{"title":"Integrative multi-omics and machine learning identify CALR as a diagnostic and therapeutic target in aneurysmal subarachnoid hemorrhage","authors":"Qikai Tang , Xiaoming Zhou , Bingtao Zhang , Chenfeng Ma , Yan Zou , Zixuan Yuan , Liang Chen , Zhaoxiang Zhang , Shujuan Chen , Qi Wu , Wei Wu , Xin Zhang","doi":"10.1016/j.expneurol.2025.115396","DOIUrl":"10.1016/j.expneurol.2025.115396","url":null,"abstract":"<div><h3>Background</h3><div>Aneurysmal subarachnoid hemorrhage (aSAH), caused by the rupture of intracranial aneurysms, is a devastating cerebrovascular event with high mortality and disability. However, effective diagnostic biomarkers and therapeutic targets remain limited.</div></div><div><h3>Methods</h3><div>We combined 4D label-free quantitative proteomics with transcriptomic datasets (GSE122897, GSE36791, GSE73378) for integrative analysis. Weighted Gene Co-expression Network Analysis (WGCNA) identified key gene modules. Functional enrichment (GO, KEGG) and GeneMANIA interaction networks were constructed. A diagnostic model was built using 113 machine learning algorithm combinations and validated across multiple datasets. Immune infiltration was evaluated by CIBERSORT. Gene Set Enrichment Analysis (GSEA) explored underlying biological processes. A nomogram was developed using the “rms” package. Experimental aSAH models were established in vivo and in vitro to validate candidate gene expression and function via qPCR, Western blot, immunofluorescence, and immunohistochemistry. AAV-mediated gene modulation and primary cortical neuron cultures were used for mechanistic validation.</div></div><div><h3>Results</h3><div>CALR was identified as a key diagnostic biomarker through WGCNA and machine learning. The diagnostic model demonstrated high accuracy (AUC > 0.85). CALR was significantly associated with immune cell infiltration and endoplasmic reticulum stress. In vivo, AAV-mediated CALR overexpression attenuated neuronal damage in SAH mice. In vitro, CALR exerted neuroprotective effects on primary neurons under SAH conditions.</div></div><div><h3>Conclusion</h3><div>CALR serves as a promising diagnostic and therapeutic target in aneurysmal subarachnoid hemorrhage. This study highlights the role of multi-omics and machine learning in uncovering novel mechanisms and targets in cerebrovascular diseases.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115396"},"PeriodicalIF":4.6,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144704799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ning Xu , Chenchen Du , Yuan Yu , Yile Li , Shixuan Gao , Shuyan Yu , Baozhu Sun , Haiyan Lou
{"title":"Urolithin A improves Parkinson's disease-associated cognitive impairment through modulation of neuroinflammation and neuroplasticity","authors":"Ning Xu , Chenchen Du , Yuan Yu , Yile Li , Shixuan Gao , Shuyan Yu , Baozhu Sun , Haiyan Lou","doi":"10.1016/j.expneurol.2025.115395","DOIUrl":"10.1016/j.expneurol.2025.115395","url":null,"abstract":"<div><div>Cognitive impairment is one of the most common disabling non-motor manifestations of Parkinson's disease (PD), an age-onset condition for which there are no effective therapies available to date. Urolithin A (UA) is a natural compound produced by gut bacteria from ingested ellagitannins (ETs) and ellagic acid (EA). Our previous study showed that UA ameliorates motor deficits and dopaminergic neurodegeneration in experimental models of PD. However, its effect on PD non-motor symptoms has not been elucidated. This study aims to explore the effect of UA on cognitive impairment in MPTP-induced PD mouse model as well as in transgenic mice that overexpresses human A53T mutant α-synuclein (A53T mice). Treatment with UA reversed cognitive dysfunction as measured by Morris water maze, Y maze and novel object recognition tests in both PD models. Enhanced cognition was associated with decreased neuroinflammation in the hippocampus. Additionally, UA also reduced hippocampal neuronal dendritic spine loss and synaptic damage. Further mechanistic analyses revealed that the beneficial effects of UA on cognitive impairment appears to involve the activation of the highly protective AKT/CREB/BDNF signaling pathway. Collectively, these findings strongly suggest that UA mitigates cognitive deficits in both MPTP-induced PD mouse model and A53T mice by reducing neuroinflammation and sustaining neuroplasticity. This study provides the first evidence for a potential therapeutic effect of UA on cognitive impairment in vivo, and supports further assessment for the possible use of UA as a dietary supplement to prevent cognitive deficits in PD, and related neurodegenerative diseases.