The Journal of Physiology最新文献

{"title":"Novel insights into the autonomous role played by vitamin D receptor in the regulation of skeletal muscle mass.","authors":"Tomer Jordi Chaffer, Jean-Philippe Leduc-Gaudet, Alaa Moamer, Felipe E Broering, Gilles Gouspillou, Sabah N A Hussain","doi":"10.1113/JP281211","DOIUrl":"https://doi.org/10.1113/JP281211","url":null,"abstract":"Tomer Jordi Chaffer1,2,3 , Jean-Philippe Leduc-Gaudet1,2,4 , Alaa Moamer1, Felipe E. Broering1,2, Gilles Gouspillou2,4 and Sabah N.A. Hussain1,2 1Meakins-Christie Laboratories and Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre, Department of Critical Care, McGill University Health Centre, Quebec, Canada 2Division of Experimental Medicine, McGill University, Quebec, Canada 3Department of Biology, AcadiaUniversity, Wolfville, Nova Scotia, Canada 4Département des sciences de l’activité physique, Faculté des Sciences, UQAM, Québec, Canada","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1955-1956"},"PeriodicalIF":5.5,"publicationDate":"2021-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38848074","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}

{"title":"Glial amplification of synaptic signals.","authors":"Kaoru Beppu,&nbsp;Naoko Kubo,&nbsp;Ko Matsui","doi":"10.1113/JP280857","DOIUrl":"https://doi.org/10.1113/JP280857","url":null,"abstract":"<p><strong>Key points: </strong>Recent studies have repeatedly demonstrated the cross-talk of heterogeneous signals between neuronal and glial circuits. Here, we investigated the mechanism and the influence of physiological interactions between neurons and glia in the cerebellum. We found that the cerebellar astrocytes, Bergmann glial cells, react to exogenously applied glutamate, glutamate transporter substrate (d-aspartate) and synaptically released glutamate. In response, the Bergmann glial cells release glutamate through volume-regulated anion channels. It is generally assumed that all of the postsynaptic current is mediated by presynaptically released glutamate. However, we showed that a part of the postsynaptic current is mediated by glutamate released from Bergmann glial cells. Optogenetic manipulation of Bergmann glial state with archaerhodpsin-T or channelrhodopsin-2 reduced or augmented the amount of glial glutamate release, respectively. Our data indicate that glutamate-induced glutamate release in Bergmann glia serves as an effective amplifier of excitatory information processing in the brain.</p><p><strong>Abstract: </strong>Transmitter released from presynaptic neurons has been considered to be the sole generator of postsynaptic excitatory signals. However, astrocytes of the glial cell population have also been shown to release transmitter that can react on postsynaptic receptors. Therefore, we investigated whether astrocytes take part in generation of at least a part of the synaptic current. In this study, mice cerebellar acute slices were prepared and whole cell patch clamp recordings were performed. We found that Bergmann glial cells (BGs), a type of astrocyte in the cerebellum, reacts to a glutamate transporter substrate, d-aspartate (d-Asp) and an anion conductance is generated and glutamate is released from the BGs. Glutamate release was attenuated or augmented by modulating the state of BGs with activation of light-sensitive proteins, archaerhodopsin-T (ArchT) or channelrhodopsin-2 (ChR2) expressed on BGs, respectively. Glutamate release appears to be mediated by anion channels that can be blocked by a volume-regulated anion channel-specific blocker. Synaptic response to a train of parallel fibre stimulation was recorded from Purkinje cells. The latter part of the response was also attenuated or augmented by glial modulation with ArchT or ChR2, respectively. Thus, BGs effectively function as an excitatory signal amplifier, and a part of the 'synaptic' current is actually mediated by glutamate released from BGs. These data show that the state of BGs have potential for having direct and fundamental consequences on the functioning of information processing in the brain.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"2085-2102"},"PeriodicalIF":5.5,"publicationDate":"2021-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25321924","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}

