Experimental Neurology最新文献

{"title":"A model of L-DOPA-induced dyskinesia in parkinsonian mice produced by AAV vector-mediated overexpression of α-synuclein","authors":"Jin Yong Hong ,&nbsp;Jin Suk Lee ,&nbsp;Seo Hyun Kim ,&nbsp;Phil Hyu Lee","doi":"10.1016/j.expneurol.2025.115264","DOIUrl":"10.1016/j.expneurol.2025.115264","url":null,"abstract":"<div><div>L-3,4-dihydroxyphenylalanin (L-DOPA) is the most effective drug for treating Parkinson's disease (PD); however, long-term L-DOPA therapy can lead to L-DOPA-induced dyskinesia (LID). While the 6-hydroxydopamine-lesioned rodent model for LID fails to reproduce the pathological hallmarks of PD, a newly introduced rodent model using adeno-associated virus (AAV)-mediated overexpression of α-synuclein results in α-synuclein aggregation and progressive loss of dopaminergic neurons. The present study aimed to provoke LID in parkinsonian mice generated by AAV vector-mediated overexpression of α-synuclein and to explore histologic features associated with LID. A recombinant AAV2/7 vector containing the human α-synuclein transgene was injected into the substantia nigra (SN) of wild-type mice. Eight weeks later, mice received daily injections of 10 mg/kg of L-DOPA for one week, followed by 25 mg/kg of L-DOPA daily for the subsequent week. LID was observed in 3 out of 19 mice at the 10 mg/kg L-DOPA dose and in 14 mice at 25 mg/kg dose. The number of tyrosine hydroxylase (TH)-positive neurons in the AAV vector-injected side of the SN was reduced to an average of 59 % of the intact side, and the optical density of TH-positive fibers in the ipsilateral striatum was reduced to an average of 37 %. Abnormal Involuntary Movement scores were correlated with decrease in both the number of TH-positive neurons in SN and optical density of striatal TH-positive fibers. This study establishes a mouse model for LID using AAV vector-mediated overexpression of α-synuclein, providing a useful tool for investigating the progressive changes and associated pathophysiology during occurrence of LID.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"389 ","pages":"Article 115264"},"PeriodicalIF":4.6,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143839475","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":"Maresin-1 alleviates lipid peroxidation-induced ferroptosis after radiation-induced brain injury in mice through the RORα/NRF2 pathway","authors":"Duan Jiajia ,&nbsp;Wang Yiping ,&nbsp;Jiang Enyan ,&nbsp;Zhu Shouwu ,&nbsp;Yang Shuai ,&nbsp;Zhang Xiaojian ,&nbsp;Jiang Juan ,&nbsp;Fang Zhen ,&nbsp;Zeng Jia ,&nbsp;Wang Jikai ,&nbsp;Yan Yang ,&nbsp;Li Huiqing ,&nbsp;Liu Fei","doi":"10.1016/j.expneurol.2025.115258","DOIUrl":"10.1016/j.expneurol.2025.115258","url":null,"abstract":"<div><div>Ferroptosis plays a critical role in radiation-induced brain injury (RIBI). The role of Maresin-1, which has anti-inflammatory and antiferroptotic properties, in RIBI is still unclear. This study aimed to explore the effects and mechanisms of Maresin-1 on ferroptosis after RIBI in mice. A mouse model of RIBI was constructed through whole-brain irradiation. Short-term neurological functions were evaluated by the modified Garcia score and the beam balance score, and long-term neurological functions were evaluated by the Morris water maze and the rotarod test. Changes in the number of NeuN-positive neurons were detected through immunohistochemistry. The lipid peroxidation level was evaluated by detecting the contents of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), glutathione-reduced (GSH) and glutathione-oxidized (GSSG). The expression of the ferroptosis-related markers glutathione peroxidase 4 (GPX4) and cyclooxygenase 2 (COX2) was assessed via Western blotting. Adeno-associated viruses were used to knock down retinoic acid receptor-related orphan receptor alpha (RORα) or nuclear factor erythroid 2-related factor 2 (NRF2) to explore the mechanism by which Maresin-1 alleviates ferroptosis. The results showed that Maresin-1 could significantly reduce the levels of MDA, 4-HNE, GSSG, and COX2 after RIBI; increase the contents of GSH and GPX4; reduce neuronal loss in the cortex and hippocampus; and improve the short-term and long-term neurological functions of mice. After the knockdown of RORα or NRF2, the protective effects of Maresin-1 in mediating anti-lipid peroxidation and anti-ferroptosis were abolished. Our study revealed that Maresin-1 partially alleviates lipid peroxidation-induced ferroptosis after RIBI in mice via the RORα and NRF2 pathways, improving their neurological functions. This study highlights the protective role of Maresin-1 in RIBI and provides a feasible therapeutic strategy for subsequent in-depth research and clinical intervention.