Experimental Neurology最新文献

{"title":"Sex-dependent effects of peptidylarginine deiminases on neutrophil function and long-term outcomes after spinal cord injury","authors":"Shelby K. Reid ,&nbsp;Ashley V. Tran ,&nbsp;Miranda E. Leal-Garcia ,&nbsp;Sachit Devaraj ,&nbsp;Mustafa Ozturgut ,&nbsp;Dylan A. McCreedy","doi":"10.1016/j.expneurol.2025.115414","DOIUrl":"10.1016/j.expneurol.2025.115414","url":null,"abstract":"<div><div>Traumatic spinal cord injury (SCI) initiates an influx of peripheral immune cells to the spinal cord parenchyma that compound tissue damage and restrict functional recovery. Neutrophils infiltrate the spinal cord within the first day after injury, releasing extracellular traps (NETs) comprised of decondensed DNA, modified histones, and granule enzymes, that can worsen tissue damage. Peptidylarginine demininases (PADs), particularly PAD4, have been indicated as mediators of NET formation by facilitating the decondensation of nuclear chromatin via histone citrullination. Though PADs have been shown to be regulated by sex hormones, sex-differences in PAD regulation of neutrophil function in the context of CNS injury have yet to be explored. In this work, we investigated the role of PADs in recovery after SCI using Cl-amidine, a pan-PAD inhibitor. Strikingly, Cl-amidine treated mice exhibited sex-dependent changes to motor function, body weight, and white matter sparing after SCI. Acutely, Cl-amidine treated mice had reduced NET accumulation in the blood and decreased spinal cord neutrophil granularity. Analysis of publicly available scRNA-seq data revealed that female bone marrow neutrophils exhibited elevated <em>Padi4</em> expression relative to their male counterparts. We then utilized <em>Padi4</em> knockout (<em>Padi4</em>^{<em>−/−</em>}) mice to assess the role of PAD4 in long-term recovery of male and female mice after SCI. While we observed no changes in motor recovery, a sex-dependent effect on tissue sparing was observed with <em>Padi4</em> deficiency. These data are the first description of sex differences in PAD-mediated neutrophil function after SCI and highlight the importance of inclusion of both sexes in pre-clinical research.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115414"},"PeriodicalIF":4.2,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793879","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":"Sex-dependent differences in the antiseizure and neuroprotective effects of midazolam after soman exposure: Superior, sex-independent efficacy of tezampanel and caramiphen","authors":"Taiza H. Figueiredo ,&nbsp;Vassiliki Aroniadou-Anderjaska ,&nbsp;Volodymyr I. Pidoplichko ,&nbsp;Marcio De Araujo Furtado ,&nbsp;Katia Rossetti ,&nbsp;Lucille A. Lumley ,&nbsp;Maria F.M. Braga","doi":"10.1016/j.expneurol.2025.115412","DOIUrl":"10.1016/j.expneurol.2025.115412","url":null,"abstract":"<div><div>Nerve agents are lethal chemical weapons and highly potent chemoconvulsants. For the treatment of nerve agent-induced status epilepticus (SE), the FDA has approved the use of benzodiazepines—initially diazepam and recently midazolam (MDZ); however, benzodiazepines are not neuroprotective, particularly if not administered promptly. Here, we compared the antiseizure and neuroprotective efficacy of MDZ with that of tezampanel (LY293558; an AMPA/GluK1 receptor antagonist) administered with caramiphen (CRM; an antagonist of muscarinic and NMDA receptors), 30 min after the onset of SE induced by exposure of young-adult male and female rats to the nerve agent soman; neuropathology assessments were conducted from 7 days to 6 months post-exposure. Latency to suppression of the initial SE was comparable after MDZ or LY293558 + CRM treatment. However, seizures reoccurred, and MDZ-treated rats had longer SE, followed by significant neurodegeneration, neuronal and interneuronal loss in the CA1 hippocampal area and the basolateral amygdala, hippocampal and amygdalar atrophy, reduced spontaneous IPSCs in the basolateral amygdala, increased anxiety, and spontaneous recurrent seizures (SRS). MDZ-treated males had longer SE than MDZ-treated females and lower 24-h and long-term survival. MDZ-treated females displayed delayed hippocampal neurodegeneration and atrophy, as well as delayed SRS. Males and females treated with LY293558 + CRM presented minimal neurodegeneration and only delayed appearance of brain damage, without significant sex differences. The results suggest that MDZ treatment may carry higher risks for males. Replacing benzodiazepines with antiglutamatergic first-line treatments to prevent long-term brain damage and associated morbidities is overdue; LY293558 + CRM has produced remarkably promising results.