Experimental Neurology最新文献

{"title":"A pharmacological vasoconstrictor cocktail targeting endothelin signalling generates a stable, reproducible focal cerebral infarct with associated functional deficits in mice","authors":"Kevin CL Law ,&nbsp;Andrew T. Quattrocchi ,&nbsp;Brianna E. Xuereb ,&nbsp;Niamh Moriarty ,&nbsp;Lachlan H. Thompson ,&nbsp;Clare L. Parish","doi":"10.1016/j.expneurol.2025.115215","DOIUrl":"10.1016/j.expneurol.2025.115215","url":null,"abstract":"<div><div>Necessary for enhanced understanding of brain injury, and for developing new therapies, is the generation of reliable animal models. While many models are available, each comes with benefits and limitations. Intracerebral injection of the vasoconstrictive peptide endothelin-1 creates one of the most widely adopted models of focal ischemic stroke in rats, yet its potency is underwhelming in mice. This is likely underpinned by the greater proportions of vasodilatory compared to vasoconstrictive receptor subtypes in the mouse brain. Yet mouse models of ischemic stroke provide the benefit of exploiting the wide range of transgenic strains that can aid in further understanding pathophysiology mechanisms of acute and secondary damage, as well as endogenous recovery. To improve the efficiency of focal endothelin-1 infarcts in mice, we investigated the impact of co-administering pharmacological compounds that target endothelin receptor subtypes and downstream signalling, aimed at selectively enhancing vasoconstriction whilst reducing vasodilation. We report exacerbated neuronal loss and tissue atrophy resulting in motor and cognitive dysfunction when endothelin-1 was co-administered with the nitric oxide synthase inhibitor L-NAME and the selective ET_B1 antagonist RES-701-1. These infarcts were stable, reproducible and achievable across brain regions. These findings demonstrate a new and effective mouse model to study focal ischemic stroke.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"388 ","pages":"Article 115215"},"PeriodicalIF":4.6,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143620663","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":"TNF-α mediates activation of neuronal necroptotic signaling in rat with syringomyelia","authors":"Jinze Li ,&nbsp;Shengyu Cui ,&nbsp;Yanqiu Li ,&nbsp;Jun Bai ,&nbsp;Can Zhang ,&nbsp;Kang Li ,&nbsp;Fengzeng Jian","doi":"10.1016/j.expneurol.2025.115214","DOIUrl":"10.1016/j.expneurol.2025.115214","url":null,"abstract":"<div><div>Syringomyelia is a severe and progressive disease characterized by fluid-filled cavities that form within the spinal cord, leading to progressive neurological deterioration. However, the molecular mechanisms that cause neuronal death and subsequent dysfunction remain incompletely understood. This study demonstrates that tumor necrosis factor-α (TNF-α)-mediated necroptosis plays a crucial role in neuronal death during syringomyelia progression. RNA-seq analysis revealed significantly elevated necroptosis scores at both 14 and 28 days after syrinx formation, with identified disease-related differentially expressed necroptosis genes primarily enriched in TNF-α-related signaling pathways. Through establishing a rat model of syringomyelia with central canal dilation, significant activation of necroptosis markers, phosphorylated receptor-interacting protein kinase 3 (p-RIPK3) and phosphorylated mixed lineage kinase domain-like protein (p-MLKL), was observed in the area surrounding the syrinx, with their expression predominantly localized to neurons. Concurrently, we found markedly elevated TNF-α levels around the syrinx, and primarily originating from reactive astrocytes (70.29 %). Upregulation of TNF receptor 1 (TNFR1) in perilesional neurons suggested enhanced sensitivity to TNF-α-mediated death signals. Subsequently, administration of the TNF-α inhibitor infliximab at day 14 post-modeling significantly alleviated the expression of necroptosis markers and attenuated the progression of sensory dysfunction at day 28, even in the presence of persistent syrinx. This study is the first to reveal TNF-α-mediated neuronal necroptosis as a crucial mechanism in neurological deterioration in syringomyelia, providing novel molecular targets for treatment. These findings suggest that targeting this pathway, particularly in combination with conventional surgical approaches, may offer therapeutic benefits for patients with syringomyelia.