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The substantia nigra modulates proximal colon tone and motility in a vagally-dependent manner in the rat. 在大鼠中,黑质以迷走神经依赖的方式调节结肠近端张力和运动。
Pub Date : 2023-05-01 DOI: 10.1152/physiol.2023.38.s1.5733721
Tiaosi Xing, G. Nanni, Cameron R Burkholder, K. Browning, R. Travagli
A monosynaptic pathway connects the substantia nigra pars compacta (SNpc) to neurons of the dorsal motor nucleus of the vagus (DMV). This monosynaptic pathway modulates the vagal control of gastric motility. It is not known, however, whether this nigro-vagal pathway also modulates the tone and motility of the proximal colon. In rats, microinjection of retrograde tracers in the proximal colon and of anterograde tracers in SNpc showed that bilaterally labelled colonic-projecting neurons in the DMV received inputs from SNpc neurons. Microinjections of the ionotropic glutamate receptor agonist, NMDA, in the SNpc increased proximal colonic motility and tone, as measured via a strain gauge aligned with the colonic circular smooth muscle; the motility increase was inhibited by acute subdiaphragmatic vagotomy. Upon transfection of SNpc with pAAV-hSyn-hM3D(Gq)-mCherry, chemogenetic activation of nigro-vagal nerve terminals by brainstem application of clozapine-N-oxide increased the firing rate of DMV neurons and proximal colon motility; both responses were abolished by brainstem pretreatment with the dopaminergic D1-like antagonist SCH23390. Chemogenetic inhibition of nigro-vagal nerve terminals following SNpc transfection with pAAV-hSyn-hM4D(Gi)-mCherry decreased the firing rate of DMV neurons and inhibited proximal colon motility. These data suggest that a nigro-vagal pathway modulates activity of the proximal colon motility tonically via a discrete dopaminergic synapse in a manner dependent on vagal efferent nerve activity. Impairment of this nigro-vagal pathway may contribute to the severely reduced colonic transit and prominent constipation observed in both patients and animal models of parkinsonism. KEY POINTS: Substantia nigra pars compacta (SNpc) neurons are connected to the dorsal motor nucleus of the vagus (DMV) neurons via a presumed direct pathway. Brainstem neurons in the lateral DMV innervate the proximal colon. Colonic-projecting DMV neurons receive inputs from neurons of the SNpc. The nigro-vagal pathway modulates tone and motility of the proximal colon via D1-like receptors in the DMV. The present study provides the mechanistic basis for explaining how SNpc alterations may lead to a high rate of constipation in patients with Parkinson's Disease.
一条单突触通路将黑质致密部(SNpc)与迷走神经背运动核(DMV)的神经元连接起来。这种单突触通路调节迷走神经对胃运动的控制。然而,尚不清楚这种黑迷走神经通路是否也调节近端结肠的张力和运动性。在大鼠中,在近端结肠中微量注射逆行示踪剂和在SNpc中微量注射顺行示踪剂表明,DMV中双侧标记的结肠突出神经元接受来自SNpc神经元的输入。在SNpc中微量注射嗜离子性谷氨酸受体激动剂(NMDA)可以增加结肠近端运动性和张力,这是通过与结肠环形平滑肌对准的应变计测量的;急性膈下迷走神经切开术可抑制运动性增加。pAAV-hSyn-hM3D(Gq)-mCherry转染SNpc后,脑干应用氯氮平- n-氧化物对迷走神经末梢的化学激活增加了DMV神经元的放电率和近端结肠运动;脑干预处理多巴胺能d1样拮抗剂SCH23390可消除这两种反应。pAAV-hSyn-hM4D(Gi)-mCherry转染SNpc后,对迷走神经末梢的化学发生抑制降低了DMV神经元的放电率,抑制了近端结肠运动。这些数据表明,黑迷走神经通路通过一个独立的多巴胺能突触,以依赖于迷走传出神经活动的方式,强直地调节结肠近端运动的活动。在帕金森患者和动物模型中观察到,这种黑迷走神经通路的损伤可能导致结肠运输严重减少和明显的便秘。重点:黑质致密部(SNpc)神经元与迷走神经背运动核(DMV)神经元通过一条假定的直接通路相连。外侧DMV的脑干神经元支配结肠近端。结肠突起的DMV神经元接收SNpc神经元的输入。迷走神经通路通过DMV中的d1样受体调节近端结肠的张力和运动性。本研究为解释SNpc改变如何导致帕金森病患者高便秘率提供了机制基础。