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115395"},"PeriodicalIF":4.2,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rafi Matin , Kristina Zhang , Flavia Venetucci Gouveia , George M. Ibrahim
{"title":"Effects of centromedian thalamic deep brain stimulation on striatal glutamate and GABA in a rodent model of epilepsy","authors":"Rafi Matin , Kristina Zhang , Flavia Venetucci Gouveia , George M. Ibrahim","doi":"10.1016/j.expneurol.2025.115394","DOIUrl":"10.1016/j.expneurol.2025.115394","url":null,"abstract":"<div><h3>Background</h3><div>Deep brain stimulation (DBS) of the centromedian nucleus of thalamus (CM) represents a promising treatment for drug-resistant epilepsy. The anti-seizure effects of CM-DBS have been linked to thalamostriatal projections, however, the neurochemical effects of stimulation on the striatum remain unexplored.</div></div><div><h3>Objective</h3><div>This study aimed to characterize the acute neurochemical effects of CM-DBS on glutamate and GABA signaling within thalamostriatal circuits in healthy and epileptic mouse models.</div></div><div><h3>Methods</h3><div>C57BL/6 J healthy controls (<em>n</em> = 18) and the Cntnap2KO mouse model of epilepsy (n = 18) underwent surgery for CM-DBS implants. Mice in the DBS-ON group received stimulation, while mice in the DBS-OFF group underwent surgery but did not receive stimulation. Immediately after stimulation experiments, the brains were recovered and tissue was dissected from regions within the thalamostriatal network (i.e. thalamus, caudate putamen) and nodes from a separate limbic network (i.e. amygdala, hippocampus, ventral pallidum). Finally, liquid chromatography with tandem mass spectrometry was used to quantify glutamate and GABA concentrations in brain tissue samples. The effects of DBS on regional neurotransmitter levels and neurotransmitter networks were studied.</div></div><div><h3>Results</h3><div>At baseline, the striatal Glutamate/GABA ratio was lower in Cntnap2KO mice compared to healthy controls. Following CM-DBS, glutamate levels increased within the striatum in both mouse strains. Furthermore, CM-DBS altered neurotransmitter relationships within striatal networks and selectively reduced GABA-GABA and glutamate-GABA correlations in C57BL/6 J mice.</div></div><div><h3>Conclusion</h3><div>CM-DBS induced region- and strain-dependent changes in glutamate and GABA levels with effects on neurotransmitter network dynamics. These findings highlight potential neurochemical changes in thalamostriatal projections following CM-DBS.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115394"},"PeriodicalIF":4.2,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abdul Razak , Amy E. Sutherland , Yen Pham , Tamara Yawno , Ilias Nitsos , Lindsay Zhou , Tegan A. White , Charmaine Rock , Rod W. Hunt , Atul Malhotra , Beth J. Allison , Suzanne L. Miller , Courtney A. McDonald
{"title":"Persistent inflammation and white matter damage in the preterm brain: Insights from a novel ovine model of chronic inflammation","authors":"Abdul Razak , Amy E. Sutherland , Yen Pham , Tamara Yawno , Ilias Nitsos , Lindsay Zhou , Tegan A. White , Charmaine Rock , Rod W. Hunt , Atul Malhotra , Beth J. Allison , Suzanne L. Miller , Courtney A. McDonald","doi":"10.1016/j.expneurol.2025.115397","DOIUrl":"10.1016/j.expneurol.2025.115397","url":null,"abstract":"<div><h3>Background</h3><div>Preterm brain injury involves persistent inflammation, making it a potential therapeutic target. Current large animal models focus on short-term outcomes, limiting understanding of long-term effects. We developed an ovine model of inflammation-induced preterm brain injury to assess long-term neuropathology at an age equivalent to early cerebral palsy diagnosis in human infants.