Phasic release of acetylcholine (ACh) in the neocortex facilitates attentional processes. Acting at a single metabotropic receptor subtype, ACh exerts two opposing actions in cortical pyramidal neurons: transient inhibition and longer‐lasting excitation. Cholinergic inhibitory responses depend on calcium release from intracellular calcium stores, and run down rapidly at resting membrane potentials when calcium stores become depleted. We demonstrate that cholinergic excitation promotes calcium entry at subthreshold membrane potentials to rapidly refill calcium stores, thereby maintaining the fidelity of inhibitory cholinergic signalling. We propose a ‘unifying hypothesis’ for M1 receptor signalling whereby inhibitory and excitatory responses to ACh in pyramidal neurons represent complementary mechanisms governing rapid calcium cycling between the endoplasmic reticulum, the cytosol and the extracellular space.
{"title":"A unifying hypothesis for M1 muscarinic receptor signalling in pyramidal neurons","authors":"Sameera Dasari, C. Hill, Allan T. Gulledge","doi":"10.1113/JP273627","DOIUrl":"https://doi.org/10.1113/JP273627","url":null,"abstract":"Phasic release of acetylcholine (ACh) in the neocortex facilitates attentional processes. Acting at a single metabotropic receptor subtype, ACh exerts two opposing actions in cortical pyramidal neurons: transient inhibition and longer‐lasting excitation. Cholinergic inhibitory responses depend on calcium release from intracellular calcium stores, and run down rapidly at resting membrane potentials when calcium stores become depleted. We demonstrate that cholinergic excitation promotes calcium entry at subthreshold membrane potentials to rapidly refill calcium stores, thereby maintaining the fidelity of inhibitory cholinergic signalling. We propose a ‘unifying hypothesis’ for M1 receptor signalling whereby inhibitory and excitatory responses to ACh in pyramidal neurons represent complementary mechanisms governing rapid calcium cycling between the endoplasmic reticulum, the cytosol and the extracellular space.","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"64 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72611893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The most powerful way to study cerebral network function and connectivity is by tracking the activity of large populations of neurons in relation to a stimulus or behaviour. Various techniques have been applied to monitor neuronal activity. For instance, labelling based on immediate early gene (IEG) expression (such as cFos and Arc) reveals a long-lasting trace of plasticity-related neuronal activity. This permits post hoc analysis in relatively large brain volumes, but it most likely excludes neurons exhibiting modest activity levels. On the contrary, calcium indicators such as GCaMPs (Chen et al. 2013) can report neuronal activity in real time with high sensitivity. However, due to the transient nature of calcium events, simultaneous visualization or post hoc analysis of activated neurons in large brain volumes proved to be challenging. Ideally, for functional synaptic circuit mapping, one would like to employ a method that combines the better of the enduring but somewhat enigmatic IEG-based labelling and the exact but fleeting calcium indicators. The recently developed activity reporter CaMPARI (calcium-modulated photoactivatable ratiometric integrator) potentially fulfils these requirements (Fosque et al. 2015). CaMPARI is a new type of fluorescent calcium indicator that efficiently undergoes an irreversible green-to-red