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115412"},"PeriodicalIF":4.2,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144766788","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":"Pyridoxal phosphate inhibits alpha-synuclein-induced ferroptosis by activating GOT1 to enhance the methionine salvage pathway in Parkinson's disease","authors":"Xudong Min ,&nbsp;Zhuolin Du ,&nbsp;Jirui Wei ,&nbsp;Zhao Yuan ,&nbsp;Yang She ,&nbsp;Xiayu Jin ,&nbsp;Zequn Su ,&nbsp;Hengxu Mao ,&nbsp;Jing Cai ,&nbsp;Zhiyuan Zhu ,&nbsp;Xiaozheng He","doi":"10.1016/j.expneurol.2025.115411","DOIUrl":"10.1016/j.expneurol.2025.115411","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a neurodegenerative disorder characterized by the overpression of α-synuclein (α-syn) and the degeneration of dopaminergic neurons. Ferroptosis, a form of cell death driven by aberrant iron metabolism and lipid peroxidation, has been reported to play a crucial role in the pathogenesis of dopaminergic neurons death while the precise mechanisms remain elusive. In this study, we identified a cytosolic enzyme glutamic-oxalacetic transaminase (GOT)-1 as a negative regulator of ferroptosis through analyses of public databases. Inhibition of GOT1 exaggerated the ferroptosis of dopaminergic neurons death in both in vitro and in vivo PD models. Furthermore, database analysis showed that GOT1 modulate ferroptosis via its intrinsic enzymatic role: depletion of GOT1 substantially blocked the salvage synthesis of methionine and its downstream product glutathione (GSH), which led to oxidative stress and neuronal ferroptosis. Importantly, we found that pyridoxal phosphate (Vitamin B6), a well-used drug in clinical practice, could activate GOT1 thereby enhance the synthesis of methionine and alleviate neuronal ferroptosis. In conclusion, we identified GOT1 as a critical protector of dopaminergic neurons via inhibiting ferroptosis. Activation of GOT1 by pyridoxal phosphate could therefore be a promising therapeutic strategy for patient with PD. Clinical studies are warranted to validate the new translational value of this common-prescribed drug.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115411"},"PeriodicalIF":4.2,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144763607","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":"Hyperreflexia after corticospinal tract lesion reflects 1 A afferent circuit changes not increased KCC2 hyperexcitability","authors":"Thelma Bethea ,&nbsp;Temitope Adegbenro ,&nbsp;John H. Martin","doi":"10.1016/j.expneurol.2025.115401","DOIUrl":"10.1016/j.expneurol.2025.115401","url":null,"abstract":"<div><div>Hyperreflexia is a consequence of spinal cord injury (SCI) and motor system lesions in the brain. Two major mechanisms underpinning hyperreflexia have been reported: proprioceptive afferent (PA) circuit changes produced by 1 A fiber sprouting, which could enhance reflex signaling, together with reduced GABAergic inhibitory presynaptic regulation (GABApre); and increased intrinsic motor neuron excitability, for example, produced by reduced motor neuron membrane-bound potassium-chloride co-transporter2 (KCC2). Here we examine how selective unilateral CST injury in the medullary pyramid (PTX), which eliminates the CST from one hemisphere, allows investigation of different mechanisms to determine their contributions to hyperreflexia. We used rate-dependent depression (RDD) of the Hoffmann (H)-reflex for the forelimb and hindlimb 5th-digit abductor muscles to assess hyperreflexia on both the contra- and ipsilesional sides. We compared RDD longitudinally in intact rats and after unilateral-PTX rats at 7-dpi and 42-dpi, supplemented with additional timepoints to examine hyperreflexia development. Immunohistochemistry was used to identify PA synapses (VGlut1), GABA presynaptic boutons (GABApre), motor neurons (ChAT), and to measure motor neuronal KCC2. Following unilateral PTX, we observed significant hyperreflexia in the contralesional forelimb only. Membrane-bound KCC2 was unchanged in contralesional cervical motor neurons. Whereas both cervical and lumbar motor neurons showed increased PA sprouting contralesionally, there was a concomitant increase in GABApre terminals for the lumbar not cervical cord, which associated with a normal hindlimb H-reflex. Our findings show that KCC2 is disassociated from hyperreflexia in the uniPTX model. Instead, forelimb hyperreflexia can be explained by cervical motor neuron PA sprouting and an uncompensated GABApre regulation.