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引用次数: 0
Mechanisms of Hebbian‐like plasticity in the ventral premotor – primary motor network 腹侧前运动-初级运动网络中Hebbian样可塑性的机制
Pub Date : 2022-11-03 DOI: 10.1016/j.brs.2023.01.447
Andrea Casarotto, E. Dolfini, P. Cardellicchio, L. Fadiga, A. D’Ausilio, G. Koch
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引用次数: 11
Motor unit dysregulation following 15 days of unilateral lower limb immobilisation 单侧下肢固定15天后运动单元失调
Pub Date : 2022-06-03 DOI: 10.1101/2022.06.01.494421
T. Inns, J. Bass, E. Hardy, D. Stashuk, P. Atherton, B. Phillips, M. Piasecki
Disuse atrophy, caused by situations of unloading such as limb immobilisation, causes a rapid yet diverging reduction in skeletal muscle function compared to muscle mass. While mechanistic insight into the loss of mass is well studied, deterioration of muscle function with a focus towards the neural input to muscle remains underexplored. This study aimed to determine the role of motor unit adaptation in disuse-induced neuromuscular deficits. 10 young, healthy male volunteers underwent 15 days of unilateral lower limb immobilisation. Intramuscular EMG (iEMG) was recorded from the vastus lateralis during knee extensor contractions normalised to maximal voluntary contraction (MVC) pre and post disuse-induced loss of function. Muscle cross-sectional area was determined by ultrasound. Individual MUs were sampled and analysed for changes in discharge characteristics and MU potential (MUP) shape and structure. Vastus lateralis CSA was reduced by approximately 15% which was exceeded by a two-fold decrease of 31% in muscle strength in the immobilised limb, with no change to the non-immobilised. Parameters of MUP size were largely reduced, while neuromuscular junction (NMJ) transmission instability increased at several contraction levels and MU firing rate reduced. All adaptations were observed in the immobilised limb only. These findings highlight impaired neural input following immobilisation reflected by suppressed MU discharge rate and instability of transmission at the NMJ which may underpin the disproportionate reductions of strength relative to muscle size.
由肢体固定等卸载情况引起的废用性萎缩,与肌肉质量相比,会导致骨骼肌功能的快速而分散的减少。虽然对质量损失的机理研究很好,但肌肉功能的退化与神经输入肌肉的关系仍未得到充分探讨。本研究旨在确定运动单元适应在废用性神经肌肉缺陷中的作用。10名年轻健康的男性志愿者接受了15天的单侧下肢固定。肌内肌电图(iEMG)记录从股外侧肌在膝关节伸肌收缩正常化到最大自愿收缩(MVC)期间的肌内肌电图(iEMG)。超声测定肌肉横截面积。对单个MU进行采样并分析其放电特性和MU电位(MUP)形状和结构的变化。股外侧肌CSA减少了约15%,超过了固定肢体肌肉力量的两倍,减少了31%,而非固定肢体没有变化。MUP的大小参数明显减小,神经肌肉接点(NMJ)传递不稳定性在多个收缩水平增加,MU放电速率降低。所有的适应性都只在固定的肢体上观察到。这些发现强调了固定后的神经输入受损,反映在抑制的MU放电率和NMJ传输的不稳定性上,这可能是力量相对于肌肉大小不成比例的减少的基础。
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引用次数: 12
Maternal obesity: influencing the heart right from the start 产妇肥胖:从一开始就影响心脏
Pub Date : 2022-06-03 DOI: 10.1113/JP283190
N. Sergienko, J. Bell, K. Weeks