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"389 ","pages":"Article 115258"},"PeriodicalIF":4.6,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143844282","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":"Intestinal alterations of mucosal barrier integrity, motility and enteric nerve in cynomolgus monkey model of Parkinson's disease","authors":"Yuling Zhang ,&nbsp;Caiyan Liang ,&nbsp;Miaorong Weng ,&nbsp;Zhouquan Zhang ,&nbsp;Lin Zhang ,&nbsp;Xue Jiang ,&nbsp;Feng Yue","doi":"10.1016/j.expneurol.2025.115256","DOIUrl":"10.1016/j.expneurol.2025.115256","url":null,"abstract":"<div><div>The most prevalent non-motor symptoms in individuals with Parkinson's disease (PD) such as constipation and bloating that significantly impact patients' quality of life. However, the pathophysiological mechanisms underlying these symptoms remain unclear. PD model with typical and stable symptoms was induced by individualized dosing of MPTP with Kurlan score increased to 10 or above and remained steady for three months or more. TH-positive neurons in the injured substantia nigra (SN) of the brain of PD monkeys showed up to 83.95 % reduction. Histopathological examination indicated severe damage to both enteric nerve and TH neurons, along with significant disruption of mucosal structure, intestinal barrier integrity and motility in PD monkeys across all four intestinal segments, including the duodenum, ileum, transverse colon, and rectum. The association between dopaminergic neuronal deficits in SN and these above mentioned intestinal disorders, that might be attributed to the abnormal regulation of gastrointestinal function due to the breakdown of the integrity of the nigrostriatal dopaminergic nervous system. Therefore, the abnormal alterations found in gut of PD monkeys and its triggered possible secondary pathophysiological cascade reactions might be a potential mechanism underlying the presence of constipation and other intestinal symptoms observed in PD patients. These findings in this study provide a valuable scientific basis for investigating the pathogenesis of gastrointestinal symptoms in PD patients and potential therapeutic approaches. (The graphical abstract is by Figdraw).</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"389 ","pages":"Article 115256"},"PeriodicalIF":4.6,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143829868","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":"Dysfunction of pancreatic exocrine secretion after experimental spinal cord injury.","authors":"Emily N. Blanke ,&nbsp;Gregory M. Holmes","doi":"10.1016/j.expneurol.2025.115257","DOIUrl":"10.1016/j.expneurol.2025.115257","url":null,"abstract":"<div><div>Pancreatic exocrine dysfunction is an underdiagnosed comorbidity in individuals living with spinal cord injury (SCI) who often present cholestasis, acute pancreatitis or high levels of serum pancreatic enzymes. Parasympathetic control of pancreatic exocrine secretion (PES) is mediated in the medullary dorsal vagal complex in part through cholecystokinin (CCK) release. Our previous reports indicate high thoracic (T3-) SCI reduces vagal afferent sensitivity to GI regulatory peptides, like CCK and thyrotropin releasing hormone (TRH). To date, the effects of experimental SCI on PES are unknown. Here we investigated the modulation of PES following T3-SCI in rats. We measured PES volume and amylase concentration in control and T3-SCI rats (3-days or 3-weeks after injury) following: (i) intra-duodenal administration of a mixed-nutrient liquid meal (Ensure® ™) or (ii) central TRH injection (100 pmol) in the dorsal motor nucleus of the vagus. In a separate cohort of overnight-fasted rats, basal serum amylase levels were measured. The baseline volume of PES secretion was lower in 3-week rats destined to receive Ensure® or TRH following T3-SCI surgery compared to control. PES protein concentration was significantly reduced at baseline in 3-week T3-SCI and elevated in 3-day and 3-week T3-SCI rats postprandially but only elevated in 3-day rats following TRH microinjection. Serum amylase activity levels were elevated in 3-day T3-SCI rats and remained at similar levels post 3-weeks T3-SCI. Our data suggest that vagally-mediated regulation of multiple visceral organs is disrupted in the days and weeks following experimental SCI.