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"388 ","pages":"Article 115214"},"PeriodicalIF":4.6,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143591984","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":"Spatiotemporal activation of lumbar sensorimotor networks","authors":"A.G. Steele ,&nbsp;G. Taccola ,&nbsp;V. Dietz ,&nbsp;A.M. Frazier ,&nbsp;P.J. Horner ,&nbsp;A.H. Faraji ,&nbsp;D.G. Sayenko","doi":"10.1016/j.expneurol.2025.115206","DOIUrl":"10.1016/j.expneurol.2025.115206","url":null,"abstract":"<div><div>Spinal cord injury (SCI) research is primarily conducted using rodent models, which has resulted in significant advances, including novel treatment strategies that promote recovery. Unfortunately, many of these treatments do not have the same efficacy once translated to human clinical trials. Large animal models, such as Yucatan miniature pigs (minipigs), may provide a superior alternative to translating findings to human clinical trials due to their anatomical similarities to humans. However, porcine models are not widely used, which may be due in part to our inadequate understanding of the functional architecture of neural networks in the minipig spinal cord. This study utilized a clinical-grade epidural paddle array implanted over the lumbosacral enlargement of four minipigs. We then mapped the topographical distribution of spinally evoked motor potentials recorded in hindlimb muscles and cord dorsum potentials evoked by sub-motor threshold tibial nerve stimulation. Spatial correlation analysis suggests the motor networks and sensory networks innervated by the tibial nerve are distinct and separate within the minipig lumbosacral spinal cord. Our findings provide foundational knowledge on sensorimotor networks that are functionally diffused among the lumbar enlargement and possess distinct spatiotemporal patterns of activation along the cord for control of motor output and the processing of sensory input. The results reveal critical insights about the variability of electrophysiological measures across animals, offering a foundation for more individualized approaches in future studies. Furthermore, we demonstrate that using an epidural paddle array to map motor responses is a clinically feasible method, though our results highlight the subject-specific nature of these maps and their sensitivity to paddle location and orientation.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"388 ","pages":"Article 115206"},"PeriodicalIF":4.6,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585396","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":"Roles of Adam8 in Neuroinflammation in experimental ischemic Stroke: Insights from single-cell and ribosome-bound mRNA sequencing","authors":"Jiale Liu ,&nbsp;Li Xu ,&nbsp;Jinxin Lu ,&nbsp;Xi Shen ,&nbsp;Di Li ,&nbsp;Lei Bai ,&nbsp;Xiang Li Jr ,&nbsp;Zhengquan Yu ,&nbsp;Haiying Li","doi":"10.1016/j.expneurol.2025.115207","DOIUrl":"10.1016/j.expneurol.2025.115207","url":null,"abstract":"<div><div>Stroke remains a leading cause of global mortality, with neuroinflammation significantly exacerbating clinical outcomes. Microglia serve as key mediators of post-stroke neuroinflammation, though the mechanisms driving their migration to injury sites remain poorly understood. In this study, using publicly available single-cell sequencing data (GSE234052), we identified a migration-associated microglial subtype in a murine model of distal middle cerebral artery occlusion (dMCAO). Additionally, ribosome-bound mRNA sequencing data (GSE225110) from microglia isolated from peri-infarct cortical tissue uncovered dMCAO-induced alterations in microglial mRNA translation. By integrating these datasets, we identified A Disintegrin And Metalloproteinase 8 (Adam8) as a key gene upregulated at both the transcriptional and translational levels post-dMCAO. Protein analysis revealed that both the precursor and active forms of Adam8 were predominantly expressed in microglia and significantly upregulated in peri-infarct regions following dMCAO. Notably, Adam8 inhibition with BK-1361 significantly reduced Adam8 cleavage, M1 microglial migration, inflammation, infarct size, and improved neurological outcomes. Bioinformatics analysis further identified Myo1e as a potential interacting partner of Adam8, a finding validated through immunofluorescence co-localization. These findings highlight Adam8 as a promising therapeutic target for mitigating post-stroke neuroinflammation and offer new insights into the mechanisms of microglial migration.