Nicola M. Sergienko1,2, James R. Bell3 and Kate L. Weeks4,5,6 1Central, Clinical School, Monash University, Melbourne, Victoria, Australia 2Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia 3Department of Microbiology, Anatomy, Physiology & Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Victoria, Australia 4Department of Anatomy & Physiology, The University of Melbourne, Parkville, Victoria, Australia 5Baker Department of Cardiometabolic Health, The University of Melbourne, Parkville, Victoria, Australia 6Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
Nicola M. Sergienko1,2, James R. Bell3和Kate L. week4,5,6 1澳大利亚维多利亚州墨尔本莫纳什大学临床学院中心2澳大利亚维多利亚州墨尔本贝克心脏与糖尿病研究所3澳大利亚维多利亚州邦杜拉拉拉卓伯大学农业、生物医学与环境学院微生物、解剖、生理与药理学系4澳大利亚维多利亚州帕克维尔墨尔本大学解剖与生理学系澳大利亚5墨尔本大学心脏代谢健康学系,帕克维尔,维多利亚州,澳大利亚6莫纳什大学中心临床学院糖尿病学系,墨尔本,维多利亚州,澳大利亚
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引用次数: 0
Peptide transporters in teleost fish: a look into the distant past for a more sustainable future 硬骨鱼中的肽转运体:为更可持续的未来展望遥远的过去
Pub Date : 2022-06-02 DOI: 10.1113/JP283171
M. Sala-Rabanal
The proton-coupled oligopeptide transporters, namely PepT1 (human gene, SLC15A1) and PepT2 (SLC15A2), have been subject to intense scrutiny due to their implications in absorption, reabsorption and distribution of peptidomimetic drugs, notably β-lactam antibiotics (Minhas & Newstead, 2020). While much is known about the pharmacology, molecular mechanisms and structure of the human orthologues (see for example Killer et al., 2021; Sala-Rabanal et al., 2008), less attention has been paid to lower vertebrates, in particular fish. In this issue ofThe Journal of Physiology, Vacca et al. (2022) help to bridge this knowledge gap by using a combination of phylogenetic, biochemical and biophysical approaches to characterize two distinct genes of the Atlantic salmon (Salmo salar) PepT2. Data are put forward that these transporters are expressed, thus potentially serving a physiological purpose, in fish epithelial and neural tissues. The exquisitely conserved mechanistic properties of teleost peptide transport unveiled here showcase the essential role of this ancient family of genes in weathering the selective pressures of protein homeostasis. Critically, this work puts the spotlight on how by-products of human activity may be adding to the ongoing environmental emergency: β-lactams, such as penicillin derivatives and cephalosporins, which are among the most heavily used antibiotics in global healthcare and industrial land farming, are increasingly polluting streams, lakes and oceans, from where they may find their way into the fish bloodstream through gill, intestine or kidney PepTs. Vacca et al. (2022) focus primarily on cultured salmon, and periodic food safety screenings, such as those performed by the Norwegian Institute of Marine Research, ensure that levels of contaminants in farmed seafood are negligible (see, for example, https://www.hi.no/en/hi/nettrapporter/ rapport-fra-havforskningen-en-2021-40); however, less is known about wild-caught fish and shellfish, which are a major part of the diet in many parts of the world. Pharmacokinetics data seem to suggest β-lactam antibiotics do not significantly accumulate in seafood of human consumption, such as the gilthead sea bream (Sparus aurata) (Katharios et al., 2004), thereby questioning the likelihood that they may end up on our dinner plate. But these studies are still few and far between, and more research