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"389 ","pages":"Article 115257"},"PeriodicalIF":4.6,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143833787","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":"Corrigendum to “LanCL1 protects developing neurons from long-term isoflurane anesthesia-induced neurotoxicity” [Experimental Neurology 381 (2024) 114880]","authors":"Wenjia Xie ,&nbsp;Yuqing Xi ,&nbsp;Daoqian Dong ,&nbsp;Shuai Liu ,&nbsp;Zhengliang Ma ,&nbsp;Liangyu Peng ,&nbsp;Tianjiao Xia ,&nbsp;Xiaoping Gu","doi":"10.1016/j.expneurol.2025.115251","DOIUrl":"10.1016/j.expneurol.2025.115251","url":null,"abstract":"","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"389 ","pages":"Article 115251"},"PeriodicalIF":4.6,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143879206","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":"Novel application potential of lisdexamfetamine for visual discrimination and reversal learning improvement in rats: A translational cognitive research","authors":"Chen Jian-min ,&nbsp;Wang Zhi-yuan ,&nbsp;Wu Shi-xuan ,&nbsp;Zhang Cheng ,&nbsp;Lu Guan-yi ,&nbsp;Li Jin ,&nbsp;Wu Ning","doi":"10.1016/j.expneurol.2025.115254","DOIUrl":"10.1016/j.expneurol.2025.115254","url":null,"abstract":"<div><div>Impairments in visual discrimination and cognitive flexibility are prevalent in several neuropsychiatric disorders. Here, we explored the effects of lisdexamfetamine, the prodrug of d-amphetamine, on visual discrimination and cognitive flexibility using touchscreen-based visual discrimination and reversal learning task, a translational cross-species cognitive paradigm in rats. A single administration of 1.0 mg/kg lisdexamfetamine significantly improved the accuracy of visual discrimination. Furthermore, repeated treatment with 1.0 mg/kg lisdexamfetamine during the visual discrimination training period significantly shortened training sessions to achieve 80 % accuracy. However, neither acute nor chronic administration of d-amphetamine (0.05–0.5 mg/kg) significantly improved visual discrimination performance in rats. Furthermore, both 3.0 mg/kg lisdexamfetamine and 1.5 mg/kg d-amphetamine significantly improved reversal learning. Given the crucial involvement of <em>N</em>-methyl-D-aspartic acid glutamate receptors (NMDARs) in discrimination learning process, the membranous/cytosolic distribution of NMDARs after chronic treatment with lisdexamfetamine and d-amphetamine was tested using Western Blotting. Lisdexamfetamine (1.0 mg/kg), rather than d-amphetamine (0.05–0.5 mg/kg) significantly increased the membranous distribution of GluN1, GluN2A, GluN2B, the main subunits of NMDARs in hippocampus, the key brain region associated with learning process, but not in medial prefrontal cortex. Together, these results revealed that lisdexamfetamine improved visual discrimination and cognitive flexibility in rats. The chronic effects of lisdexamfetamine on enhancing visual discrimination learning may be partly related to increase membranous NMDARs distribution in the hippocampus. The present study suggests a novel potential application of lisdexamfetamine for improving visual discrimination and cognitive flexibility, which may facilitate the clinical application to address certain cognitive deficits in neuropsychiatric disorders.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"389 ","pages":"Article 115254"},"PeriodicalIF":4.6,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143821534","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":"Nicotinamide N-methyltransferase as a potential therapeutic target for neurodegenerative disorders: Mechanisms, challenges, and future directions","authors":"An Liu,&nbsp;Xiao-Juan Zhu,&nbsp;Wei-Dong Sun,&nbsp;Shuang-Zhou Bi,&nbsp;Chen-Ying Zhang,&nbsp;Shi-Yan Lai,&nbsp;Jiang-Hua Li","doi":"10.1016/j.expneurol.2025.115253","DOIUrl":"10.1016/j.expneurol.2025.115253","url":null,"abstract":"<div><div>Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), are characterized by progressive neuronal loss and functional decline, posing significant global health challenges. Emerging evidence highlights nicotinamide <em>N</em>-methyltransferase (NNMT), a cytosolic enzyme regulating nicotinamide (NAM) methylation, as a pivotal player in NDs through its dual impact on epigenetic regulation and metabolic homeostasis. This review synthesizes current knowledge on NNMT's role in disease pathogenesis, focusing on its epigenetic modulation via DNA hypomethylation and histone modifications, alongside its disruption of NAD⁺ synthesis and homocysteine (Hcy) metabolism. Elevated NNMT activity depletes NAD⁺, exacerbating mitochondrial dysfunction and impairing energy metabolism, while increased