conversion upon violet light illumination and binding of calcium (Fosque et al. 2015). The experimenter defines the time window of photoconversion, which can be repeatedly synchronized with a chosen stimulus. As a result, the intensity of red fluorescence scales with the sum of the calcium levels present at the time of all photoconversion epochs. This feature has been employed to generate a lasting ‘snapshot’ of evoked neuronal activity in various animal models such as zebrafish larvae, flies and in head fixed adult mice (Fosque et al. 2015). The study by Zolnik et al. (Zolnik et al. 2017), published in this issue of The Journal of Physiology, further characterizes and expands the possible applications of CaMPARI. They show that CaMPARI photoconversion is effective at low violet light intensities and linearly correlates with the dose of light (Fosque et al. 2015). This feature may extend the use of CaMPARI to experiments in which violet light delivery is challenging, such as in scattering tissue in vivo. The authors also cleverly employed CaMPARI’s sensitivity to reveal, in addition to spiking, sub-threshold synaptic activity in mouse brain slices, thereby offering a method for functional synaptic connectivity mapping. Subthreshold synaptic potentials typically generate localized dendritic calcium events, which are insufficient to be detected at the soma using transient calcium indicators. Nonetheless, Zolnik et al. demonstrate that repeatedly combining the violet light illumination with subthreshold stimulation causes a persistent accumulation of photoconverted CaMPARI at the soma. Thus, post hoc measurements based on CaMPAR
研究大脑网络功能和连通性的最有效方法是跟踪与刺激或行为相关的大量神经元的活动。各种技术已被应用于监测神经元活动。例如，基于即时早期基因(IEG)表达(如cfo和Arc)的标记揭示了与可塑性相关的神经元活动的长期痕迹。这允许对相对较大的脑容量进行事后分析，但它很可能排除了表现出适度活动水平的神经元。相反，钙指标如GCaMPs (Chen et al. 2013)可以高灵敏度实时报告神经元活动。然而，由于钙事件的短暂性，在大脑容量中同时可视化或事后分析激活神经元被证明是具有挑战性的。理想情况下，对于功能性突触电路的映射，人们希望采用一种方法，将持久但有些神秘的基于eeg的标记和精确但稍纵即逝的钙指标结合起来。最近开发的活性报告器CaMPARI(钙调制光激活比率积分器)可能满足这些要求(Fosque等，2015)。CaMPARI是一种新型的荧光钙指示剂，在紫光照射和钙的结合下，可以有效地发生不可逆的绿到红转换(Fosque et al. 2015)。实验者定义光转换的时间窗口，该时间窗口可以与选定的刺激重复同步。因此，红色荧光的强度与所有光转换时期存在的钙水平的总和有关。这一特征已被用于在各种动物模型中生成诱发神经元活动的持久“快照”，如斑马鱼幼虫、苍蝇和头部固定的成年小鼠(Fosque et al. 2015)。Zolnik et al. (Zolnik et al. 2017)发表在本期《The Journal of Physiology》上的研究进一步描述并扩展了CaMPARI的可能应用。他们表明，CaMPARI光转换在低紫光强度下是有效的，并且与光剂量呈线性相关(Fosque et al. 2015)。这一特性可以将CaMPARI扩展到紫光传输具有挑战性的实验中，例如在体内散射组织中。作者还巧妙地利用CaMPARI的灵敏度，揭示了小鼠大脑切片中除尖峰外的亚阈值突触活动，从而提供了一种功能性突触连接映射的方法。阈下突触电位通常会产生局部树突状钙事件，这些事件不足以用瞬态钙指示剂在体细胞中检测到。尽管如此，Zolnik等人证明，反复结合紫光照明和阈下刺激会导致体细胞中光转化CaMPARI的持续积累。因此，基于CaMPARI的事后测量可以揭示突触后神经元接受阈上和阈下输入的完整功能图谱(图1)。进一步利用CaMPARI揭示阈下活动的潜力，
{"title":"New recipes with CaMPARI for ‘snapshots’ of synaptic circuit activity","authors":"Ronan Chéreau, A. Holtmaat","doi":"10.1113/JP273733","DOIUrl":"https://doi.org/10.1113/JP273733","url":null,"abstract":"The most powerful way to study cerebral network function and connectivity is by tracking the activity of large populations of neurons in relation to a stimulus or behaviour. Various techniques have been applied to monitor neuronal activity. For instance, labelling based on immediate early gene (IEG) expression (such as cFos and Arc) reveals a long-lasting trace of plasticity-related neuronal activity. This permits post hoc analysis in relatively large brain volumes, but it most likely excludes neurons exhibiting modest activity levels. On the contrary, calcium indicators such as GCaMPs (Chen et al. 2013) can report neuronal activity in real time with high sensitivity. However, due to the transient nature of calcium events, simultaneous visualization