Mariana L. Müller , Angela E. Uchoa , Laura Blanco , Kimberly Fontoura , Rossano M. Silva , Julia Canzian , Barbara D. Fontana , Denis B. Rosemberg
{"title":"The shallow water test (SWT) as a novel behavioral paradigm to measure anxiety- and despair-like states in zebrafish","authors":"Mariana L. Müller , Angela E. Uchoa , Laura Blanco , Kimberly Fontoura , Rossano M. Silva , Julia Canzian , Barbara D. Fontana , Denis B. Rosemberg","doi":"10.1016/j.neulet.2025.138302","DOIUrl":"10.1016/j.neulet.2025.138302","url":null,"abstract":"<div><div>Affective disorders represent psychiatric conditions characterized by mood and emotional dysregulations, with depression and anxiety being among the most prevalent and frequently co-occurring. Depressive- and anxiety-related disorders can be associated with monoaminergic dysfunction and dysregulation of the GABAergic system. Stress plays a crucial role in the development and progression of these disorders, contributing to neurochemical disbalances. Because despair, a core symptom of depression, lacks well-established paradigms in zebrafish models based on naturalistic conditions, our goal was to report the use of the shallow water test (SWT) as a novel paradigm to assess despair-like behavior in zebrafish when placed in an unescapable shallow water environment. Basically, we exposed zebrafish to two distinct aversive conditions: mild electric shock (ES) as a physical stimulation or the conspecific alarm substance (CAS) as a naturalistic chemical cue (Experiment 1); and tested two pharmacological interventions: fluoxetine and diazepam (Experiment 2). Both stressors significantly reduced distance traveled, absolute turn angle, and average velocity, but only CAS increased the latency to mobility. While diazepam increased distance traveled, maximum speed, and average velocity, fluoxetine had no significant effects. Overall, these findings suggest the SWT as a sensitive and reliable tool for evaluating affective-like states in zebrafish, with implications for translational neurobehavioral research on affective disorders and potential therapeutic interventions.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"862 ","pages":"Article 138302"},"PeriodicalIF":2.5,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144310233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kang Jia , Qianhui Shen , Zhixian Zhang , Yuan Liu , Yanping Chen , Chao Ding , Shisong Wang , Cailv Wei , Yu Ren , Zhi Liang , Rongbiao Pi , Sigui Zhou
{"title":"Masitinib attenuates neuropathological changes in acrolein-induced sAD mouse model via NF-κB/NLRP3/Caspase-1 signaling pathway","authors":"Kang Jia , Qianhui Shen , Zhixian Zhang , Yuan Liu , Yanping Chen , Chao Ding , Shisong Wang , Cailv Wei , Yu Ren , Zhi Liang , Rongbiao Pi , Sigui Zhou","doi":"10.1016/j.neulet.2025.138300","DOIUrl":"10.1016/j.neulet.2025.138300","url":null,"abstract":"<div><div>Alzheimer’s Disease (AD) is a global health crisis, with sporadic AD (sAD) accounting for more than 95 % of all cases. The lack of effective disease-modifying therapies for sAD, driven by its complex pathogenesis involving genetic, environmental, and lifestyle factors, underscores the urgent need for novel treatments. Masitinib, an oral tyrosine kinase inhibitor originally developed for cancer treatment, has shown potential to regulate mast cells and neuroinflammation, making it a promising candidate against AD. In this study, we investigated the therapeutic effects of masitinib (60 mg/kg/day) in acrolein-induced sAD mouse model. A comprehensive series of behavioral tests, including the buried food pellet tests, Morris water maze, Y-maze, open field, and elevated plus maze, along with Western blot, immunofluorescence and Golgi-Cox staining were used to evaluate pathological changes. The results showed that masitinib significantly improved acrolein-induced olfactory deficits, cognitive dysfunction, particularly in learning and memory, and anxiety-like behaviors. Additionally, masitinib not only reduced p-Tau levels, increased PSD95 expression and restored dendritic spine density, but also suppressed neuroinflammation by inhibiting the NF-κB/NLRP3/caspase-1 inflammatory pathway and microglial activation. These findings demonstrate that masitinib, for the first time, attenuates sAD pathology through dual mechanisms of cognitive enhancement and neuroprotection. Our study provides strong preclinical evidence to support further clinical development of masitinib as a disease-modifying therapy for sAD.