is needed to determine the movement of pollutants along the food chain. Most importantly, the biological, physiological and ecological effects of sustained exposure of fish to runoff antibiotics, as well as how this is contributing to the worldwide antibiotic resistance crisis, remain to be systematically investigated. As industrialization presses on, work in the field of fish transport physiology as that presented here by Vacca et al. (2022) is crucial, not merely for a deeper understanding of the cellular and pharmacological mechanisms involved, but perhaps to ignite a tidal change regarding sus
质子偶联的寡肽转运体,即PepT1(人类基因,SLC15A1)和PepT2 (SLC15A2),由于其对拟肽药物的吸收、再吸收和分布的影响,特别是β-内酰胺类抗生素,已经受到了严格的审查(Minhas & Newstead, 2020)。虽然对人类同源物的药理学、分子机制和结构了解甚多(参见Killer等人,2021;Sala-Rabanal et al., 2008),对低等脊椎动物,特别是鱼类的关注较少。在这一期的《生理学杂志》上,Vacca等人(2022)通过结合系统发育、生化和生物物理方法来表征大西洋鲑鱼(Salmo salar) PepT2的两个不同基因,帮助弥合了这一知识差距。数据表明,这些转运蛋白在鱼类上皮和神经组织中表达,因此可能具有生理目的。硬骨鱼肽运输的精细保守的机械特性揭示了这个古老的基因家族在抵御蛋白质稳态的选择压力方面的重要作用。至关重要的是,这项工作将重点放在人类活动的副产品如何加剧当前的环境紧急情况上:β-内酰胺,如青霉素衍生物和头孢菌素,它们是全球医疗保健和工业化土地农业中使用最多的抗生素之一,正在日益污染溪流、湖泊和海洋,它们可能通过鳃、肠或肾的胃进入鱼类血液。Vacca等人(2022)主要关注养殖鲑鱼,并定期进行食品安全筛查,例如挪威海洋研究所进行的筛查,确保养殖海产品中的污染物水平可以忽略不计(例如,参见https://www.hi.no/en/hi/nettrapporter/ rapportfra -havforskningen-en-2021-40);然而,人们对野生捕捞的鱼类和贝类知之甚少,它们是世界上许多地方饮食的主要组成部分。药代动力学数据似乎表明,β-内酰胺类抗生素不会在人类食用的海产品中显著积累,例如鲷鱼(Sparus aurata) (Katharios et al., 2004),因此质疑它们最终出现在我们餐盘上的可能性。但这些研究仍然很少,而且相隔甚远,需要更多的研究来确定污染物沿着食物链的运动。最重要的是,鱼类持续暴露于径流抗生素的生物、生理和生态影响,以及这如何导致全球抗生素耐药性危机,仍有待系统调查。随着工业化的推进,鱼类运输生理学领域的工作至关重要,正如Vacca等人(2022)所介绍的那样,这不仅是为了更深入地了解所涉及的细胞和药理机制,而且可能会引发药物可持续生产、使用和处置的潮汐变化。
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引用次数: 0
Back to the beginning: can we stop brain injury before it starts? 回到开头:我们能在脑损伤开始之前阻止它吗?
Pub Date : 2022-06-02 DOI: 10.1113/JP283330
J. Davidson, A. Gunn, J. Dean
Neonatal hypoxic–ischaemic encephalopathy (HIE) attributable to a lack of oxygen and reduced blood flow around the time of birth remains a major global problem, with more than a million associated deaths and 400,000 babies with brain injury every year, contributing to 2.4% of the total global burden of disease. Neonatal HIE affects approximately one to three infants per 1000 in high-income countries and ∼10 times more in lowto middle-income countries. We now know that in high-income countries, therapeutic hypothermia started within 6 h of birth significantly improves survival and reduces disability after HIE. However, nearly half of infants treated with therapeutic hypothermia die or survive with disability, although subsequent trials suggest that current protocols are near optimal. Crucially, the recent large, well-designed HELIX trial in lowto middle-income countries showed that therapeutic hypothermia did not improve outcomes after moderate-to-severe HIE (Thayyil et al., 2021). A common element that might explain the lack of benefit of hypothermia for some infants with HIE is that hypoxia–ischaemia can start well before birth and can evolve for many hours over the course of labour. Thus, at the time of birth, in many cases the brain injury is no longer at a treatable stage. In this issue of The Journal of Physiology, Tran et al. (2022) propose