or post hoc analysis of activated neurons in large brain volumes proved to be challenging. Ideally, for functional synaptic circuit mapping, one would like to employ a method that combines the better of the enduring but somewhat enigmatic IEG-based labelling and the exact but fleeting calcium indicators. The recently developed activity reporter CaMPARI (calcium-modulated photoactivatable ratiometric integrator) potentially fulfils these requirements (Fosque et al. 2015). CaMPARI is a new type of fluorescent calcium indicator that efficiently undergoes an irreversible green-to-red conversion upon violet light illumination and binding of calcium (Fosque et al. 2015). The experimenter defines the time window of photoconversion, which can be repeatedly synchronized with a chosen stimulus. As a result, the intensity of red fluorescence scales with the sum of the calcium levels present at the time of all photoconversion epochs. This feature has been employed to generate a lasting ‘snapshot’ of evoked neuronal activity in various animal models such as zebrafish larvae, flies and in head fixed adult mice (Fosque et al. 2015). The study by Zolnik et al. (Zolnik et al. 2017), published in this issue of The Journal of Physiology, further characterizes and expands the possible applications of CaMPARI. They show that CaMPARI photoconversion is effective at low violet light intensities and linearly correlates with the dose of light (Fosque et al. 2015). This feature may extend the use of CaMPARI to experiments in which violet light delivery is challenging, such as in scattering tissue in vivo. The authors also cleverly employed CaMPARI’s sensitivity to reveal, in addition to spiking, sub-threshold synaptic activity in mouse brain slices, thereby offering a method for functional synaptic connectivity mapping. Subthreshold synaptic potentials typically generate localized dendritic calcium events, which are insufficient to be detected at the soma using transient calcium indicators. Nonetheless, Zolnik et al. demonstrate that repeatedly combining the violet light illumination with subthreshold stimulation causes a persistent accumulation of photoconverted CaMPARI at the soma. Thus, post hoc measurements based on CaMPAR","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"82 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82950311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The functional importance of residues in loop G of the GABAA receptor has not been investigated. D43 and T47 in the α1 subunit are of particular significance as their structural modification inhibits activation by GABA. While the T47C substitution had no significant effect, non‐conservative substitution of either residue (D43C or T47R) reduced the apparent potency of GABA. Propofol potentiated maximal GABA‐evoked currents mediated by α1(D43C)β2γ2 and α1(T47R)β2γ2 receptors. Non‐stationary variance analysis revealed a reduction in maximal GABA‐evoked Popen, suggesting impaired agonist efficacy. Further analysis of α1(T47R)β2γ2 receptors revealed that the efficacy of the partial agonist THIP (4,5,6,7‐tetrahydroisoxazolo[5,4‐c]pyridine‐3‐ol) relative to GABA was impaired. GABA‐, THIP‐ and propofol‐evoked currents mediated by α1(T47R)β2γ2 receptors deactivated faster than those mediated by α1β2γ2 receptors, indicating that the mutation impairs agonist‐evoked gating. Spontaneous gating caused by the β2(L285R) mutation was also reduced in α1(T47R)β2(L285R)γ2 compared to α1β2(L285R)γ2 receptors, confirming that α1(T47R) impairs gating independently of agonist activation.