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"394 ","pages":"Article 115401"},"PeriodicalIF":4.2,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768540","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":"Caloric restriction worsens decision-making impairments and gut dysbiosis after brain injury in male rats","authors":"Reagan L. Speas,&nbsp;Jenna E. McCloskey,&nbsp;Noah M. Bressler,&nbsp;Michelle A. Frankot,&nbsp;Carissa Gratzol,&nbsp;Kristen M. Pechacek,&nbsp;Kris M. Martens,&nbsp;Cole Vonder Haar","doi":"10.1016/j.expneurol.2025.115410","DOIUrl":"10.1016/j.expneurol.2025.115410","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) causes long-term deficits in decision-making and disrupts the gut microbiome. Dysbiosis of the gut microbiome is a potential contributor to the development of multiple psychiatric and neurological disorders and may be a contributor to chronic symptoms from TBI. Caloric restriction is often used to assess psychiatric-related behaviors in animals, but also affects the gut microbiome. Thus, understanding how caloric restriction interacts with the microbiome, injury processes, and behavioral outcomes is critical. In the current study, we evaluated the effects of caloric restriction versus free feeding on a frontal controlled cortical impact TBI. Rats were trained on the rodent gambling task, an analog of the Iowa gambling task, to assess risk-based decision-making. The microbiome was sampled through the acute to subacute period post-injury and lesion size and microglia counts evaluated at 10 weeks post-injury. Caloric restriction did not affect decision-making at baseline, but did affect motivational variables. TBI impaired decision-making and this effect was exacerbated by caloric restriction. Other motivation-related variables followed a similar pattern of impairment with TBI driving impairments that were worsened by caloric restriction. The gut microbiome was initially dysbiotic, but largely recovered within 14 days post-injury. Despite this, acute gut measurements were predictive of chronic decision-making impairment. This finding could indicate a role for the gut microbiome in modifying acute and subacute TBI pathology and suggest that interventions targeting the gut may have a limited window of opportunity to treat long-term deficits.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115410"},"PeriodicalIF":4.2,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768538","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":"Sex-dependent impairments in oligodendrocyte maturation and myelination in offspring mice exposed to preeclampsia","authors":"Ziyi Wu ,&nbsp;Yue Qiu ,&nbsp;Xiaoyan Chen,&nbsp;Zhangting Xia,&nbsp;Jiangming Lv,&nbsp;Yufei Jia,&nbsp;Hang Xue,&nbsp;Ping Zhao","doi":"10.1016/j.expneurol.2025.115405","DOIUrl":"10.1016/j.expneurol.2025.115405","url":null,"abstract":"<div><div>Preeclampsia, a prevalent obstetric complication with systemic implications for maternal and fetal health, has been increasingly linked to altered neurodevelopment and long-term neuropsychological sequelae in offspring. While existing evidence highlights its potential to disrupt brain development, the sex-specific effects of preeclampsia on white matter development and oligodendrocyte maturation remain poorly characterized. This study focused on assessing the effects of preeclampsia on offspring oligodendrocyte maturation, myelination and neurobehavioral outcomes. A preeclampsia mouse model was established by continuously subcutaneous injecting 125 mg/kg/day of N(G)-Nitro-L-arginine methyl ester (L-NAME) into pregnant mice from gestational day 10.5 to 17.5, with concurrent monitoring systolic blood pressure and urinary protein levels. Postnatal reflex assessments were followed by comprehensive behavioral testing and neurohistological analyses in offspring. Behavioral results indicated that male offspring exposed to preeclampsia demonstrated sex-specific deficits in anxiety-related behaviors, cognitive function, and social exploration, alongside disruptions in white matter development. These included impaired oligodendrocyte maturation, reduced myelination, and axonal damage, likely attributable to diminished oligodendrocyte lineage cells proliferation. It is inspiring that environmental enrichment during adolescence ameliorated behavioral deficits and partially restored white matter development in preeclampsia-exposed offspring. In conclusion, our findings suggest that male mice exposed to preeclampsia are more likely to experience alterations in long-term behavior and white matter development than in female mice. Environmental enrichment warrants further investigation as a potential preventive or therapeutic approach to address neurodevelopmental risks associated with prenatal preeclampsia exposure.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115405"},"PeriodicalIF":4.