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"862 ","pages":"Article 138300"},"PeriodicalIF":2.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"CB1 receptor antagonism reverses social and cognitive deficits induced by repeated exposure to distressed conspecifics in rats","authors":"Fatemeh Rahimi Shourmasti , Seyedeh Masoumeh Seyedhosseini Tamijani , Raheleh Rafaiee , Mehdi Khodamoradi , Mohammad Shabani , Fatemeh Mohammadi , Abolhassan Ghaderi , Hamed Ghazvini","doi":"10.1016/j.neulet.2025.138299","DOIUrl":"10.1016/j.neulet.2025.138299","url":null,"abstract":"<div><div>Empathy is a behavioral phenomenon characterized by the capacity to share in another individual’s distressing experiences, including pain, discrimination, and social rejection. The cannabinoid system, recognized as one of the brain’s neuromodulatory systems, appears to play a significant role in social and prosocial behaviors, particularly in the context of empathy. This study aimed to investigate the potential role of the cannabinoid system in mediating empathic pain and behavior, an area that has not been thoroughly explored to date. To this end, an empathic pain model was employed, wherein pain was socially transmitted from a sibling demonstrator, who received five formalin injections, to a sibling observer. Naïve observer rats were administered either the cannabinoid type 1 receptor (CB1R) antagonist rimonabant (1 mg/kg, i.p.) or the CB1R agonist WIN 55,212–2 (WIN; 3 mg/kg, i.p.) 30 min prior to behavioral assessments. The animals were subsequently evaluated using tail-flick and social interaction tasks. The behavioral findings revealed that both the demonstrator and observer groups exhibited significant increases in hyperalgesia and impairments in social memory. Notably, the administration of rimonabant, but not WIN, partially restored cognitive functions and induced analgesia in the observer rats. Furthermore, hippocampal levels of brain-derived neurotrophic factor (BDNF) decreased in both demonstrator and observer rats, whereas rimonabant administration resulted in an increase in BDNF levels in the hippocampus, in contrast to WIN. These results suggest that the CB1R may be intricately involved in prosocial behavior and emotional contagion, potentially through the modulation of BDNF levels in the hippocampus.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"863 ","pages":"Article 138299"},"PeriodicalIF":2.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"High-amylose diet ameliorates LPS-induced cognitive impairment and depression-like phenotype","authors":"Kohei Takura , Ran Wei , Rina Takayanagi , Yasumitsu Sakai , Masahira Hattori , Toshio Ohshima","doi":"10.1016/j.neulet.2025.138295","DOIUrl":"10.1016/j.neulet.2025.138295","url":null,"abstract":"<div><div>Neuroinflammation is accompanied by the activation of glial cells, such as microglia and astrocytes. The cytokines released by these glial cells affect neurons, causing their dysfunction and eventually leading to cell death. Neuroinflammation has been suggested to cause cognitive function decline as well as psychiatric disorders, such as major depressive disorders (MDD). In recent years, from the perspective of the gut-brain axis, a prebiotic approach has been considered to improve neuroinflammation. The ingestion of resistant starch has been reported to increase the number of short-chain fatty acid (SCFA)-producing bacteria, and SCFA may suppress neuroinflammation through the gut-brain relationship in both humans and rodents.