that instead of trying to reduce brain injury by suppressing the evolution of established HIE, we should instead go back to the beginning and build up the defences of the brain against hypoxia–ischaemia before it occurs. Conceptually, if the intervention were to be sufficiently inexpensive and safe, it could be given even to low-risk mothers well before labour and thereby protect babies around the world. In this study, the authors tested fetal creatine supplementation before hypoxic–ischaemic brain injury in near-term fetal sheep. Creatine is a simple guanidine compound abundantly expressed throughout the body, which is both synthesized endogenously and ingested in foods and is widely used as a sports and exercise supplement. Creatine and its phosphorylated form, phosphocreatine, act physiologically in vertebrates as an ATP buffer to maintain ATP-dependent cellular metabolism in all organs. After hypoxia–ischaemia, failure of brain oxidative energy metabolism is the central event initiating brain cell injury and cell death. Thus, creatine supplementation could increase the capacity to maintain cerebral mitochondrial ATP homeostasis during hypoxia–ischaemia. Furthermore, there is some evidence that creatine might have beneficial antioxidant actions. In this study, fetal creatine supplementation (at doses that increased the total creatine content in the brain) reduced baseline brain pyruvate and glycerol concentrations (measured by brain microdialysis) and reduced cerebral hydroxyl radical efflux up to 24 h after hypoxia–ischaemia. Furthermore, fetuses with higher arterial creatine concentrations had small
新生儿缺氧缺血性脑病(HIE)在出生时缺氧和血流量减少,仍然是一个主要的全球问题,每年有100多万例相关死亡和40万例婴儿脑损伤,占全球疾病总负担的2.4%。在高收入国家,每1000名婴儿中约有1至3名受到新生儿HIE的影响,而在低收入至中等收入国家,这一比例约为10倍。我们现在知道,在高收入国家,在出生后6小时内开始治疗性低温可显著提高生存率并减少HIE后的残疾。然而,近一半接受治疗性低温治疗的婴儿死亡或残疾存活,尽管随后的试验表明,目前的方案接近最佳。至关重要的是,最近在中低收入国家进行的设计良好的大型HELIX试验表明,低温治疗并不能改善中度至重度HIE患者的预后(Thayyil等,2021)。对于一些患有HIE的婴儿来说,低温治疗缺乏益处的一个共同因素可能是,缺氧-缺血可以在出生前很早就开始,并在分娩过程中持续数小时。因此,在出生时,在许多情况下,脑损伤不再处于可治疗阶段。在这一期的《生理学杂志》上,Tran等人(2022)提出,我们不应该通过抑制已建立的HIE的进化来试图减少脑损伤,而应该回到一开始,在缺氧缺血发生之前建立大脑的防御机制。从概念上讲,如果干预措施足够便宜和安全,它甚至可以在分娩前就提供给低风险的母亲,从而保护世界各地的婴儿。在这项研究中,作者在近期胎羊缺氧缺血性脑损伤前测试了胎儿肌酸补充。肌酸是一种简单的胍类化合物,在体内大量表达,既可内源性合成,也可从食物中摄取,被广泛用作运动和运动补充剂。在脊椎动物中,肌酸及其磷酸化形式磷酸肌酸在生理上起ATP缓冲作用,维持所有器官中ATP依赖的细胞代谢。缺氧缺血后,脑氧化能代谢失败是引发脑细胞损伤和细胞死亡的中心事件。因此,补充肌酸可以增加在缺氧缺血时维持脑线粒体ATP稳态的能力。此外,有证据表明肌酸可能具有有益的抗氧化作用。在这项研究中,胎儿补充肌酸(在增加脑总肌酸含量的剂量下)降低了基线脑丙酮酸和甘油浓度(通过脑微透析测量),并减少了缺氧缺血后24小时的脑羟基自由基外排。此外,动脉肌酸浓度较高的胎儿在缺氧缺血期间动脉氧分压和氧饱和度的降低幅度较小,并且在缺氧缺血后脑丙酮酸、乳酸和羟基自由基积累减少。这些发现表明,预防性补充肌酸可以在低氧血症期间维持更长时间的ATP周转,从而减少线粒体氧化磷酸化的需求,改善大脑生物能量学。读者应该考虑到,在本研究中,肌酸治疗并没有减弱缺氧缺血后3天大脑氧化应激的组织学证据。此外,预防性肌酸治疗的脑损伤程度尚未在本研究或任何其他大型围产儿缺氧-缺血动物转化模型中得到广泛评估。然而,正如最近回顾的那样(Tran et al., 2021),围产期缺氧缺血性脑损伤的多项临床前啮齿动物研究显示,补充肌酸具有神经保护作用。例如,母鼠饮食中补充肌酸与出生窒息后皮质亚板、梨状皮质和丘脑细胞凋亡的显著减少有关(Ireland等,2011)。在出生第7天的大鼠缺氧缺血前后给予肌酸也与大脑半球体积的显著增加和皮质和海马神经元坏死的减少有关(见Tran et al., 2021)。预防性肌酸治疗策略的一个优点是,它也可以保护全身缺氧缺血后容易损伤的其他器官。例如,母体补充肌酸可以减少雄性刺鼠出生窒息后成年早期的肾功能障碍(Ellery等,2017)。然而,这种治疗策略的局限性在于,它可能需要在出生前进行长时间的治疗。Tran等人。
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引用次数: 0
Persistent inward currents in spinal motoneurones: how can we study them in human participants? 脊髓运动神经元的持续向内电流:我们如何在人类参与者中研究它们?