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764804","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":"Full manuscript title: Ultrasound-guided intraparenchymal injection of slow release Chondroitinase ABC-37 in the chronic phase of spinal cord injury improves long-term recovery","authors":"L. Weise ,&nbsp;R. Joseph ,&nbsp;Q.E.A. Sirianni ,&nbsp;J.A. Bryan ,&nbsp;S. Bake ,&nbsp;A. Konda ,&nbsp;M.S. Shoichet ,&nbsp;M.A. Hook","doi":"10.1016/j.expneurol.2025.115402","DOIUrl":"10.1016/j.expneurol.2025.115402","url":null,"abstract":"<div><div>It is well-established that early treatment with chondroitinase ABC (ChABC) improves functional recovery in preclinical models of spinal cord injury (SCI). To increase the potential for clinical translation, research is now focused on optimizing treatment conditions and enhancing the enzymatic stability of ChABC formulations. The current study tested the in vivo efficacy of a novel formulation of ChABC, Src homology-3 (SH3)-ChABC-37, that has 37 mutations and is delivered by affinity release from a crosslinked methylcellulose (xMC) modified with SH3-binding peptides (bp). The study also tested a gap in knowledge, comparing the effects of the route of administration on the efficacy of SH3-ChABC-37/xMC-bp. Male Sprague Dawley rats were given a single subarachnoid injection or a novel ultrasound guided intraparenchymal injection of SH3-ChABC-37/xMC-bp or vehicle (xMC-bp only), 28 days after a moderate, lower thoracic contusion injury. Recovery of locomotor and sensory function was assessed for 27 days post SCI, and prior to SH3-ChABC-37/xMC-bp treatment, and then following treatment until 112 days post SCI. We found that the single intraparenchymal injection of SH3-ChABC-37/xMC-bp produced a significant 1.5-point increase in BBB scores after day 28. There was no effect of subarachnoid administered SH3-ChABC-37/xMC-bp. Importantly, irrespective of the administration route, SH3-ChABC-37/xMC-bp did not produce pain. While pain symptoms worsened after day 28 in rats treated with xMC-bp only, SH3-ChABC-37/xMC-bp blocked further development of pain symptoms. These data confirm the in vivo efficacy of SH3-ChABC-37/xMC-bp and indicate that intraparenchymal administration may further improve treatment efficacy, even when applied in the chronic phase of SCI.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115402"},"PeriodicalIF":4.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764803","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":"Research progress on platelet factor 4 in improving cognition","authors":"Hao Zhuo ,&nbsp;Ning Chen ,&nbsp;Xiaohui Hu ,&nbsp;Zihua Liu","doi":"10.1016/j.expneurol.2025.115403","DOIUrl":"10.1016/j.expneurol.2025.115403","url":null,"abstract":"<div><div>Platelet Factor 4 (PF4) is a chemokine that plays a crucial role in coagulation and immune functions. Previous studies have identified numerous biological functions of PF4, including its involvement in hematopoiesis, inhibition of angiogenesis, modulation of platelet coagulation, promotion of the host inflammatory response, vascular inhibition, and anti-tumor properties.</div><div>Surprisingly, recent research has revealed that PF4 also contributes to improving cognitive abilities and restoring neural aging. Mice treated with PF4 demonstrated enhanced performance in behavioral experiments, indicating that PF4 not only boosts cognition in aged mice but also has beneficial effects in younger mice.</div><div>The impact of PF4 on neural function can be categorized into central and peripHeral mechanisms. In the central nervous system, PF4 directly modulates the hippocampus and interacts with <em>N</em>-methyl-<span>d</span>-aspartate receptors (NMDARs) to enhance synaptic plasticity. Peripherally, PF4 alleviates neuroinflammation and helps reverse age-related changes in the immune system. Moreover, PF4 is capable of restoring the expression of cognitive-related factors (synaptic plasticity-related proteins) in the hippocampus of aging mice to youthful levels.</div><div>PF4 demonstrates potential therapeutic effects in murine aging models, providing a foundation for further investigation of its possible applications in neurological disorders such as Alzheimer's disease, Parkinson's disease, intracerebral hemorrhage, and Huntington's disease. These preliminary findings warrant additional research to evaluate PF4's translational potential in neuroscience and anti-aging fields.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115403"},"PeriodicalIF":4.