</div><div>It is reported that diets rich in amylose, a type of resistant starch, lead to an increase in SCFA levels in the feces of mice. Based on these findings, we hypothesized that a high-amylose diet can ameliorate cognitive impairment and depression-like behaviors driven by neuroinflammation. In the present study, we employed lipopolysaccharides (LPS) to induce neuroinflammation in mice. A fear conditioning test showed that this prebiotic method suppressed the decline of associative learning caused by LPS. In addition, tail suspension and forced swim tests showed the ameliorating effect of this prebiotic method on LPS-induced depression-like behaviors. These results suggest that resistant starch has a prebiotic effect, improving cognitive function decline and depression-like symptoms caused by LPS.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"862 ","pages":"Article 138295"},"PeriodicalIF":2.5,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Characterization of the N-terminal region of Crtac1B/LOTUS, an endogenous Nogo receptor-1 antagonist, required for secretion and soluble function","authors":"Yutaka Kawakami , Haruna Tezuka , Hirokazu Takaya , Junpei Matsubayashi , Kohtaro Takei","doi":"10.1016/j.neulet.2025.138284","DOIUrl":"10.1016/j.neulet.2025.138284","url":null,"abstract":"<div><div>Lateral olfactory tract usher substance (LOTUS), also known as cartilage acidic protein-1B (Crtac1B), is a potent endogenous antagonist of Nogo receptor type-1 (NgR1). LOTUS exists in both membrane-bound (m-LOTUS) and soluble (s-LOTUS) forms. m-LOTUS inhibits NgR1 by binding to its C-terminal domain (UA-EC domain), thereby blocking ligand interactions, whereas s-LOTUS disrupts NgR1 signaling by interfering with its interaction with the p75 co-receptor. However, the molecular characteristics of s-LOTUS, including the functional domains required for secretion and NgR1 binding, remain unclear.</div><div>In this study, we identified the N-terminal 35Met-532Pro region as essential for s-LOTUS secretion. While N-type glycosylation patterns remained unchanged, differences in intracellular localization with the Golgi apparatus were observed between secretory and non-secretory forms. The non-secretory form exhibited higher aggregation and ubiquitination levels. Functionally, the soluble 35Met-532Pro fragment bound to both NgR1 and p75, disrupting the NgR1-p75 complex. In contrast, the UA-EC domain, corresponding to the functional domain of m-LOTUS, bound only to NgR1 and did not interfere with p75 interaction.</div><div>A growth cone collapse assay using cultured olfactory bulb neurons from <em>lotus</em>-deficient embryonic mice demonstrated that exogenous 35Met-532Pro, but not UA-EC, inhibited Nogo66-induced growth cone collapse. These findings indicate that the N-terminal 35Met-532Pro region of s-LOTUS functions as its active domain, antagonizing NgR1 signaling through dual binding to NgR1 and p75. In contrast, the UA-EC domain lacks this antagonistic property, highlighting the distinct functional domains and mechanisms of action between s-LOTUS and m-LOTUS.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"862 ","pages":"Article 138284"},"PeriodicalIF":2.5,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144254448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yuan Miao , Ruifang Luo , Fang Lin , Bei Tong , Junyan Yan , Ting Yang , Zhujun Sun , Tingyu Li , Lu Xiao , Jie Chen
{"title":"Increasing indoxyl sulfate induces iNOS expression via aryl hydrocarbon receptor leading to microglia hyperactivation in the prefrontal cortex of autism-like offspring rats","authors":"Yuan Miao , Ruifang Luo , Fang Lin , Bei Tong , Junyan Yan , Ting Yang , Zhujun Sun , Tingyu Li , Lu Xiao , Jie Chen","doi":"10.1016/j.neulet.2025.138298","DOIUrl":"10.1016/j.neulet.2025.138298","url":null,"abstract":"<div><div>The abnormal indole metabolism is associated with the progression of Autism Spectrum Disorder (ASD). Indoxyl sulfate (IS), one of the active products of indole metabolism, still has an unknown role in ASD progression. This study investigates the role of IS/Aryl hydrocarbon receptor (AhR)/iNOS pathway in microglial activation in the prefrontal cortex (PFC) of ASD-like rats. Prenatal LPS-exposed induced autism-like behaviors offspring rats, concomitant with increased IS levels in the PFC. The levels of nuclear-AhR, IBA1, CD16 and iNOS proteins expression were increased in the PFC of LPS-exposed