</div></div><div><h3>Methods</h3><div>Fetal sheep were instrumented at gestational day (d) 90–91 (term is 148d): one group received lipopolysaccharide (LPS 200 ng; <em>n</em> = 9) on 96d, 97d, and 98d (0.65 gestation, ∼25–26 weeks human brain development), and a control group received saline (<em>n</em> = 8). Birth was induced on 138d, and lambs were euthanised within 24 h of birth. Brains were evaluated for white matter injury, microglial/macrophage activation and astrogliosis in the subcortical (SCWM), periventricular (PVWM), and cortical (CWM) white matter, subventricular zone (SVZ), and corpus callosum (CC).</div></div><div><h3>Results</h3><div>Antenatal LPS administration was associated with significant persistent microglial/macrophage activation in the PVWM (<em>P</em> = 0.04), SCWM (<em>P</em> = 0.01), and CWM (<em>P</em> = 0.006). Furthermore, LPS exposure was associated with reduced oligodendrocyte cell number in the PVWM (<em>P</em> = 0.02), SCWM (<em>P</em> = 0.001), and CWM (<em>P</em> = 0.0001), and reduced nyelination in CWM (CNPase, <em>P</em> < 0.0001 and MBP, P = 0.04) and SVZ (MBP, <em>P</em> = 0.05). No difference in astrogliosis or microhaemorrhages was observed.</div></div><div><h3>Conclusion</h3><div>We demonstrated that in a large animal model of inflammation-induced intrauterine preterm brain injury, long-term persistent inflammation occurs, along with significant white matter injury, including loss of oligodendrocytes and reduced myelination in multiple white matter regions. This model paves the way for long-term evaluation of promising therapeutics and behavioral assessment in this clinically relevant model of persistent preterm brain injury.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115397"},"PeriodicalIF":4.6,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144714088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yalan Liu , Rui Wang , Fengjiao Sun , Nan Wang , Mengdi Wang , Jinfeng Cai , Bin Zhao , Qingqing Zhang , Ruli Ge , Hongcai Wang
{"title":"Stereotactic infusion of rotenone into the SN induced a late-stage model of Parkinson's disease","authors":"Yalan Liu , Rui Wang , Fengjiao Sun , Nan Wang , Mengdi Wang , Jinfeng Cai , Bin Zhao , Qingqing Zhang , Ruli Ge , Hongcai Wang","doi":"10.1016/j.expneurol.2025.115382","DOIUrl":"10.1016/j.expneurol.2025.115382","url":null,"abstract":"<div><div>The establishment of an in vivo model for Parkinson's disease (PD) that accurately mimics late-stage clinical features is crucial for elucidating disease pathogenesis and developing novel therapeutic strategies. To establish this model, rotenone (ROT) was stereotactically infused into the substantia nigra (SN). Motor behavior in PD mice was assessed using the pole test and rotarod test. Apomorphine (APO)-induced rotation and dystonia were also evaluated. Alterations in anxiety, depression, and cognitive function were examined using the open field test, sucrose preference test, Y-maze test, and Morris water maze test, respectively. Gastrointestinal (GI) motility was determined by examining the timing of pink stool passage. Changes in gut microbiota composition were analyzed via 16S rRNA sequencing. The expression and localization of nucleotide-binding oligomerization domain-leucine-rich repeat-pyrin domain-containing 3 (NLRP3), caspase-1, and α-synuclein (α-syn) within astrocytes were determined using immunofluorescence. Peripheral organ toxicity induced by ROT was investigated using hematoxylin and eosin (HE) staining. Experimental results demonstrated that the number of APO-induced rotations in the ROT group exceeded 210 rpm at 4 weeks and decreased significantly by 36 weeks, reflecting progressive disease characteristics. Specifically, the incidence of APO-induced dystonia was significantly higher in the ROT group at 36 weeks compared to 4 weeks (<em>P</em> < 0.05). Compared to the vehicle group, ROT-treated mice exhibited prolonged pole test descent time and reduced rotarod latency. The