Hcy levels drive oxidative stress, neuroinflammation, and aberrant protein aggregation (e.g., Aβ, tau, α-synuclein). Notably, NNMT overexpression in AD and PD correlates with neuronal hypomethylation and neurotoxicity, as observed in postmortem brain studies and transgenic models. Mechanistically, NNMT consumes S-adenosylmethionine (SAM), limiting methyl donor availability for DNA methyltransferases (DNMTs) and histone methyltransferases (HMTs), thereby altering gene expression patterns critical for neuronal survival. Concurrently, NNMT-mediated NAD⁺ depletion disrupts sirtuin activity (e.g., SIRT1) and mitochondrial biogenesis, accelerating axonal degeneration. Therapeutic strategies targeting NNMT, such as RNA interference (RNAi), small-molecule inhibitors and exercise therapy, show promise in preclinical models by restoring NAD⁺ levels and reducing Hcy toxicity. However, challenges persist in achieving cellular specificity, optimizing blood-brain barrier penetration, and mitigating off-target effects. This review underscores NNMT's potential as a multifactorial therapeutic target, bridging metabolic and epigenetic dysregulation in NDs. Future research should prioritize elucidating tissue-specific NNMT interactions, refining inhibitor pharmacokinetics, and validating translational efficacy in clinical trials. Addressing these gaps could pave the way for novel disease-modifying therapies to combat the rising burden of neurodegeneration.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"389 ","pages":"Article 115253"},"PeriodicalIF":4.6,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826315","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":"Intermittent theta burst stimulation regulates microglial polarization through Cry1 to enhance neuroplasticity for stroke recovery","authors":"Chenye Qiao ,&nbsp;Yuanyuan Ran ,&nbsp;Ning Li ,&nbsp;Congxiao Wang ,&nbsp;Jinglu Li ,&nbsp;Xiaoming Xi ,&nbsp;Zihan Li ,&nbsp;Lin Ye ,&nbsp;Wei Su ,&nbsp;Zongjian Liu ,&nbsp;Shuyan Qie","doi":"10.1016/j.expneurol.2025.115255","DOIUrl":"10.1016/j.expneurol.2025.115255","url":null,"abstract":"<div><h3>Background</h3><div>Neuroplasticity is crucial for functional recovery after stroke, with modulation of microglial polarization enhancing this process. Intermittent theta burst stimulation (iTBS), as a neuromodulation technique, can simultaneously generate electric and magnetic fields to act on the central nervous system. Neurons can induce electrochemical signal transduction as excitable cells. Meanwhile, iTBS can regulate microglial inflammatory polarization post-stroke. However, how iTBS exerts its effect on microglia remains unclear. The magnetoreceptive protein Cryptochrome (Cry) can respond to the magnetic effect and is known to regulate macrophage-mediated inflammatory responses. However, whether iTBS modulates microglial polarization through Cry1 is unknown.</div></div><div><h3>Objective</h3><div>To explore the magnetic effects of iTBS on microglial polarization through Cry1, thereby enhancing neuroplasticity and stroke recovery, and also elucidate the role of the Cry1-NF-κB pathway in iTBS-mediated regulation of microglial polarization.</div></div><div><h3>Methods</h3><div>A mouse model was established using photothrombosis (PT), followed by 7-day iTBS intervention. BV2 cells and primary neurons were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) respectively, followed by once-daily iTBS treatment for two days. Brain damage and functional recovery were assessed using Map-2 staining and behavioral tests. RT-PCR, western blot, immunofluorescence and transwell co-culture experiments were employed to evaluate the effects of iTBS on microglial polarization and neuroplasticity. Cry1 knockdown via siRNA transfection was used to explore the Cry1-NF-κB signaling pathway.</div></div><div><h3>Results</h3><div>iTBS ameliorated neuronal damage induced by ischemic injury, reduced pro-inflammatory microglial activation, and promoted anti-inflammatory polarization. Cry1 expression was upregulated in BV2 cells in response to iTBS, while Cry1 knockdown increased CD16 expression, decreased CD206 expression and further alleviate the inhibition of NF-κB activation. In primary neurons, anti-inflammatory microglia induced by iTBS could enhance neuroplasticity.</div></div><div><h3>Conclusion</h3><div>This study demonstrates that post-stroke iTBS promotes neuroplasticity and functional recovery by regulating microglial polarization via the Cry1-NF-κB pathway.