{"title":"Loop G in the GABAA receptor α1 subunit influences gating efficacy","authors":"D. Baptista‐Hon, Simona Gulbinaite, T. Hales","doi":"10.1113/JP273752","DOIUrl":"https://doi.org/10.1113/JP273752","url":null,"abstract":"The functional importance of residues in loop G of the GABAA receptor has not been investigated. D43 and T47 in the α1 subunit are of particular significance as their structural modification inhibits activation by GABA. While the T47C substitution had no significant effect, non‐conservative substitution of either residue (D43C or T47R) reduced the apparent potency of GABA. Propofol potentiated maximal GABA‐evoked currents mediated by α1(D43C)β2γ2 and α1(T47R)β2γ2 receptors. Non‐stationary variance analysis revealed a reduction in maximal GABA‐evoked Popen, suggesting impaired agonist efficacy. Further analysis of α1(T47R)β2γ2 receptors revealed that the efficacy of the partial agonist THIP (4,5,6,7‐tetrahydroisoxazolo[5,4‐c]pyridine‐3‐ol) relative to GABA was impaired. GABA‐, THIP‐ and propofol‐evoked currents mediated by α1(T47R)β2γ2 receptors deactivated faster than those mediated by α1β2γ2 receptors, indicating that the mutation impairs agonist‐evoked gating. Spontaneous gating caused by the β2(L285R) mutation was also reduced in α1(T47R)β2(L285R)γ2 compared to α1β2(L285R)γ2 receptors, confirming that α1(T47R) impairs gating independently of agonist activation.","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"147 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83103380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dominik Kaczmarek, J. Ristikankare, Elzbieta Jankowska
Trans‐spinal polarization was recently introduced as a means to improve deficient spinal functions. However, only a few attempts have been made to examine the mechanisms underlying DC actions. We have now examined the effects of DC on two spinal modulatory systems, presynaptic inhibition and post‐activation depression, considering whether they might weaken exaggerated spinal reflexes and enhance excessively weakened ones. Direct current effects were evoked by using local intraspinal DC application (0.3–0.4 μA) in deeply anaesthetized rats and were compared with the effects of trans‐spinal polarization (0.8–1.0 mA). Effects of local intraspinal DC were found to be polarity dependent, as locally applied cathodal polarization enhanced presynaptic inhibition and post‐activation depression, whereas anodal polarization weakened them. In contrast, both cathodal and anodal trans‐spinal polarization facilitated them. The results suggest some common DC‐sensitive mechanisms of presynaptic inhibition and post‐activation depression, because both were facilitated or depressed by DC in parallel.
{"title":"Does trans‐spinal and local DC polarization affect presynaptic inhibition and post‐activation depression?","authors":"Dominik Kaczmarek, J. Ristikankare, Elzbieta Jankowska","doi":"10.1113/JP272902","DOIUrl":"https://doi.org/10.1113/JP272902","url":null,"abstract":"Trans‐spinal polarization was recently introduced as a means to improve deficient spinal functions. However, only a few attempts have been made to examine the mechanisms underlying DC actions. We have now examined the effects of DC on two spinal modulatory systems, presynaptic inhibition and post‐activation depression, considering whether they might weaken exaggerated spinal reflexes and enhance excessively weakened ones. Direct current effects were evoked by using local intraspinal DC application (0.3–0.4 μA) in deeply anaesthetized rats and were compared with the effects of trans‐spinal polarization (0.8–1.0 mA). Effects of local intraspinal DC were found to be polarity dependent, as locally applied cathodal polarization enhanced presynaptic inhibition and post‐activation depression, whereas anodal polarization weakened them. In contrast, both cathodal and anodal trans‐spinal polarization facilitated them. The results suggest some common DC‐sensitive mechanisms of presynaptic inhibition and post‐activation depression, because both were facilitated or depressed by DC in parallel.","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87351281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Martínez-Bellver, A. Cervera-Ferri, Aina Luque‐García, J. Martínez-Ricós, A. Valverde-Navarro, M. Bataller, Juan Guerrero, V. Teruel-Martí
The nucleus incertus is a key node of the brainstem circuitry involved in hippocampal theta rhythmicity. Synchronisation exists between the nucleus incertus and hippocampal activities during theta periods. By the Granger causality analysis, we demonstrated a directional information flow between theta rhythmical neurons in the nucleus incertus and the hippocampus in theta‐on states. The electrical stimulation of the nucleus incertus is also able to evoke a phase reset of the hippocampal theta wave. Our data suggest that the nucleus incertus is a key node of theta generation and the modulation network.