open field test revealed decreased center duration and crossings. Morris water maze showed fewer platform crossings and reduced target quadrant time. However, no statistically significant differences were observed between groups in the sucrose preference test at either 4 or 36 weeks. By 36 weeks, ROT-treated mice demonstrated a significantly lower spontaneous alternation rate compared to vehicle controls. ROT infusion also reduced overall gut microbiota abundance and altered microbial composition. Specifically, the ROT group showed decreased abundance of Allobaculum, Atopobium, Sneathia, Rikenella, Aestuariispira, Bacillus, Barnesiella, Escherichia/Shigella, Klebsiella, Eisenbergiella, and Parasutterella. Immunostaining analysis revealed that compared with the vehicle group, NLRP3, cleaved caspase-1, and α-syn expression was increased in astrocytes in the ROT group. The ROT-based model reproduced the clinical features of the early and late stages of PD, particularly dystonia and inflammasome activation, thus providing a reliable framework for studying late-stage PD.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115382"},"PeriodicalIF":4.2,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144689692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"High fat diet and low dose-rotenone exposure exacerbate Parkinson's disease like pathology through gut-brain axis disruption","authors":"Aditya A. Singh , Zarna Pathak , Ashwini Chawathe , Manjeet Chopra , Vimal P. Rupareliya , Nitish Sharma , Hemant Kumar","doi":"10.1016/j.expneurol.2025.115384","DOIUrl":"10.1016/j.expneurol.2025.115384","url":null,"abstract":"<div><div>Parkinson's disease (PD) affects millions worldwide. In recent years, the role of the gut-brain axis and gut microbiome alterations in neurodegenerative diseases has gained significant attention. Lifestyle and environment factors play a crucial role in shaping the overall health. Herein, we investigated whether obesity induced by high-fat diet (HFD) combined with low-dose rotenone (5 mg/kg; orally, twice a day) exacerbates PD-like pathology. Our findings reveal non-motor symptoms of PD alongside gut inflammation, α-synuclein (α-syn) accumulation, and dysbiosis, possibly mediated by transient receptor potential vanilloid 1 (TRPV1) channel. In the brain, we observed the characteristic α-syn pathology in the substantia nigra (SN) and the striatum. Finally, we observe neuroinflammation including astrogliosis, microgliosis and increased expression of TRPV1 channel in the SN and striatum possibly hinting to PD like pathological features. The <em>in-vitro</em> findings in N2a and C6 glial cell lines hint towards possible co-relation of increased TRPV1 in response to lipotoxicity and rotenone exposure which was recovered when treated with TRPV1 antagonist; Capsazepine. In summary, we propose that HFD along with low dose rotenone poses a risk for neuronal health; exaggerating the neuroinflammatory states.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115384"},"PeriodicalIF":4.6,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Overexpression of endothelial β4 integrin has no impact on blood-brain barrier integrity or the pathogenesis of experimental autoimmune encephalomyelitis","authors":"Arjun Sapkota, Sebok K. Halder, Richard Milner","doi":"10.1016/j.expneurol.2025.115381","DOIUrl":"10.1016/j.expneurol.2025.115381","url":null,"abstract":"<div><div>Laminin is a major component of the vascular basement membrane and transgenic mice deficient in astrocyte or pericyte laminin manifest blood-brain barrier (BBB) disruption, implying an important stabilizing role for laminin in BBB integrity. As the laminin receptor α6β4 integrin is strongly induced on CNS blood vessels in the neuroinflammatory animal model experimental autoimmune encephalomyelitis (EAE), and mice deficient in endothelial β4 integrin (β4-EC-KO) display worse EAE, here we tested in a novel transgenic knock-in mouse, whether constitutive overexpression of endothelial β4 integrin (β4-EC-KI) would enhance BBB integrity and reduce EAE development and progression. In immunofluorescent analysis of brain and spinal