Pub Date : 2022-05-26 DOI: 10.1113/JP283249
Jacob R. Thorstensen
Activation of a motoneurone occurs when excitatory synaptic input from descending motor pathways, or sensory projections, is sufficient to bring the membrane potential of the motoneurone above its firing threshold. The input–output gain of motoneurones is enhanced by monoamine neuromodulators released from raphe-spinal neurons (serotonin, 5-HT) and locus coeruleus neurons (noradrenaline, NA). These pathways form monosynaptic connections with the dendrites of motoneurones and have multiple effects on motoneurone excitability. Notably, 5-HT and NA have strong facilitation effects on voltage-gated persistent inward currents (PICs), which amplify synaptic input and promote the self-sustained discharge of motoneurones. In animal preparations with restricted neuromodulator release, intracellular recordings of motoneurones reveal that increasing the magnitude of injected current increases discharge rate linearly. However, in the presence of neuromodulation and PIC activation, the relationship between injected current and discharge rate becomes non-linear. This is reflected in the hysteresis between the magnitude of injected current needed for recruitment and at de-recruitment, one of many PIC-induced non-linearities (e.g. acceleration of firing, firing rate saturation). Compared to recruitment, injected current is lower at de-recruitment as less excitatory input is needed tomaintain ongoingmotoneurone discharge as PICs are active and are generating a strong intrinsic depolarization. Human motoneurones also exhibit hysteresis in the amount of excitatory drive needed to recruit compared to de-recruitment. Instead of injecting current to cause recruitment and de-recruitment, voluntary isometric contractions can be performed to activate motoneurones via synaptic input, and the magnitude of synaptic activation can be inferred from motor unit discharge recorded with electromyography (EMG). Specifically, the discharge rate of a voluntarily recruited lower-threshold ‘control’ unit can be used as an estimate of net synaptic input to the motoneurone pool and a higher-threshold ‘test’ unit. The difference in firing rates for the control unit at the time of recruitment and de-recruitment of the test unit (delta frequency, F) is used to determine the contribution of PICs to test unit activation, with smaller differences indicating a smaller contribution of PICs to motoneurone activation (Gorassini et al., 2002). Animal preparations indicate that the amplitude of PICs in motoneurones is directly proportional to neuromodulatory drive (Heckman et al., 2009), and hence estimating PIC amplitude with the paired motor unit technique provides an opportunity to study the neuromodulatory control of human motoneurones. Neuromodulatory drive to the spinal cord is dynamic, whereby the amount of monoamine release depends on certain behaviours. 5-HT release is coupled with the intensity of motor activity, where higher-intensity motor activities result in more release. NA release t