{"title":"Causal relationships between neurons of the nucleus incertus and the hippocampal theta activity in the rat","authors":"S. Martínez-Bellver, A. Cervera-Ferri, Aina Luque‐García, J. Martínez-Ricós, A. Valverde-Navarro, M. Bataller, Juan Guerrero, V. Teruel-Martí","doi":"10.1113/JP272841","DOIUrl":"https://doi.org/10.1113/JP272841","url":null,"abstract":"The nucleus incertus is a key node of the brainstem circuitry involved in hippocampal theta rhythmicity. Synchronisation exists between the nucleus incertus and hippocampal activities during theta periods. By the Granger causality analysis, we demonstrated a directional information flow between theta rhythmical neurons in the nucleus incertus and the hippocampus in theta‐on states. The electrical stimulation of the nucleus incertus is also able to evoke a phase reset of the hippocampal theta wave. Our data suggest that the nucleus incertus is a key node of theta generation and the modulation network.","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84702057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
I. Álvarez‐Miguel, P. Cidad, M. Pérez-García, J. López-López
Canonical transient receptor potential (TRPC)3 and TRPC6 channels of vascular smooth muscle cells (VSMCs) mediate stretch‐ or agonist‐induced cationic fluxes, contributing to membrane potential and vascular tone. Native TRPC3/C6 channels can form homo‐ or heterotetrameric complexes, which can hinder individual TRPC channel properties. The possibility that the differences in their association pattern may change their contribution to vascular tone in hypertension is unexplored. Functional characterization of heterologously expressed channels showed that TRPC6‐containing complexes exhibited Pyr3/Pyr10‐sensitive currents, whereas TRPC3‐mediated currents were blocked by anti‐TRPC3 antibodies. VSMCs from hypertensive (blood pressure high; BPH) mice have larger cationic basal currents insensitive to Pyr10 and sensitive to anti‐TRPC3 antibodies. Consistently, myography studies showed a larger Pyr3/10‐induced vasodilatation in BPN (blood pressure normal) mesenteric arteries. We conclude that the increased TRPC3 channel expression in BPH VSMCs leads to changes in TRPC3/C6 heteromultimeric assembly, with a higher TRPC3 channel contribution favouring depolarization of hypertensive VSMCs.
{"title":"Differences in TRPC3 and TRPC6 channels assembly in mesenteric vascular smooth muscle cells in essential hypertension","authors":"I. Álvarez‐Miguel, P. Cidad, M. Pérez-García, J. López-López","doi":"10.1113/JP273327","DOIUrl":"https://doi.org/10.1113/JP273327","url":null,"abstract":"Canonical transient receptor potential (TRPC)3 and TRPC6 channels of vascular smooth muscle cells (VSMCs) mediate stretch‐ or agonist‐induced cationic fluxes, contributing to membrane potential and vascular tone. Native TRPC3/C6 channels can form homo‐ or heterotetrameric complexes, which can hinder individual TRPC channel properties. The possibility that the differences in their association pattern may change their contribution to vascular tone in hypertension is unexplored. Functional characterization of heterologously expressed channels showed that TRPC6‐containing complexes exhibited Pyr3/Pyr10‐sensitive currents, whereas TRPC3‐mediated currents were blocked by anti‐TRPC3 antibodies. VSMCs from hypertensive (blood pressure high; BPH) mice have larger cationic basal currents insensitive to Pyr10 and sensitive to anti‐TRPC3 antibodies. Consistently, myography studies showed a larger Pyr3/10‐induced vasodilatation in BPN (blood pressure normal) mesenteric arteries. We conclude that the increased TRPC3 channel expression in BPH VSMCs leads to changes in TRPC3/C6 heteromultimeric assembly, with a higher TRPC3 channel contribution favouring depolarization of hypertensive VSMCs.","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73026278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Neuropathy of the enteric nervous system (ENS) is one of the major underlying causes of debilitating gastrointestinal (GI) motility disorders in diabetic patients. Recent studies suggest that diet–microbiome–host interactions – in particular, excess dietary calories, microbial metabolites, lipopolysaccharide (LPS) and disrupted mucosal barrier – play a fundamental role in the pathobiology of obesity and type II diabetes (Boulangé et al. 2016). Furthermore, the composition of the GI microbiome influences ENS physiology, neurochemistry and nerve cell health, as well as GI motility patterns, and vice versa (Kashyap et al. 2013). However, links between such interactions and the