{"title":"Junctophilin-4 facilitates inflammatory signalling at plasma membrane-endoplasmic reticulum junctions in sensory neurons.","authors":"Alexandra Hogea,&nbsp;Shihab Shah,&nbsp;Frederick Jones,&nbsp;Chase M Carver,&nbsp;Han Hao,&nbsp;Ce Liang,&nbsp;Dongyang Huang,&nbsp;Xiaona Du,&nbsp;Nikita Gamper","doi":"10.1113/JP281331","DOIUrl":"https://doi.org/10.1113/JP281331","url":null,"abstract":"<p><strong>Key points: </strong>Rat somatosensory neurons express a junctional protein, junctophilin-4 (JPH4) JPH4 is necessary for the formation of store operated Ca²⁺ entry (SOCE) complex at the junctions between plasma membrane and endoplasmic reticulum in these neurons. Knockdown of JPH4 impairs endoplasmic reticulum Ca²⁺ store refill and junctional Ca²⁺ signalling in sensory neurons. In vivo knockdown of JPH4 in the dorsal root ganglion (DRG) sensory neurons significantly attenuated experimentally induced inflammatory pain in rats. Junctional nanodomain Ca²⁺ signalling maintained by JPH4 is an important contributor to the inflammatory pain mechanisms.</p><p><strong>Abstract: </strong>Junctions of endoplasmic reticulum and plasma membrane (ER-PM junctions) form signalling nanodomains in eukaryotic cells. ER-PM junctions are present in peripheral sensory neurons and are important for the fidelity of G protein coupled receptor (GPCR) signalling. Yet little is known about the assembly, maintenance and physiological role of these junctions in somatosensory transduction. Using fluorescence imaging, proximity ligation, super-resolution microscopy, in vitro and in vivo gene knockdown we demonstrate that a member of the junctophilin protein family, junctophilin-4 (JPH4), is necessary for the formation of store operated Ca²⁺ entry (SOCE) complex at the ER-PM junctions in rat somatosensory neurons. Thus we show that JPH4 localises to the ER-PM junctional areas and co-clusters with SOCE proteins STIM1 and Orai1 upon ER Ca²⁺ store depletion. Knockdown of JPH4 impairs SOCE and ER Ca²⁺ store refill in sensory neurons. Furthermore, we demonstrate a key role of the JPH4 and junctional nanodomain Ca²⁺ signalling in the pain-like response induced by the inflammatory mediator bradykinin. Indeed, an in vivo knockdown of JPH4 in the dorsal root ganglion (DRG) sensory neurons significantly shortened the duration of nocifensive behaviour induced by hindpaw injection of bradykinin in rats. Since the ER supplies Ca²⁺ for the excitatory action of multiple inflammatory mediators, we suggest that junctional nanodomain Ca²⁺ signalling maintained by JPH4 is an important contributor to the inflammatory pain mechanisms.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"2103-2123"},"PeriodicalIF":5.5,"publicationDate":"2021-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25356403","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}

{"title":"Keeping pain away by distancing the plasma membrane from the endoplasmic reticulum.","authors":"Tibor Rohacs","doi":"10.1113/JP281480","DOIUrl":"https://doi.org/10.1113/JP281480","url":null,"abstract":"Cytoplasmic Ca2+ signals regulate many biological processes, including muscle contraction, neurotransmitter release and hormone secretion. The two major sources of increased cytoplasmic Ca2+ are the extracellular space and the endoplasmic reticulum (ER). In many cell types, there is an intricate crosstalk between the ER, or equivalent intracellular membrane compartments, and the plasma membrane in regulating Ca2+ homeostasis. One classical example is the skeletal muscle, where the action potential initiated in the plasma membrane travels down the T-tubule and activates voltage gated Ca2+ channels (dihydropyridine receptors), which in turn activate the Ca2+ release channel ryanodine receptors via protein-protein interaction in the membrane of the sarcoplasmic reticulum (SR) (Fig. 1A). This signalling mechanism requires the maintenance of the physical proximity between the SR and the T-tubule. This is achieved by various adaptor proteins, including junctophilin-1 (Landstrom et al. 2014), which bridges the gap between the two membranes and keeps them together (Fig. 1A). Another more recently discovered signalling paradigm where the close proximity of the plasma membrane and the ER is critical is the store operatedCa2+ entry through Orai1 channels. Plasma membrane receptors that couple to heterotrimeric Gq proteins, activate phospholipase C enzymes leading to the formation of the second messenger inositol 1,4,5 trisphosphate (IP3). IP3 binds to its receptor in the ER, which leads to the release of Ca2+ to the cytoplasm, and to decreased Ca2+ content in the ER. The decrease in ER Ca2+ is sensed by STIM1 proteins, which aggregate and move closer to the plasma membrane, and activate Orai1 channels by protein-protein interaction (Woo et al. 2018) (Fig. 1B). This signalling mechanism was also shown to require various adaptor proteins that stabilize the plasmamembrane ER junctions (Woo et al. 2018). One of these proteins is junctophilin-4, which was shown to regulate Ca2+ dynamics in T-lymphocytes (Woo et al. 2016) (Fig. 1B). Store operated Ca2+ entry was originally described in non-excitable cells such as epithelial cells and T-lymphocytes. However, its role is emerging in a variety of excitable cells, including peripheral sensory neurons of the dorsal root ganglia (DRG), where it has been shown to regulate nociception, the detection of painful stimuli (Munoz & Hu, 2016). In this issue of The Journal of Physiology, Hogea et al. (2021) address the role of junctophilins in nociceptive DRG neurons. The authors stained rat DRG neurons with antibodies against all four junctophilin isoforms (JPH1-4), and identified junctophilin-4 as the dominant isoform, with some expression of JPH1 and JPH3, but not JPH2. Importantly, JPH4 showed a high degree of co-expression with STIM1","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1941-1942"},"PeriodicalIF":5.5,"publicationDate":"2021-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016710/pdf/nihms-1679687.