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756699","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":"miR-497-5p augments sevoflurane-induced neurotoxicity by facilitating ubiquitination-dependent degradation of NOTCH1 via targeting SMURF2","authors":"Yuanyuan Wang ,&nbsp;Xin Men ,&nbsp;Xiaodong Huang ,&nbsp;Pei Chen ,&nbsp;Weilong Wang ,&nbsp;Jin Zhou ,&nbsp;Zhenfeng Zhou","doi":"10.1016/j.expneurol.2025.115404","DOIUrl":"10.1016/j.expneurol.2025.115404","url":null,"abstract":"<div><div>This study aimed to explore how miR-497-5p affects sevoflurane-induced neurotoxicity and cognitive impairment in neonatal rats, examining its role in promoting neuronal survival by regulating the protein SMURF2 and its effect on NOTCH1 signaling. Neonatal rats were exposed to sevoflurane, and their learning and memory were assessed using the Morris water maze and fear conditioning tests. RNA sequencing identified a significant decrease in miR-497-5p levels. To further investigate miR-497-5p's protective role, we treated neuronal cells with miR-497-5p mimics and sevoflurane, conducting cell viability assays, LDH release assays, apoptosis analysis and Western blotting for apoptosis markers. Bioinformatics tools predicted target genes of miR-497-5p, confirming that SMURF2 was a direct target through co-immunoprecipitation and dual-luciferase reporter assays. Increasing miR-497-5p levels improved cell viability and reduced apoptosis in neuronal cultures exposed to sevoflurane. MiR-497-5p directly targeted SMURF2, reducing its levels and increasing NOTCH1 protein levels. Silencing SMURF2 preserved NOTCH1 signaling and improved cell viability, while knocking down NOTCH1 eliminated these protective effects, highlighting its importance for neuronal survival. In vivo, miR-497-5p mimic treatment significantly alleviated sevoflurane-induced cognitive deficits and neuronal damage in rats by reducing hippocampal apoptosis, promoting neuronal proliferation, and restoring SMURF2/NOTCH1 signaling.These findings demonstrate that miR-497-5p protects against sevoflurane-induced neurotoxicity by affecting SMURF2 and NOTCH1 pathways. By improving cognitive function and supporting neuronal health, miR-497-5p could be a potential therapeutic target for reducing anesthetic-related neurotoxicity, emphasizing its role in preserving cognitive and neuronal integrity during anesthetic exposure and suggesting future research directions for neuroprotective therapies.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115404"},"PeriodicalIF":4.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144748709","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":"CGRP+ fibers sprout within gastrocnemius muscle following complete spinal cord injury in rodents","authors":"Morgan J. Forston ,&nbsp;Alan Ohkubo ,&nbsp;Michael D. Forston ,&nbsp;Mary Ellen DeHoff ,&nbsp;Alice Shum-Siu ,&nbsp;David S.K. Magnuson","doi":"10.1016/j.expneurol.2025.115400","DOIUrl":"10.1016/j.expneurol.2025.115400","url":null,"abstract":"<div><div>Following spinal cord injury nociceptive afferents exhibit functional and anatomical plasticity within the spinal dorsal horn. This plasticity is, at least in part, maladaptive, contributing to secondary complications related to neuropathic pain, autonomic dysreflexia, and spasticity. While previous studies have shown that nociceptors, particularly CGRP⁺ C-fibers, are also capable of sprouting peripherally following pathologies of chronic inflammation, muscle disuse, and denervation, the peripheral plasticity of C-fibers following spinal cord injury remains largely uninvestigated. Here, we show that CGRP⁺ nerve fibers, likely nociceptors, display expanded innervation within the gastrocnemius muscle, particularly near blood vessels and within the calcaneal tendon. Furthermore, CGRP⁺ sensory axons exhibit a fundamental change in their innervation pattern near motor axons, innervating independently of, rather than along, motor trunks. These changes occurred alongside significantly reduced size and expression of CGRP by motor axon terminals following spinal transection. We also report positive correlations between volume of CGRP⁺ fibers in the gastrocnemius muscle and muscle atrophy, hypersensitivity, intraspinal plasticity, and activation of glia within the lumbar spinal cord. Importantly, bulk RNA sequencing of muscle revealed upregulation of genes indicative of biological processes occurring at 6 weeks post-SCI that may contribute to sensory plasticity including inflammation, immune cell infiltration, and apoptosis. Taken together, these data suggest that many nociceptor-dependent complications that are thought to be spinally mediated may be driven or exacerbated by nociceptor plasticity occurring in the periphery.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115400"},"PeriodicalIF":4.2,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144729049","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}