mechanisms underlying this neuropathy are not fully understood. In this issue of The Journal of Physiology, Reichardt et al. (2017) address the question of whether ingesting a Western diet (WD) rich in saturated fatty acids and the associated alteration to the gut microbiome disrupts motility, and induces loss of nitrergic myenteric neurons (NMNs), the phenotype that is commonly damaged in diabetic neuropathy (Yarandi & Srinivasan, 2014). The rationale is that most studies have used a high fat diet (HFD; 60–72% kcal from fat), leading to little understanding of how a normal WD affects GI motility, the ENS and their role in the pathobiology of the metabolic syndrome and diabetes. The authors used C57BL/6 mice fed WD (35% kcal from fat, enriched in palmitate) or a regular diet (RD, 16.9% kcal from fat, 4× less palmitate) for 3, 6, 9 and 12 weeks, and TLR4 and germ free mice fed WD and RD diets for 6 weeks. Gastrointestinal motility was measured, and damage to myenteric neurons and NMNs was studied in the ileum and proximal colon. Palmitateand LPS-induced damage to NMNs and the role of nitric oxide synthase (nNOS) in such injury were determined in vitro using immortalized myenteric neurons. Faecal metabolites, systemic and visceral fat and mucosal inflammation were analysed. After ingesting WD for 6 weeks, mice were ‘overweight’, developed gut microbiota dysbiosis, altered faecal metabolites, increased intraluminal LPS and increased plasma free fatty acid (FFA) levels. Interestingly, unlike HFD, WD did not elicit hyperglycaemia, endotoxaemia and inflammation, suggesting the need to define key differences between the effect of HFD and WD on gut microbiome and metabolic profiles. Another important observation was that WD caused GI dysmotility before
肠神经系统(ENS)神经病变是糖尿病患者胃肠运动障碍的主要潜在原因之一。最近的研究表明，饮食-微生物-宿主的相互作用，特别是过量的饮食热量、微生物代谢物、脂多糖(LPS)和黏膜屏障的破坏，在肥胖和II型糖尿病的病理生物学中起着重要作用(boulang等，2016)。此外，胃肠道微生物组的组成影响ENS生理学、神经化学和神经细胞健康，以及胃肠道运动模式，反之亦然(Kashyap et al. 2013)。然而，这种相互作用与这种神经病变的机制之间的联系尚不完全清楚。在本期的《生理学杂志》上，Reichardt等人(2017)探讨了摄入富含饱和脂肪酸的西方饮食(WD)和肠道微生物组的相关改变是否会破坏运动性，并导致氮能肌神经元(NMNs)的损失，这是糖尿病神经病变中常见的表型(Yarandi & Srinivasan, 2014)。其基本原理是，大多数研究使用的是高脂肪饮食(HFD;60-72%卡路里来自脂肪)，导致对正常WD如何影响GI运动，ENS及其在代谢综合征和糖尿病病理生物学中的作用知之甚少。C57BL/6小鼠分别饲喂WD(35%卡路里来自脂肪，富含棕榈酸酯)或常规饮食(RD, 16.9%卡路里来自脂肪，少4倍棕榈酸酯)3、6、9和12周，TLR4和无菌小鼠分别饲喂WD和RD饮食6周。测量胃肠道运动，研究回肠和结肠近端肌肠神经元和NMNs的损伤。在体外永生化肌肠神经元实验中，测定了棕榈酸酯和脂多糖诱导的NMNs损伤以及一氧化氮合酶(nNOS)在这种损伤中的作用。分析粪便代谢物、全身和内脏脂肪以及粘膜炎症。在摄入WD 6周后，小鼠“超重”，肠道微生物群失调，粪便代谢物改变，腔内LPS增加，血浆游离脂肪酸(FFA)水平增加。有趣的是，与HFD不同，WD不会引起高血糖、内毒素血症和炎症，这表明有必要确定HFD和WD对肠道微生物群和代谢谱的影响之间的关键差异。另一个重要的观察结果是，WD之前引起了胃肠道运动障碍
{"title":"Diet‐induced dysmotility and neuropathy in the gut precedes endotoxaemia and metabolic syndrome: the chicken and the egg revisited","authors":"Yvonne Nyavor, O. Balemba","doi":"10.1113/JP273888","DOIUrl":"https://doi.org/10.1113/JP273888","url":null,"abstract":"Neuropathy of the enteric nervous system (ENS) is one of the major underlying causes of debilitating gastrointestinal (GI) motility disorders in diabetic patients. Recent studies suggest that diet–microbiome–host interactions – in particular, excess dietary calories, microbial metabolites, lipopolysaccharide (LPS) and disrupted mucosal barrier – play a fundamental role in the pathobiology of obesity and type II diabetes (Boulangé et al. 2016). Furthermore, the composition of the GI microbiome influences ENS physiology, neurochemistry and nerve cell health, as well as GI motility patterns, and vice versa (Kashyap et al. 2013). However, links between such interactions and the mechanisms underlying this neuropathy are not fully understood. In this issue of The Journal of Physiology, Reichardt et al. (2017) address the question of whether ingesting a Western diet (WD) rich in saturated fatty acids and the associated alteration to the gut microbiome disrupts motility, and induces loss of nitrergic myenteric neurons (NMNs), the phenotype that is commonly damaged in diabetic neuropathy (Yarandi & Srinivasan, 2014). The rationale is that most studies have used a high fat diet (HFD; 60–72% kcal from fat), leading to little understanding of how a normal WD affects GI motility, the ENS and their role in the pathobiology of the metabolic syndrome and diabetes. The authors used C57BL/6 mice fed WD (35% kcal from fat, enriched in palmitate) or a regular diet (RD, 16.9% kcal from fat, 4× less palmitate) for 3, 6, 9 and 12 weeks, and TLR4 and germ free mice fed WD and RD diets for 6 weeks. Gastrointestinal motility was measured, and damage to myenteric neurons and NMNs was studied in the ileum and proximal colon. Palmitateand LPS-induced damage to NMNs