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25411153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MET currents and otoacoustic emissions from mice with a detached tectorial membrane indicate the extracellular matrix regulates Ca²⁺ near stereocilia.","authors":"Jing-Yi Jeng, Csaba Harasztosi, Adam J Carlton, Laura F Corns, Philine Marchetta, Stuart L Johnson, Richard J Goodyear, Kevin P Legan, Lukas Rüttiger, Guy P Richardson, Walter Marcotti","doi":"10.1113/JP280905","DOIUrl":"10.1113/JP280905","url":null,"abstract":"<p><strong>Key points: </strong>The aim was to determine whether detachment of the tectorial membrane (TM) from the organ of Corti in Tecta/Tectb^-/- mice affects the biophysical properties of cochlear outer hair cells (OHCs). Tecta/Tectb^-/- mice have highly elevated hearing thresholds, but OHCs mature normally. Mechanoelectrical transducer (MET) channel resting open probability (P_o ) in mature OHC is ∼50% in endolymphatic [Ca²⁺ ], resulting in a large standing depolarizing MET current that would allow OHCs to act optimally as electromotile cochlear amplifiers. MET channel resting P_o in vivo is also high in Tecta/Tectb^-/- mice, indicating that the TM is unlikely to statically bias the hair bundles of OHCs. Distortion product otoacoustic emissions (DPOAEs), a readout of active, MET-dependent, non-linear cochlear amplification in OHCs, fail to exhibit long-lasting adaptation to repetitive stimulation in Tecta/Tectb^-/- mice. We conclude that during prolonged, sound-induced stimulation of the cochlea the TM may determine the extracellular Ca²⁺ concentration near the OHC's MET channels.</p><p><strong>Abstract: </strong>The tectorial membrane (TM) is an acellular structure of the cochlea that is attached to the stereociliary bundles of the outer hair cells (OHCs), electromotile cells that amplify motion of the cochlear partition and sharpen its frequency selectivity. Although the TM is essential for hearing, its role is still not fully understood. In Tecta/Tectb^-/- double knockout mice, in which the TM is not coupled to the OHC stereocilia, hearing sensitivity is considerably reduced compared with that of wild-type animals. In vivo, the OHC receptor potentials, assessed using cochlear microphonics, are symmetrical in both wild-type and Tecta/Tectb^-/- mice, indicating that the TM does not bias the hair bundle resting position. The functional maturation of hair cells is also unaffected in Tecta/Tectb^-/- mice, and the resting open probability of the mechanoelectrical transducer (MET) channel reaches values of ∼50% when the hair bundles of mature OHCs are bathed in an endolymphatic-like Ca²⁺ concentration (40 μM) in vitro. The resultant large MET current depolarizes OHCs to near -40 mV, a value that would allow optimal activation of the motor protein prestin and normal cochlear amplification. Although the set point of the OHC receptor potential transfer function in vivo may therefore be determined primarily by endolymphatic Ca²⁺ concentration, repetitive acoustic stimulation fails to produce adaptation of MET-dependent otoacoustic emissions in vivo in the Tecta/Tectb^-/- mice. Therefore, the TM is likely to contribute to the regulation of Ca²⁺ levels around the stereocilia, and thus adaptation of the OHC MET channel during prolonged sound stimulation.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"2015-2036"},"PeriodicalIF":0.0,"publicationDate":"2021-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612128/pdf/EMS140585.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25347726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Three challenges of being a scientist in an age of misinformation.","authors":"Lykke Sylow","doi":"10.1113/JP281434","DOIUrl":"https://doi.org/10.1113/JP281434","url":null,"abstract":"Policy and life choices rely on accurate and credible information (Scheufele andKrause, 2019), yet there is a growing concern about the spread and consumption of information that is either patently false or misleading. Once planted, misinformation is difficult to debunk as exemplified by the falsely proposed link between the measles, mumps and rubella vaccine and autism (Kotwal and Ansari, 2012) – misinformation that is now considered one of the world’s most pressing public health issues by the World Health Organization. In many ways, we are in a