当来自下行运动通路或感觉投射的兴奋性突触输入足以使运动神经元的膜电位超过其放电阈值时,运动神经元就会被激活。运动神经元的输入-输出增益可通过腰脊髓神经元(5-羟色胺)和蓝斑神经元(去甲肾上腺素)释放的单胺神经调节剂增强。这些通路与运动神经元的树突形成单突触连接,对运动神经元的兴奋性有多重影响。值得注意的是,5-HT和NA对电压门控持续内向电流(PICs)有很强的促进作用,PICs可以放大突触输入并促进运动神经元的自我持续放电。在限制神经调节剂释放的动物制剂中,运动神经元的细胞内记录显示,注射电流的大小增加,放电率线性增加。然而,在神经调节和PIC激活的情况下,注入电流与放电速率之间的关系变为非线性的。这反映在吸收和去吸收所需注入电流的大小之间的滞后,这是许多pic引起的非线性之一(例如,发射加速,发射速率饱和)。与募集相比,去募集时注入电流更低,因为PICs是活跃的,并且产生强烈的内在去极化,因此维持持续的运动神经元放电所需的兴奋性输入更少。人类运动神经元在兴奋性驱动的数量上也表现出滞后,需要与去募集相比。而不是注入电流来引起招募和去招募,自愿等距收缩可以通过突触输入来激活运动神经元,突触激活的大小可以从肌电图(EMG)记录的运动单元放电中推断出来。具体来说,自愿招募的低阈值“控制”单元的放电率可以用作对运动神经元池和高阈值“测试”单元的净突触输入的估计。控制单元在测试单元招募和去招募时的放电率差异(δ频率,F)用于确定PICs对测试单元激活的贡献,差异越小表明PICs对运动神经元激活的贡献越小(Gorassini et al., 2002)。动物实验表明运动神经元中PIC的振幅与神经调节驱动成正比(Heckman et al., 2009),因此用配对运动单元技术估计PIC的振幅为研究人类运动神经元的神经调节控制提供了机会。脊髓的神经调节驱动是动态的,因此单胺释放的量取决于某些行为。5-HT的释放与运动活动的强度有关,其中高强度的运动活动导致更多的释放。向脊髓释放NA可能与高水平的压力/焦虑相对应。不管促进神经调节驱动的行为是什么,脊髓中的单胺能投射是弥漫性的,轴突在多个脊髓水平分支。这种弥漫性释放对于运动神经元池的靶向激活可能是有问题的,因为它可以同时增加多个池的增益,有时对关节运动有相反的影响(即激动剂和拮抗剂池的促进可能导致共同收缩)。为了减轻弥漫性神经调节驱动的影响,并提高运动神经元募集的特异性,椎内中间神经元可能会抑制特定运动任务不需要的运动神经元。例如,踝关节被动运动可以延长相对的踝关节屈肌,相互抑制可以显著降低踝关节伸肌运动神经元的PIC振幅(Hyngstrom等人,2007)。这可能代表了当多个运动神经元池的兴奋性高时抑制运动神经元中的PICs的策略。虽然可以估计人类运动神经元的PIC振幅,并且抑制和神经调节对动物运动神经元的PIC振幅有很强的影响,但很少有人类研究将相互抑制和/或神经调节驱动与PIC活性联系起来。
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引用次数: 1
Concurrent exposure to (acute intermittent) hypoxia and hypercapnia: a promising therapeutic cocktail for neuroplasticity? 同时暴露于(急性间歇性)缺氧和高碳酸血症:一种有前途的神经可塑性治疗鸡尾酒?
Pub Date : 2022-05-23 DOI: 10.1113/JP283215
R. Mesquita
(peripheral chemoreceptor activation) raphe-spinal serotonergic activation of the serotonergic chemoreceptor activation).
(外周化学感受器激活)脊髓5 -羟色胺能激活的5 -羟色胺能化学感受器激活)。
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引用次数: 0
Remote ischaemic preconditioning – translating cardiovascular benefits to humans 远程缺血预处理-转化心血管对人类的益处
Pub Date : 2022-05-21 DOI: 10.1113/JP282568
J. Lang, Jahyun Kim
Remote ischaemic preconditioning (RIPC), induced by intermittent periods of limb ischaemia and reperfusion, confers cardiac and vascular protection from subsequent ischaemia–reperfusion (IR) injury. Early animal studies reliably demonstrate that RIPC attenuated infarct size and preserved cardiac tissue. However, translating these adaptations to clinical practice in humans has been challenging. Large clinical studies have found inconsistent results with respect to RIPC eliciting IR injury protection or improving clinical outcomes. Follow‐up studies have implicated several factors that potentially affect the efficacy of RIPC in humans such as age, fitness, frequency, disease state and interactions with medications. Thus, realizing the clinical potential for RIPC may require a human experimental model where confounding factors are more effectively controlled and underlying mechanisms can be further elucidated. In this review, we highlight recent experimental findings in the peripheral circulation that have added valuable insight on the mechanisms and clinical benefit of RIPC in humans. Central to this discussion is the critical role of timing (i.e. immediate vs. delayed effects following a single bout of RIPC) and the frequency of RIPC. Limited evidence in humans has demonstrated that repeated bouts of RIPC over several days uniquely improves vascular function beyond that observed with a single bout alone. Since changes in resistance vessel and microvascular function often precede symptoms and diagnosis of cardiovascular disease, repeated bouts of RIPC may be promising as a preclinical intervention to prevent or delay cardiovascular disease progression.