and the role of nitric oxide synthase (nNOS) in such injury were determined in vitro using immortalized myenteric neurons. Faecal metabolites, systemic and visceral fat and mucosal inflammation were analysed. After ingesting WD for 6 weeks, mice were ‘overweight’, developed gut microbiota dysbiosis, altered faecal metabolites, increased intraluminal LPS and increased plasma free fatty acid (FFA) levels. Interestingly, unlike HFD, WD did not elicit hyperglycaemia, endotoxaemia and inflammation, suggesting the need to define key differences between the effect of HFD and WD on gut microbiome and metabolic profiles. Another important observation was that WD caused GI dysmotility before","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80765163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Voltage‐gated calcium channels represent the sole mechanism converting electrical signals of excitable cells into cellular functions such as contraction, secretion and gene regulation. Specific voltage‐sensing domains detect changes in membrane potential and control channel gating. Calcium ions entering through the channel function as second messengers regulating cell functions, with the exception of skeletal muscle, where CaV1.1 essentially does not function as a channel but activates calcium release from intracellular stores. It has long been known that calcium currents are dispensable for skeletal muscle contraction. However, the questions as to how and why the channel function of CaV1.1 is curtailed remained obscure until the recent discovery of a developmental CaV1.1 splice variant with normal channel functions. This discovery provided new means to study the molecular mechanisms regulating the channel gating and led to the understanding that in skeletal muscle, calcium currents need to be restricted to allow proper regulation of fibre type specification and to prevent mitochondrial damage.
{"title":"How and why are calcium currents curtailed in the skeletal muscle voltage‐gated calcium channels?","authors":"B. Flucher, Petronel Tuluc","doi":"10.1113/JP273423","DOIUrl":"https://doi.org/10.1113/JP273423","url":null,"abstract":"Voltage‐gated calcium channels represent the sole mechanism converting electrical signals of excitable cells into cellular functions such as contraction, secretion and gene regulation. Specific voltage‐sensing domains detect changes in membrane potential and control channel gating. Calcium ions entering through the channel function as second messengers regulating cell functions, with the exception of skeletal muscle, where CaV1.1 essentially does not function as a channel but activates calcium release from intracellular stores. It has long been known that calcium currents are dispensable for skeletal muscle contraction. However, the questions as to how and why the channel function of CaV1.1 is curtailed remained obscure until the recent discovery of a developmental CaV1.1 splice variant with normal channel functions. This discovery provided new means to study the molecular mechanisms regulating the channel gating and led to the understanding that in skeletal muscle, calcium currents need to be restricted to allow proper regulation of fibre type specification and to prevent mitochondrial damage.","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"1 1","pages":"1451 - 1463"},"PeriodicalIF":0.0,"publicationDate":"2017-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89026084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
E. Martinez‐Valdes, F. Negro, Christopher M. Laine, Deborah Falla, Frank Mayer, Dario Farina, Dario Farina
Classic motor unit (MU) recording and analysis methods do not allow the same MUs to be tracked across different experimental sessions, and therefore, there is limited experimental evidence on the adjustments in MU properties following training or during the progression of neuromuscular disorders. We propose a new processing method to track the same MUs across experimental sessions (separated by weeks) by using high‐density surface electromyography. The application of the proposed method in two experiments showed that individual MUs can be identified reliably in measurements separated by weeks and that changes in properties of the tracked MUs across experimental sessions can be identified with high sensitivity. These results indicate that the behaviour and properties of the same MUs can be monitored across multiple testing sessions. The proposed method opens new possibilities in the understanding of adjustments in motor unit properties due to training interventions or the progression of pathologies.