perfect storm of rapidly changing social media news environments, political polarization, and societal debates in which scientific facts have a hard time competing with misinformation and misleading claims. And to put the punch line first: science alone cannot navigate us out of this storm. But we can avoid making things worse. Toward that end, this editorial considers three challenges of being a scientist in an age of misinformation and what we can do about it. But why do we, as scientists, engage in public communication in the first place, especially during global pandemics like COVID-19? One goal, of course, is to inform the public. Science cannot determine public policy, but at the very least it should inform the choices of citizens and policymakers. A second goal of scientists connecting directly with the public is to maintain or build public trust, especially as it is under assault by populist leaders, as has been the case recently in some countries where policymaking is not informed by the best available science. A third and somewhat unique challenge is when scientists try to battle public reluctance to wearmasks or vaccinate, i.e. to influence behaviours that are often separate from the need for people to understand the science behind their choices. None of these challenges are ones that the scientific community can solve by itself. Solutions will require collaborations across policy, (social) science, public health and many practitioner communities, ranging from museums to science filmmakers. At the same time, science has made avoidable missteps. In other words, we as scientists might inadvertently contribute to misinformation due to three major challenges facing scientists in the communication of our results.","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1937-1938"},"PeriodicalIF":5.5,"publicationDate":"2021-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25339211","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}

{"title":"Divergence of neuroimmune circuits activated by afferent and efferent vagal nerve stimulation in the regulation of inflammation.","authors":"Kaitlin Murray,&nbsp;Kavi M Rude,&nbsp;Jessica Sladek,&nbsp;Colin Reardon","doi":"10.1113/JP281189","DOIUrl":"https://doi.org/10.1113/JP281189","url":null,"abstract":"<p><strong>Key points: </strong>It has previously been shown that afferent and efferent vagal nerve stimulation potently inhibits lipopolysaccharide (LPS)-induced inflammation Our data show inhibition of inflammation by efferent but not afferent vagal nerve stimulation requires T-cell derived acetylcholine We show that afferent and efferent neuroimmune circuits require β₂ -adrenergic receptor signalling ABSTRACT: Chronic inflammation due to inappropriate immune cell activation can have significant effects on a variety of organ systems, reducing lifespan and quality of life. As such, highly targeted control of immune cell activation is a major therapeutic goal. Vagus nerve stimulation (VNS) has emerged as a therapeutic modality that exploits neuroimmune communication to reduce immune cell activation and consequently inflammation. Although vagal efferent fibres were originally identified as the primary driver of anti-inflammatory actions, the vagus nerve in most species of animals predominantly comprises afferent fibres. Stimulation of vagal afferent fibres can also reduce inflammation; it is, however, uncertain how these two neuroimmune circuits diverge. Here we show that afferent VNS induces a mechanism distinct from efferent VNS, ameliorating lipopolysaccharide (LPS)-induced inflammation independently of T-cell derived acetylcholine (ACh) which is required by efferent VNS. Using a β₂ -adrenergic receptor antagonist (β₂ -AR), we find that immune regulation induced by intact, afferent, or efferent VNS occurs in a β_2- AR-dependent manner. Together, our findings indicate that intact VNS activates at least two distinct neuroimmune circuits each with unique mechanisms of action. Selective targeting of either the vagal efferent or afferent fibres may provide more personalized, robust and effective control over inappropriate immune responses.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"2075-2084"},"PeriodicalIF":5.5,"publicationDate":"2021-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016722/pdf/nihms-1675278.