rats, whereas ARG1 protein expression level decreased, indicates microglia hyperactivation coupled with altered microglia morphology. ELISA analysis and further measure of synapses changes showed significantly increased inflammatory factors (TNF-α and IL-1β) and synaptic alterations. <em>In vitro</em> experiments demonstrated that IS treatment significantly upregulated the expression level of nuclear-AhR, enhanced microglia marker (IBA1, CD16 and iNOS) proteins and pro-inflammation factors levels (TNF-α and IL-1β), while concurrently reducing ARG1 protein expression and IL-10 levels in BV2 microglial cells. Moreover, the IS treatment significantly enhanced AhR enrichment in <em>iNOS</em> promoter region by chromatin immunoprecipitation and dual luciferase reporter assays, thereby significantly elevating the iNOS expression. However, the AhR-specific antagonist CH-223191 could block this activation and reverse the above proteins and inflammation factors changes. In a word, increased IS levels in the PFC of ASD-like offspring rats activate the AhR/iNOS pathway, driving microglial hyperresponsiveness and contributing to the development of ASD disease.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"862 ","pages":"Article 138298"},"PeriodicalIF":2.5,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sabrina Zbóril , André P. Schmidt , Débora R. Ramos Maia , Talita R. Sanches , Amaro N.D. Neto , Lúcia Andrade , Jean P. Oses , Fernanda P. Moreira , José Otávio C. Auler Jr , Denise A. Otsuki
{"title":"Treatment with mesenchymal stem cells in a porcine model of sepsis: Assessment of the central nervous system","authors":"Sabrina Zbóril , André P. Schmidt , Débora R. Ramos Maia , Talita R. Sanches , Amaro N.D. Neto , Lúcia Andrade , Jean P. Oses , Fernanda P. Moreira , José Otávio C. Auler Jr , Denise A. Otsuki","doi":"10.1016/j.neulet.2025.138294","DOIUrl":"10.1016/j.neulet.2025.138294","url":null,"abstract":"<div><div>Sepsis remains a leading cause of intensive care unit admissions and a significant public health challenge worldwide. Despite efforts, the development of specific therapies for sepsis has been limited. Mesenchymal stem cell therapy, particularly with cells derived from the human umbilical cord (hUC-MSC), has shown promise in animal studies. This study evaluated the use of hUC-MSC in a porcine model of sepsis induced by fecal peritonitis, focusing on hemodynamic and metabolic effects, inflammatory response, and central nervous system impact. Twenty-two pigs were randomized into a control group receiving fluids, vasopressors, and antibiotics, and a treatment group receiving the same interventions plus hUC-MSC infusion. Hemodynamic parameters, acid-base status, cytokine levels in serum and cerebrospinal fluid (CSF), and neuron-specific enolase were assessed over 24 h. Histopathological analysis of the hippocampus was performed post-mortem. No significant differences were observed between groups regarding hemodynamic and metabolic parameters or serum cytokine levels. While interleukin-1β levels in CSF increased in all animals’ post-sepsis induction, interleukin-10 levels were significantly higher in hUC-MSC-treated animals. Histopathological analysis revealed reduced congestion, vasodilation, and neuronal karyolysis in the hippocampus of the treatment group. These findings suggest that while hUC-MSC therapy does not significantly impact hemodynamics, metabolism, systemic inflammation, or mortality in septic shock, it may offer neuroprotective effects. Further studies are required to elucidate the mechanisms underlying these potential neuroprotective properties of hUC-MSC in sepsis.