cord tissue, β4-EC-KI mice showed strong constitutive endothelial β4 integrin expression in all blood vessels, along with upregulation of its α6 integrin subunit partner and the α4 subunit of its physiological ligand, laminin 411. Under disease-free conditions, vascular structure and activation were unchanged in β4-EC-KI mice. In the EAE model, β4-EC-KI mice were no different from wild-type littermate controls in the time of onset, peak clinical score, or progression of EAE. Consistent with this, histopathological analysis revealed no observable differences in levels of BBB disruption, vascular activation, leukocyte infiltration, endothelial tight junction protein expression, or microglial and astrocyte activation. These data demonstrate that while β4-EC-KI mice show strong constitutive expression of endothelial β4 integrin, this had no discernible impact on blood-brain barrier integrity or the pathogenesis of EAE.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115381"},"PeriodicalIF":4.6,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yong Chen , Qianhui Zhou , Lang Su , Yanzhi Zhao , Xianliang Xing , Peng Yao
{"title":"Orexin A alleviates chronic cerebral hypoperfusion-induced neuroinflammation and cognitive dysfunction by inhibiting the NEK7/NLRP3 pathway","authors":"Yong Chen , Qianhui Zhou , Lang Su , Yanzhi Zhao , Xianliang Xing , Peng Yao","doi":"10.1016/j.expneurol.2025.115378","DOIUrl":"10.1016/j.expneurol.2025.115378","url":null,"abstract":"<div><h3>Objective</h3><div>Chronic cerebral hypoperfusion (CCH)-induced neuroinflammation significantly impacts the functional prognosis of patients with vascular dementia (VaD). Microglial neuroinflammation is significantly aggravated by the chronic activation of the NLRP3 inflammasome, which has emerged as a major contributing factor. Our previous research indicated that Orexin A effectively alleviates acute inflammatory responses and neurological deficits following brain injury. However, its neuroprotective role in cognitive function recovery after CCH remains to be elucidated.</div></div><div><h3>Methods</h3><div>Adult male SD rats underwent permanent bilateral common carotid artery occlusion surgery for 8 weeks to establish a VaD model. Subsequently, the rats received 4 weeks of continuous intranasal Orexin A treatment (250 μg/kg). Additionally, in order to explore the potential mechanisms and neuroprotective roles of Orexin A, BV2 cells were subjected to hypoxia to simulate in vitro CCH stimulation, either with or without Orexin A pretreatment, and were then co-cultured with HT22 neurons.</div></div><div><h3>Results</h3><div>After 8 weeks of modeling, we noted a significant decrease in Orexin A and OXR1 expression in the hippocampus of CCH rats, which was accompanied by pronounced cognitive impairments. Furthermore, CCH exposure resulted in prolonged activation of the NLRP3 inflammasome and M1-type microglia within the hippocampus, as well as blood-brain barrier disruption and neurodegenerative changes. Orexin A treatment effectively ameliorated these alterations. In vitro experiments demonstrated hypoxia exposure promoted NLRP3 inflammasome activation in microglia, along with the release of pore-forming Gasdermin-D-NT and NINJ1, ultimately causing “bystander” neuronal pyroptosis. Orexin A inhibited NLRP3 inflammasome activation in microglia, thereby promoting the transition of M1-type microglia to M2-type and mitigating neuronal pyroptosis. These effects were abolished by NEK7 overexpression.</div></div><div><h3>Conclusion</h3><div>Our findings indicate that Orexin A restores the M1/M2 microglial balance by inhibiting the NEK7/NLRP3 pathway. This, in turn, alleviates neuroinflammation and neuronal pyroptosis, ultimately improving cognitive dysfunction after CCH. This study enhances our understanding of the neuroprotective mechanisms of Orexin A, potentially offering a new therapeutic target for cognitive impairment following CCH.