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38777446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acid glia provide a synaptic boost.","authors":"Rheinallt Parri","doi":"10.1113/JP281436","DOIUrl":"https://doi.org/10.1113/JP281436","url":null,"abstract":"Astrocytes are intimately involved in synaptic transmission in the brain. Not only do they control glutamate signalling by the action of astrocyte-expressed glutamate transporters, they also release gliotransmitters such as ATP, adenosine and glutamate. These can act preor postsynaptically to affect shortand long-term synaptic modulation and plasticity (Santello et al. 2019). As the main brain neuro-transmitter, much focus has been on glutamate as a gliotransmitter. Notably, in brain areas associated with learning and memory such as the hippocampus and neocortex, this has led to the discovery of central roles for glutamate gliotransmitter in synaptic long-term potentiation and depression by its targeting of neuronal NMDA receptors. Despite this focus, there is much debate on the mechanism of glutamate release with studies presenting evidence for vesicular and channel-mediated release. Now Beppu et al. (2021) describe a novel mechanism by which gliotransmitter glutamate release from Bergmann glia, a specialised type of astrocyte in the cerebellum boosts postsynaptic glutamatemediated current. Recording from Purkinje neurons in the molecular layer of the cerebellum and stimulating parallel fibres that release glutamate to induce an AMPA receptor-mediated postsynaptic current, they found that optogenetic activation of ArchT expressed in Bergmann glia reduced the postsynaptic AMPA current, indicating that the glia were releasing glutamate during synaptic transmission. To determine the mechanism, the authors used a combination of Glial and neuronal patch-clamp recordings, optogenetic stimulation and localised agonist uncaging. Local glutamate application in the molecular layer elicited an inward, mostly AMPAR-mediated current in neurons as expected. Activation of ArchT in glia before glutamate activation led to a decrease in the neuron AMPAR response indicating that the AMPAR neuronal component was composed of a direct neuronal effect and a secondary effect mediated by glutamate release from glia. However, when specific agonist AMPA was locally applied in the same way, there was no additional glial-derived component. In contrast, d-aspartate application which is not an AMPA agonist resulted in neuronal inward current that was mediated via AMPA receptors. This nicely illustrates that glutamate is acting on different cellular targets; AMPA receptors in neurons, non-AMPA d-aspartate target in glia. ArchT is a light-activated H+/Na+ exchanger that results in intracellular alkalisation (Beppu et al. 2014). Its effect when expressed in the Bergmann glia therefore implicated a pH change as a trigger for glutamate release. This was supported by the use of Channelrhodopsin-2 (ChR2), which upon light activation permeates H+ into the glial cell leading to acidification. As would be predicted, glial ChR2 activation enhanced neuronal recorded glutamate current. d-Aspartate is a substrate for glutamate uptake transporters and also an NMDA receptor agonist. Blocking","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1939-1940"},"PeriodicalIF":5.5,"publicationDate":"2021-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25373129","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}

{"title":"Ketamine: yay or neigh? Implications for cardiovascular regulation and considerations for field use.","authors":"Lindsey F Berthelsen","doi":"10.1113/JP281254","DOIUrl":"https://doi.org/10.1113/JP281254","url":null,"abstract":"In a prehospital setting, pain management following traumatic injury is an important consideration in both military and civilian contexts. Traditionally, opioids (e.g. fentanyl) are administered to help manage pain; however, their use may result in altered cardiovascular and neural function. Furthermore, development of opioid addiction following analgesic use may contribute to an increasing incidence of opioid abuse, overdose, and death in North America. Ketamine, an NMDA receptor antagonist, has emerged as a promising alternative treatment. Previous work in humans has shown that, in anaesthetic doses, ketamine does not negatively affect the neural response to acute hypotension induced via sodium nitroprusside injection (Kienbaum et al. 2000). Furthermore, low (i.e. subanaesthetic) dose ketamine has been shown to be effective at reducing acute pain sensation during a cold pressor test (CPT) (Watso et al. 2020). Collectively, these two studies indicate that sympathetic reactivity to both hypotension (Kienbaum et al. 2000) and hypertension (Watso et al. 2020) remains intact with ketamine administration. However, the effects of lowdose ketamine on tolerance to haemorrhage remain unclear, and this has important implications for pain management and ultimately survival following trauma in a field setting. The recent paper by Huang et al. (2020) in The Journal of Physiology provides novel insights on the effects of low-dose ketamine on the cardiovascular and neural response to experimentally induced central hypovolaemia. Huang et al. (2020) employed lower body negative pressure (LBNP) as an experimental model to simulate haemorrhage. Lower body negative pressure induces central hypovolaemia via fluid redistribution from the upper