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"389 ","pages":"Article 115255"},"PeriodicalIF":4.6,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143833789","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":"Identification of NMT1/MA/VPS15 signal pathway as potential therapeutic target in rat cerebral ischemia injury","authors":"Shuguang Bao ,&nbsp;He Bu ,&nbsp;Shan Dong ,&nbsp;Yajie Wang ,&nbsp;Rui Liu ,&nbsp;Hui Wang ,&nbsp;Wenlong Ma ,&nbsp;Zhuo Li ,&nbsp;Na Shen ,&nbsp;Tao Lin ,&nbsp;Juan Chen ,&nbsp;Qi Wan","doi":"10.1016/j.expneurol.2025.115252","DOIUrl":"10.1016/j.expneurol.2025.115252","url":null,"abstract":"<div><div>Fatty acids play a critical role in cerebral ischemia injury through the regulation of lipid metabolism and inflammatory signaling. Myristic acid (MA), a 14‑carbon saturated fatty acid, serves as a substrate of N-myristoyltransferase 1 (NMT1) and modulates protein function and subcellular localization via myristoylation. We show here that intraperitoneal injection of MA has no effect on the infarct volume after rat cerebral ischemia-reperfusion (I/R) injury. However, our results reveal that the level of MA within the penumbra of ischemic brain is increased and that ischemia-induced downregulation of NMT1 is responsible for the increase of MA. We further show that upregulation of MA by knockdown of NMT1 exacerbates cerebral ischemia injury, while downregulation of MA by BCtDCS (bilateral and cathodal transcranial direct current stimulation) protects against cerebral ischemia injury. Furthermore, we demonstrate that MA reduces the expression of VPS15 (phosphoinositide 3-kinase regulatory subunit 4) to exacerbate cerebral ischemia injury, and that NMT1 acts on MA to regulate VPS15 expression in the ischemic cerebral cortex. Together, this study provides the first evidence identifying NMT1/MA/VPS15 signal pathway as potential target for stroke therapy and suggests that BCtDCS may act on MA-dependent signal pathway to confer neuroprotection.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"389 ","pages":"Article 115252"},"PeriodicalIF":4.6,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143823951","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":"Daily acute intermittent hypoxia elicits age & sex-dependent changes in molecules regulating phrenic motor plasticity","authors":"Jayakrishnan Nair ,&nbsp;Alexandria B. Marciante ,&nbsp;Carter Lurk ,&nbsp;Mia N. Kelly ,&nbsp;Capron Maclain ,&nbsp;Gordon S. Mitchell","doi":"10.1016/j.expneurol.2025.115240","DOIUrl":"10.1016/j.expneurol.2025.115240","url":null,"abstract":"<div><div>Acute intermittent hypoxia (AIH) elicits a form of respiratory motor plasticity known as phrenic long-term facilitation (pLTF). Exposure to repetitive daily AIH (dAIH) enhances pLTF, a form of metaplasticity. Little is known concerning cellular mechanisms giving rise to dAIH-induced metaplasticity and the age-dependent sexual dimorphism of AIH associated pro-plasticity mRNA expression. To test if age, sex, and dAIH effects are associated with differential expression of molecules that regulate the Q- and S-pathways and their cross-talk interactions to phrenic motor facilitation, we analyzed key regulatory molecules in ventral spinal (C3-C5) homogenates from young (3-month) and middle-aged (12-month) male and female Sprague-Dawley rats. Since CNS estrogen levels impact molecules known to regulate the Q- and S-pathways, mRNA was correlated with serum estradiol. Rats (<em>n</em> = 8/group) were exposed to sham (21 % O2) or dAIH (15, 1 min episodes of 10.5 % inspired O2) per day for 14 days and sacrificed 24 h later. mRNAs for pLTF regulating molecules were assessed via RT-PCR, including: brain-derived neurotrophic factor (<em>Bdnf</em>); serotonin 2 A (<em>Htr2a</em>), 2B (<em>Htr2b</em>), and 7 (<em>Htr7</em>) receptors; adenosine 2a (<em>Adora2a</em>) receptors; exchange protein activated by cAMP (<em>Epac1</em>); p38 MAP kinase [<em>Mapk14</em> (α) &amp; <em>Mapk11</em> (β)]; PKA regulatory (<em>Prkar1a</em>) and; catalytic subunits (<em>Prkaa1</em>); fractalkine (<em>Cx3cl1</em>), which underlies motor neuron/microglia communication; phosphodiesterase type 4b (<em>Pde4b</em>); NAPDH– gp91 (<em>Cybb</em>) and p47 (<em>ncf1</em>); and the PKC isoform, PKCδ (<em>Prkcd</em>). Here we report that age, sex, dAIH preconditioning, and estradiol influence molecules that initiate and/or regulate the Q- and S-pathways to phrenic motor facilitation.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"389 ","pages":"Article 115240"},"PeriodicalIF":4.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143816848","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}