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115378"},"PeriodicalIF":4.6,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144679608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Mapping of projection of sprouting neuron in neonate and adult mice after pyramidotomy","authors":"Hiroshi Tsujioka , Toshihide Yamashita","doi":"10.1016/j.expneurol.2025.115386","DOIUrl":"10.1016/j.expneurol.2025.115386","url":null,"abstract":"<div><div>Although severed axons of the corticospinal tract rarely regenerate, neural function is partially recovered by axonal sprouting from intact neurons. The sprouting capability is higher in neonates than in adults, making neonates an attractive model for finding novel therapeutic targets for central nervous system injury. The axonal projection pattern of the motor cortex neurons is highly heterogeneous, and high-throughput analysis at the single-cell level is required to correctly understand the projection pattern of sprouting neurons. The recently developed multiplexed analysis of projections by sequencing (MAPseq) has revealed axonal projection complexity in many brain areas; however, axonal sprouting of the corticospinal tract in neonates and adults has not yet been analyzed. Here, we evaluated the sprouting pattern of individual neurons using MAPseq in neonate and adult mice after pyramidotomy, using the intact and denervated (sprouting) sides of the cervical cord. The ratio of neurons projecting solely to the intact or denervated side or projecting to both sides was not significantly different. The cumulative projection strength on the denervated side was significantly higher in the neonatal pyramidotomy group than in the other groups. The ratio of the projection strength on the denervated side to the total projection strength (sprouting index) correlated with the projection strength on the denervated side. The ratio of the neuron with a sprouting index of 0.6–0.7 was significantly higher in the neonatal pyramidotomy group. These results show the usefulness of MAPseq in sprouting studies and provide important information regarding the sprouting patterns of individual neurons in neonates.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115386"},"PeriodicalIF":4.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ann N. Hoffman , Sonya Watson , Yuqing Huang , Rosanna Burgos Pujols , Kevin C. Bickart , Kenneth P. Roos , Michael S. Fanselow , Christopher C. Giza
{"title":"Sex differences in temperature rhythm disruption after traumatic brain injury","authors":"Ann N. Hoffman , Sonya Watson , Yuqing Huang , Rosanna Burgos Pujols , Kevin C. Bickart , Kenneth P. Roos , Michael S. Fanselow , Christopher C. Giza","doi":"10.1016/j.expneurol.2025.115385","DOIUrl":"10.1016/j.expneurol.2025.115385","url":null,"abstract":"<div><div>Circadian rhythms are a natural endogenous process that regulates many bodily functions including body temperature and are linked to overall health. Disruptions in circadian rhythms have far reaching effects on systems vulnerable to traumatic brain injury (TBI), including sleep, neuroendocrine and immune function, and mental health. Whether TBI affects temperature rhythms differently in females and males is unknown and may impact recovery trajectory. In this study we measured body temperature rhythms in adult female and male rats in the home cage via passive changes in temperature across the circadian cycle using cosinor analysis at baseline and after mild-moderate lateral fluid percussion injury (FPI). Overall, females had higher temperature compared to males. After sham surgery and FPI, temperature MESOR (midline estimate statistic of rhythm) increased in all groups but to a greater degree in males. In females however, FPI significantly reduced the amplitude and oscillation frequency of their baseline circadian temperature rhythms compared to all other groups. These data indicate sex differences in circadian temperature rhythms following TBI, with loss of rhythmicity in females. Changes in circadian function may underlie or be associated with other sex-dependent physiological changes after TBI, which may offer a potential target for treatment in the recovery after TBI in humans.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115385"},"PeriodicalIF":4.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}