limbs and abdominal region to the lower extremities, resulting in decreased venous return, and an increase in baroreflex-mediated sympathetic nerve activity to maintain blood pressure. Huang et al. (2020) collected measurements of mean arterial pressure (MAP), heart rate and radial nerve muscle sympathetic nerve activity (MSNA) and also obtained blood samples to analyse for circulating catecholamines under: (i) control conditions (saline injection) and (ii) following ketamine injection. Over these two independent and randomized trials, participants completed a ramped LBNP protocol, starting at 40 mmHg of LBNP, and increased the severity of LBNP by 10 mmHg every 3 min until reaching a maximum LBNP of 100 mmHg or until participant reached presyncope. Maximal LBNP tolerance was determined experimentally using a cumulative stress index and compared between control and ketamine conditions. Despite a similar tolerance and MSNA response to LBNP between control and ketamine conditions, MAP and heart rate were generally elevated during the ketamine trial, indicating an uncoupling between sympathetic outflow and the cardiovascular response. Although this elegant study by Huang et al. (2020) will undoubtedly serve as a solid foundation fo","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1949-1950"},"PeriodicalIF":5.5,"publicationDate":"2021-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38757097","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}

{"title":"Intermittent hypercapnic hypoxia: a model to study human respiratory motor plasticity?","authors":"Joseph F Welch","doi":"10.1113/JP281129","DOIUrl":"https://doi.org/10.1113/JP281129","url":null,"abstract":"Once considered a fixed system operating solely via closed-loop negative chemofeedback, it is now widely appreciated that the respiratory control system exhibits considerable plasticity that facilitates robust homeostatic (blood-gas) regulation. A well-studied model of respiratory motor plasticity is phrenic long-term facilitation (LTF). Phrenic LTF describes sustained augmentation of phrenic nerve activity following repeated exposure to brief periods of low oxygen (i.e. intermittent hypoxia [IH]). The prolonged increase in phrenic nerve activity in response to IH is caused by episodic activation of carotid chemoafferent neurons. Distinct from the phenomenon originally referred to as phrenic ‘afterdischarge’ (Eldridge & Millhorn, 1986), IH-induced phrenic LTF is pattern sensitive and serotonin dependent. Upon activation of Hering’s nerve, brainstem raphe nuclei release serotonin on or near phrenic motor neurons in the cervical spinal cord. Binding of serotonin with Gq-coupled 5-HT2 receptors initiates intracellular signalling cascades resulting in de novo synthesis of brain-derived neurotrophic factor, ultimately leading to enhanced glutamatergic synaptic transmission/respiratory motor output (Fuller & Mitchell, 2017). Grounded in knowledge acquired from decades of rodent experiments, attempts to replicate phrenic LTF in humans have typically used changes in minute ventilation (V̇I, ventilatory LTF) as a surrogate for phrenic nerve activity. However, demonstration of ventilatory LTF has proven difficult as variations in experimental approaches (e.g. sleep versus wakefulness, duration and severity of hypoxic intervals, influence of CO2) have yielded conflicting results and confusion over the conditions necessary to induce and observe LTF. Nevertheless, it is evident that careful control of CO2 during and following IH is a critical feature of LTF expression. For example, when CO2 is variable (poikilocapnia), LTF is not observed. Conversely, when CO2 is raised slightly (∼5 mmHg) above eupnoeic levels (including baseline and post-IH recovery), LTF is revealed. In addition to phrenic/ventilatory LTF, IH also elicits plasticity at the carotid body and nucleus of the solitary tract. Long-lasting activation of sensory (peripheral chemoreceptor) discharge following IH is observed in rats preconditioned with chronic IH (Peng et al. 2003) and in reduced preparations exposed to IHwith concurrent hypercapnia (Roy et al. 2018). This form of sensory LTF may contribute to ventilatory LTF under certain circumstances. In a study recently published in The Journal of Physiology, Vermeulen et al. (2020) tested the hypothesis that IH, consisting of hypercapnic and hypoxic intervals (IHH), elicits an increase in V̇I that persists beyond the stimulus period (i.e. ventilatory LTF). It was further hypothesised that ventilatory LTF is mediated, in part, by increased tonic peripheral chemoreceptor activity (i.e. sensory LTF). Nineteen healthy adult males and females (age= 2","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1951-1953"},"PeriodicalIF":5.5,"publicationDate":"2021-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38848550","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}