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"388 ","pages":"Article 115207"},"PeriodicalIF":4.6,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596590","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-related disparities in mobility, sensory function, and psychological outcomes in Wistar and Sprague-Dawley rats following spinal cord injury","authors":"Junrui Guo ,&nbsp;Qi Zhang ,&nbsp;Baicao Li ,&nbsp;Song Liu ,&nbsp;Yan Li ,&nbsp;Cong Xing ,&nbsp;Guangzhi Ning","doi":"10.1016/j.expneurol.2025.115204","DOIUrl":"10.1016/j.expneurol.2025.115204","url":null,"abstract":"<div><div>Spinal cord injury (SCI) causes persistent motor, sensory, psychological, and bladder dysfunctions, with clinical evidence indicating better recovery in females compared to males. However, the mechanisms driving these sex-specific differences remain unclear. This study assessed sex- and strain-specific differences in recovery using Wistar and Sprague-Dawley (SD) rats. SCI was induced at the T10 spinal level via a contusion model, and functional recovery was evaluated through standardized tests for locomotion, sensory thresholds, psychological outcomes, and bladder function. Female rats demonstrated superior motor recovery, with higher Basso, Beattie &amp; Bresnahan (BBB) scores and improved coordination, alongside improved sensory outcomes, evidenced by reduced mechanical pain sensitivity and longer thermal response latencies. Strain differences were observed, with SD rats exhibiting greater pain thresholds than Wistar rats. Females also showed improved bladder outcomes, including higher leak point pressure and reduced bladder volumes, while males displayed more pronounced depression-like behaviors. Cognitive performance did not differ significantly between sexes. These findings highlight sex-specific advantages in motor, sensory, and bladder function, as well as strain-dependent sensory differences, emphasizing the importance of considering sex and strain in designing targeted therapies for SCI rehabilitation.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"388 ","pages":"Article 115204"},"PeriodicalIF":4.6,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585394","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":"TREM2 promotes hippocampal neurogenesis through regulating microglial M2 polarization in APP/PS1 mice","authors":"Xiao-Qian Peng ,&nbsp;Hong-Song Guo ,&nbsp;Xiao Zhang ,&nbsp;Xiang-Yuan Wu ,&nbsp;John Bosco Ruganzu ,&nbsp;Song-Di Wu ,&nbsp;Ming-Tao Zhao ,&nbsp;Lei Li ,&nbsp;Yang Yang ,&nbsp;Sheng-Feng Ji ,&nbsp;Wei-Na Yang ,&nbsp;Peng-Yu Ren","doi":"10.1016/j.expneurol.2025.115205","DOIUrl":"10.1016/j.expneurol.2025.115205","url":null,"abstract":"<div><div>Triggering receptor expressed on myeloid cells-2 (TREM2) mainly expressed on microglia in the brain, and its mutations can increase the risk of Alzheimer's disease (AD). Upregulation or activation of TREM2 has been found to ameliorate several pathological features of AD, such as the reduction of amyloid beta (Aβ) plaques and tau hyperphosphorylation. However, the effects of TREM2 on neurogenesis are little understood. Here, we aimed to investigate the effects of TREM2 on hippocampal neurogenesis associated with microglial M2 polarization in APP/PS1 mice. Lentivirus vectors were used to interfere with the expression of TREM2 on microglia in the hippocampus of APP/PS1 mice and BV2 cells. The supernatant was collected from BV2 cells as a conditioned medium (CM) to culture neural stem cells (NSCs) <em>in vitro</em>. Upregulation of TREM2 partially salvaged the proliferation of NSCs and the decrease of the number of immature/mature neurons in the hippocampus of APP/PS1 mice, which was accompanied by an improvement in cognitive ability. Furthermore, upregulation of TREM2 increased the M2 microglia marker CD206, brain-derived neurotrophic factor (BDNF), and anti-inflammatory factors, while decreased the M1 microglia markers CD16/32 and CD86 and pro-inflammatory factors <em>in vivo</em> and <em>in vitro</em>. Importantly, the upregulation of TREM2 also led to a significant increase in the phosphorylation of PI3K and Akt. <em>In vitro</em>, treatment with LY294002, a PI3K inhibitor, abolished the beneficial effects of TREM2 on shifting microglia from M1 to M2 and the proliferation and differentiation of NSCs. Taken together, these findings indicated that upregulation of TREM2 activated the PI3K/Akt signaling pathway to promote microglial M2 polarization and led to the secretion of more BDNF, accompanied by an improved hippocampal neurogenesis and spatial cognitive function in APP/PS1 mice. Thus, TREM2 might be a promising target for the treatment of neurodegenerative disease.