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"862 ","pages":"Article 138294"},"PeriodicalIF":2.5,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144241848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Light-triggered delivery enables brainwide mapping of intragastric glucose sensory dynamics","authors":"Yan-miao Tian , Dao-jie Xu , Xu Feng , Yu Chen , Chun-feng Shang","doi":"10.1016/j.neulet.2025.138286","DOIUrl":"10.1016/j.neulet.2025.138286","url":null,"abstract":"<div><div>Interoception monitors the gastrointestinal tract for the brain. The intragastric chemical information is embodied in the biological molecules, like nutrients, immune factors, and microbe metabolites, which modulates animal states. Albeit the sensors for these intragastric molecules have been identified and their afferent pathways have been elucidated, their sensory dynamics remains less explored. To fulfill this requirement, a direct manipulation of the gastrointestinal chemical contents, without oral involvement or invasiveness, is needed. Here we have developed a light-triggered intragastric delivery assay and demonstrated its efficacy in modulating the nutrient content of larval zebrafish. Taking the advantage of the larval zebrafish in neural imaging, we succeeded in examining the brainwide responses to the intragastric glucose delivery. Furthermore, a similarly broad response pattern was observed on both the naive and the feeding experienced larval zebrafish, suggesting an innately brainwide network for intragastric glucose sensing.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"862 ","pages":"Article 138286"},"PeriodicalIF":2.5,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144241849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wentao Zeng , Yan Wang , Peng Yao , Qijun Wang , Xiangqiang Meng , Leyao Zou , Yang Bai , Zhen Feng
{"title":"Task-state hemodynamic responses correlate with consciousness levels and outcomes of patients with disorders of consciousness","authors":"Wentao Zeng , Yan Wang , Peng Yao , Qijun Wang , Xiangqiang Meng , Leyao Zou , Yang Bai , Zhen Feng","doi":"10.1016/j.neulet.2025.138293","DOIUrl":"10.1016/j.neulet.2025.138293","url":null,"abstract":"<div><h3>Background</h3><div>Functional near-infrared spectroscopy (fNIRS) has emerged as a valuable tool for detecting brain functional activities. Motor imagery (MI) tasks have been employed to evoke brain responses in patients with disorders of consciousness (DOC), providing potential insights into their consciousness levels. However, the utility of brain functional characteristics for patient diagnosis and prognosis remains unclear.</div></div><div><h3>Objective</h3><div>This study aims to use fNIRS to investigate the characteristics of brain functional activities evoked by MI task in populations with varying levels of consciousness, and to explore the potential of these characteristics in the diagnosis and prognosis of DOC.</div></div><div><h3>Methods</h3><div>fNIRS was used to measure hemodynamic responses during MI tasks in a cohort of 63 DOC patients (26 vegetative states [VS] and 37 minimally conscious states [MCS]) and 70 healthy controls (HC). The mean values of hemodynamic responses in each brain region were extracted for inter-group and intra-group comparisons. Additionally, the correlation between hemodynamic responses and prognosis of DOC patients was investigated.</div></div><div><h3>Results</h3><div>Inter-group comparisons revealed that HC had significantly higher hemodynamic responses than both the MCS and VS groups across all brain regions. The MCS group demonstrated significantly higher responses than the VS group in the left premotor cortex, left primary motor cortex, right primary motor cortex, and left parietal cortex. In intra-group comparisons, 33 and 7 pairs of brain regions were significantly different in the HC and MCS group, while no significant differences were observed in the VS group. Furthermore, a significant correlation was found between the hemodynamic responses and the prognosis scores of DOC patients 6 months after the fNIRS examination.</div></div><div><h3>Conclusions</h3><div>Task-evoked functional activities in various brain regions among populations with varying levels of consciousness demonstrate significant intra-group and inter-group differences. The characteristics of brain functional activities provide valuable insights for the diagnosis and prognosis of DOC patients.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"862 ","pages":"Article 138293"},"PeriodicalIF":2.5,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144241942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}