11795.
2)Ikeda-Matsuo Y, et al., Neurobiol Dis. 2019;124: 81-92.