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"388 ","pages":"Article 115205"},"PeriodicalIF":4.6,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143563458","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":"Role of substantia Nigra dopaminergic neurons in respiratory modulation and limitations of levodopa in Parkinson's disease","authors":"Nicole C. Miranda ,&nbsp;Yasmin C. Aquino ,&nbsp;Tainá O. Macedo ,&nbsp;Luiz M. Oliveira ,&nbsp;Kairo A. Albernaz-Mariano ,&nbsp;Carolina D. Munhoz ,&nbsp;Jan-Marino Ramirez ,&nbsp;Thiago S. Moreira ,&nbsp;Ana C. Takakura","doi":"10.1016/j.expneurol.2025.115193","DOIUrl":"10.1016/j.expneurol.2025.115193","url":null,"abstract":"<div><div>The substantia nigra pars compacta (SNpc), a midbrain region enriched with dopaminergic neurons projecting to the dorsal striatum, is essential for motor control and has been implicated in respiratory modulation. In Parkinson's disease (PD) models, the loss of SNpc dopaminergic neurons correlates with baseline respiratory deficits, suggesting a potential link between dopaminergic dysfunction and respiratory impairments.</div><div>To explore this, we used adult transgenic mice (Vglut₂^cre Ai6 and Vgat^cre Ai6) to map neurotransmitter phenotypes, as well as DAT^cre mice for pharmacogenetic modulation of SNpc dopaminergic neurons using excitatory (Gq) or inhibitory (Gi) designer receptors exclusively activated by designer drugs (DREADDs). Neuroanatomical tracing revealed SNpc projections to key respiratory nuclei, including the caudal and rostral ventral respiratory groups (cVRG and rVRG), Bötzinger complex (BötC), nucleus of the solitary tract (NTS), raphe magnus (RMg), and dorsal raphe (DR). While SNpc neurons were not activated by hypercapnia (7 % CO₂) or hypoxia (8 % O₂), pharmacogenetic stimulation of SNpc neurons altered respiratory parameters under both baseline and chemosensory challenge conditions. However, dopamine precursor treatment in PD models did not reverse respiratory deficits.</div><div>These findings suggest that SNpc dopaminergic neurons can modulate respiration when selectively stimulated, but we did not find evidence for an endogenous role in respiratory chemosensitivity. This study reinforces the complexity of dopaminergic contributions to respiratory control in PD and suggests that targeting these neurons may not be sufficient to restore respiratory function, emphasizing the need for broader therapeutic strategies.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"387 ","pages":"Article 115193"},"PeriodicalIF":4.6,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143511597","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":"CCL2/CCR2 signaling-mediated microglial migration leads to cerebral small vessel dysfunction in chronic hypertension model rats","authors":"Takashi Koizumi ,&nbsp;Eline M. Herckenrath ,&nbsp;Katsutoshi Taguchi ,&nbsp;Ikuko Mizuta ,&nbsp;Toshiki Mizuno ,&nbsp;Masaki Tanaka","doi":"10.1016/j.expneurol.2025.115192","DOIUrl":"10.1016/j.expneurol.2025.115192","url":null,"abstract":"<div><div>Microglia are cerebral immune cells that maintain brain homeostasis; those that are juxtaposed to vessels are sometimes called vessel-associated microglia (VAM). Recent studies have indicated a role for VAM in maintaining blood–brain barrier integrity in different stages of diseases such as ischemic stroke and systemic inflammatory disease. Hypertension is a major cause of cerebral small vessel disease (CSVD) in humans. Recently, several reports reported that microglial activation in hypertensive animal models and our previous report indicated the increase in VAM from the early stage of chronic hypertension. However, the precise involvement of VAM in hypertensive CSVD remains unclear. In the present study, we used a deoxycorticosterone-acetate-salt chronic hypertensive rat model to demonstrate that signaling via C<img>C motif chemokine ligand 2 (CCL2) and its receptor C<img>C chemokine receptor type 2 (CCR2) is crucial for the increase in VAM. This signaling was associated with microglial migration toward vessels at the early disease stage. Moreover, the inhibition of this signaling resulted in reduced VAM numbers and the preservation of astrocytic endfeet in the late disease stage. Overall, CCL2/CCR2 signaling may be a trigger for microglial migration, leading to the development of CSVD, during chronic hypertension. This signaling is therefore a potential target for future preventive treatments.