{"title":"Tracking motor units longitudinally across experimental sessions with high‐density surface electromyography","authors":"E. Martinez‐Valdes, F. Negro, Christopher M. Laine, Deborah Falla, Frank Mayer, Dario Farina, Dario Farina","doi":"10.1113/JP273662","DOIUrl":"https://doi.org/10.1113/JP273662","url":null,"abstract":"Classic motor unit (MU) recording and analysis methods do not allow the same MUs to be tracked across different experimental sessions, and therefore, there is limited experimental evidence on the adjustments in MU properties following training or during the progression of neuromuscular disorders. We propose a new processing method to track the same MUs across experimental sessions (separated by weeks) by using high‐density surface electromyography. The application of the proposed method in two experiments showed that individual MUs can be identified reliably in measurements separated by weeks and that changes in properties of the tracked MUs across experimental sessions can be identified with high sensitivity. These results indicate that the behaviour and properties of the same MUs can be monitored across multiple testing sessions. The proposed method opens new possibilities in the understanding of adjustments in motor unit properties due to training interventions or the progression of pathologies.","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"9 1","pages":"1479 - 1496"},"PeriodicalIF":0.0,"publicationDate":"2017-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86696060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Olusoji A. T. Afuwape, Catherine R. Wasser, T. Schikorski, E. Kavalali
Synaptic transmission is mediated by the release of neurotransmitters from synaptic vesicles in response to stimulation or through the spontaneous fusion of a synaptic vesicle with the presynaptic plasma membrane. There is growing evidence that synaptic vesicles undergoing spontaneous fusion versus those fusing in response to stimuli are functionally distinct. In this study, we acutely probe the effects of intravesicular free radical generation on synaptic vesicles that fuse spontaneously or in response to stimuli. By targeting vesicles that preferentially release spontaneously, we can dissociate the effects of intravesicular free radical generation on spontaneous neurotransmission from evoked neurotransmission and vice versa. Taken together, these results further advance our knowledge of the synapse and the nature of the different synaptic vesicle pools mediating neurotransmission.
{"title":"Synaptic vesicle pool‐specific modification of neurotransmitter release by intravesicular free radical generation","authors":"Olusoji A. T. Afuwape, Catherine R. Wasser, T. Schikorski, E. Kavalali","doi":"10.1113/JP273115","DOIUrl":"https://doi.org/10.1113/JP273115","url":null,"abstract":"Synaptic transmission is mediated by the release of neurotransmitters from synaptic vesicles in response to stimulation or through the spontaneous fusion of a synaptic vesicle with the presynaptic plasma membrane. There is growing evidence that synaptic vesicles undergoing spontaneous fusion versus those fusing in response to stimuli are functionally distinct. In this study, we acutely probe the effects of intravesicular free radical generation on synaptic vesicles that fuse spontaneously or in response to stimuli. By targeting vesicles that preferentially release spontaneously, we can dissociate the effects of intravesicular free radical generation on spontaneous neurotransmission from evoked neurotransmission and vice versa. Taken together, these results further advance our knowledge of the synapse and the nature of the different synaptic vesicle pools mediating neurotransmission.","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83425656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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