肢体间歇性缺血和再灌注诱导的远端缺血预处理(RIPC)可保护心脏和血管免受随后的缺血再灌注(IR)损伤。早期动物研究可靠地证明,RIPC可缩小梗死面积并保存心脏组织。然而,将这些适应性转化为人类的临床实践一直具有挑战性。大型临床研究发现,RIPC在诱导IR损伤保护或改善临床结果方面的结果不一致。后续研究表明,有几个因素可能影响RIPC在人类中的疗效,如年龄、健康状况、频率、疾病状态和与药物的相互作用。因此,实现RIPC的临床潜力可能需要一个更有效控制混杂因素的人体实验模型,并进一步阐明其潜在机制。在这篇综述中,我们重点介绍了最近在外周循环中的实验发现,这些发现为RIPC在人类中的机制和临床益处提供了有价值的见解。这个讨论的核心是时间的关键作用(即在单次RIPC之后的即时效应和延迟效应)和RIPC的频率。有限的人类证据表明,数天内反复服用RIPC比单次服用更能改善血管功能。由于阻力血管和微血管功能的改变往往先于心血管疾病的症状和诊断,反复发作的RIPC可能有希望作为预防或延缓心血管疾病进展的临床前干预措施。
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引用次数: 9
Welcome to the touch dome! 欢迎来到touch穹顶!
Pub Date : 2022-04-02 DOI: 10.1113/JP282866
V. Macefield
ThisHistorical Perspective article celebrates the 600th volume of The Journal of Physiology, recognizing the most highly cited papers published in the Journal. Here I discuss the significance of a landmark study published in 1969 by Ainsley Iggo and Alan Muir, from the Departments of Anatomy and Physiology at The University of Edinburgh. A graduate of Otago University in New Zealand, and having received training in neurophysiology under the tutelage of Jack Eccles, Iggo arrived in Edinburgh (after a 2-year stint in Aberdeen) in 1952 (Iggo, 2001). The paper of interest here, titled The structure and function of a slowly adapting touch corpuscle in hairy skin, built on his work with Muir (his student) in which they had characterized the ‘touch dome’ mechanoreceptors in the hairy skin of the cat. After shaving the hairy skin these domes can be readily seen as punctate elevations of the epidermis, which are usually (but not always) associated with a single hair. The sensory axons that supply these endings are known as the slowly adapting type I (SAI) afferents, and histological evidence showed that the mechanoreceptors are the Merkel cell receptors, now known asMerkel cell–neurite complexes. SAI afferents possess small, well-defined receptive fields composed of several ‘hot spots.’ Iggo and Muir showed that each touch dome is innervated by a single myelinated axon that branches to end as Merkel discs, although a given parent axon can supply several touch domes. Subsequent work in humans, in which single-unit recordings were made via tungsten microelectrodes inserted into the lateral antebrachial cutaneous nerve, demonstrated that the receptive fields of SAI afferents in hairy skin are composed of two to four ‘hot spots’ of maximal sensitivity, each no doubt corresponding to the location of the receptor terminal from a single axon that branches from the parent axon (Vallbo et al., 1995). In the glabrous skin of the hand there are no touch domes; here, the Merkel cell–neurite complexes are associated with the patterned elevations of the epidermis that form the fingerprint ridges. Nevertheless, the receptive fields of these SAI afferents are composed of several distinct subfields spread across multiple ridges, such that the receptor endings underlying each of these ‘hot spots’ can detect mechanical events at individual fingerprint ridges (Jarocka et al., 2021). Iggo and Muir performed an extensive analysis of the physiology of the ‘touch spot’ receptors. Earlier studies by Brown and Iggo (1963) demonstrated that, after crushing the parent nerve, the characteristic slowly adapting discharge of the afferent only returned once the axon had regrown into the touch dome and the Merkel cell complex had reformed. Iggo and Muir showed that while the receptors responded well to punctate indentation of the touch dome, they were particularly sensitive to light stroking across the receptive field, a feature exhibited by SAI afferents recorded in humans. And, like hu
然而,这一结论受到了质疑。例如,最近的研究表明,传入峰的时间模式确实提供了机械刺激质量的信息:振动颤振的感知——归因于支配梅斯纳小体的快速适应型I (FAI)传入的输入——可以通过低频刺激模式选择性刺激支配帕西尼小体的快速适应型II (FAII)传入诱导(Birznieks等人,2019)。换句话说,单个触觉传入的脉冲的时空模式可以为大脑提供潜在的模糊信息。当然,我们必须承认,机械刺激转化为脉冲序列的生理转导依赖于机械感受器及其微环境的专门化,这是Iggo和Muir在他们的论文中做出的另一个贡献。作者提供了丰富的默克尔盘和相关默克尔细胞的组织学分析。他们展示了表面
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引用次数: 0
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The Japanese journal of physiology
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