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"387 ","pages":"Article 115192"},"PeriodicalIF":4.6,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143500123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophage-myofibroblast transition contributes to the macrophage elimination and functional regeneration in the late stage of nerve injury","authors":"Yunlun Li ,&nbsp;Jiale Cai ,&nbsp;Yizhou Xu ,&nbsp;Ying Zou ,&nbsp;Shuyi Xu ,&nbsp;Xinya Zheng ,&nbsp;Lanya Fu ,&nbsp;Jiaqi Zhang ,&nbsp;Xinrui Ma ,&nbsp;Ye He ,&nbsp;Xianghai Wang ,&nbsp;Kaixian Deng ,&nbsp;Jiasong Guo","doi":"10.1016/j.expneurol.2025.115194","DOIUrl":"10.1016/j.expneurol.2025.115194","url":null,"abstract":"<div><div>Massive of macrophages are recruited to the injured nerve to remove the axonal and myelin debris for creating a conducive micro-environment for nerve regeneration. However, the fate of macrophages after the debris clearing remains unclear. In this study, we demonstrated that the number of macrophages in the crush injured sciatic nerve of mice peaked at 7 days post injury (dpi) and then decreased significantly in the late stage of nerve injury. Mechanismly, the macrophage elimination was primarily attributed to TGF-β/Smad3 signaling dependent macrophage-myofibroblast transition (MMT), rather than apoptosis or out-migration. Furthermore, MMT caused collagen deposition is conducive to nerve regeneration. Both macrophage depletion via clodronate liposomes and MMT blockade using TGF-β/Smad3 inhibitor significantly reduced collagen deposition and impaired functional nerve regeneration. In summary, the present study indicates that TGF-β/Smad3 regulated MMT contributes to macrophage elimination and functional recovery in the injury nerve.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"387 ","pages":"Article 115194"},"PeriodicalIF":4.6,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143480731","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":"Glutamate stress in the caudal nucleus tractus solitarii (nTS): Impact on respiratory function and synaptic signaling in an Alzheimer's disease model","authors":"Sarah K.R. Carter ,&nbsp;Robert K. Tipton ,&nbsp;Cassadi M. Forman ,&nbsp;Adison P. Mosher ,&nbsp;Daniela Ostrowski ,&nbsp;Tim D. Ostrowski","doi":"10.1016/j.expneurol.2025.115190","DOIUrl":"10.1016/j.expneurol.2025.115190","url":null,"abstract":"<div><div>Respiratory dysfunction is a prevalent comorbidity in Alzheimer's disease (AD), yet its underlying mechanisms are poorly understood. Using the Streptozotocin (STZ) -induced rat model of AD, which replicates respiratory dysfunction and brain pathologies observed in human AD, we analyzed how these impairments relate to central neurological integration within the peripheral chemoreflex. Our focus was on glutamatergic signaling at the synapse between peripheral chemoafferents and second-order neurons in the nucleus tractus solitarii (nTS), a critical brainstem center for respiratory control. Activating the peripheral chemoreflex with potassium cyanide (KCN) increased respiratory frequency. Response magnitudes to repeated KCN injections typically decreased over time, which was exacerbated in the STZ-AD group. Similarly, repeated glutamate nanoinjections into the caudal/commissural nTS caused a pronounced reduction of respiratory frequency responses in STZ-AD. Electrophysiological analysis of nTS neurons within the peripheral chemoreflex revealed increased network activity, enhanced excitatory postsynaptic currents evoked by solitary tract stimulation (TS-EPSCs), and elevated asynchronous glutamate release following high-frequency stimulation (aEPSCs). These data were consistent with molecular evidence for astrogliosis (elevated GFAP expression), reduced astrocytic glutamate uptake (decreased EAAT2 expression), and presynaptic calcium dysregulation (increased TRPV1 expression). Additionally, presynaptic metabotropic glutamate receptors (mGluR3) were downregulated, while postsynaptic ionotropic receptor expression remained unchanged. With high-frequency solitary tract stimulation, STZ-AD rats had greater frequency-dependent TS-EPSC depression than controls, mirroring the diminished respiratory responses to KCN and glutamate nanoinjections. Our findings connect neurophysiological and molecular changes at the first nTS synapse of the peripheral chemoreflex with impaired respiratory responses to hypoxia in the STZ-AD model.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"387 ","pages":"Article 115190"},"PeriodicalIF":4.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476161","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}