Journal of Physiology-London最新文献

{"title":"Ketogenic diet and ketone salts differentially improve cardiometabolic complications in an HFpEF rat model.","authors":"Alexandre Gonçalves, Inês N Alves, Cláudia Mendes, Daniela Miranda, Glória Conceição, João Almeida-Coelho, Diana Martins, Isabel Miranda, Alexandre Rodrigues, Carolina Silva, Sandra Marisa Oliveira, José Sereno, Maria João Ferreira, Ulrich Dischinger, Henrique Girão, Adelino F Leite-Moreira, Vasco Sequeira, Inês Falcão-Pires","doi":"10.1113/JP288229","DOIUrl":"https://doi.org/10.1113/JP288229","url":null,"abstract":"<p><p>Heart failure with preserved ejection fraction (HFpEF) remains a major health concern with limited therapeutic options. Growing evidence supports the multiple benefits of ketones in heart disease, but their impact on HFpEF remains unknown. We investigated whether increasing ketones can help to manage HFpEF. Using the ZSF1 rat model of HFpEF, 16-week-old rats were randomly assigned to one of three subgroups: (i) control diet; (ii) ketogenic diet (KD); or (iii) control diet with added exogenous ketone salts (KS) in their drinking water for 10 weeks. We found that both KD and KS ameliorated the HFpEF phenotype by improving structural echocardiographic parameters, lowering glycaemia and lipid profiles, and reducing HFpEF-related fibrosis and hypertrophy without impacting in vivo diastolic function. Nevertheless, ex vivo cardiomyocyte preparations showed improved calcium handling and myofilament relaxation, suggesting benefits at the cellular level. Interestingly, KD still proved effective, despite the potentially adverse increase in fat mass. There was decreased myofilament Ca²⁺ sensitivity and normalized active and passive tension in both groups, especially KS. These results suggest that providing ketone through the diet or supplements could be a valuable strategy to complement HFpEF treatment. Given the well-known challenges of implementing dietary changes, exogenous KS offer a more practical and effective option to achieve these benefits. KEY POINTS: Ketogenic diet and ketone salts effectively reversed the cardiac structural impairments associated with the ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype by ameliorating left ventricular mass. Both treatments reduced fibrosis and hypertrophy, leading to improved or, in the case of ketone salts, even reversed cardiomyocyte contractile and relaxation performance. Ketone salts also reversed HFpEF-related cardiomyocyte stiffness and prevented a reduction in the development of maximum force. Both treatments improved myofilament Ca²⁺ sensitivity. Both treatments also improved the metabolic profile, reducing hyperglycaemia, blood triglycerides and levels of NT-proBNP, a well-known biomarker of worsening heart failure.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corticothalamic modulation of somatosensory thalamic tactile processing.","authors":"Avisar Einav, Rony Azouz","doi":"10.1113/JP287526","DOIUrl":"https://doi.org/10.1113/JP287526","url":null,"abstract":"<p><p>The brain's processing of sensory information involves intricate interactions between feedforward and feedback pathways, including corticothalamic feedback. Although feedback from cortical Layer 6 to the sensory thalamus is known to regulate sensory signalling, its precise function remains elusive. This study delves into the impact of Layer 6 feedback on sensory transmission in the ventral posteromedial nucleus using in vivo electrophysiology recordings in lightly anesthetized rats. By local administration of drugs to the barrel cortex during thalamic recordings, we investigate how corticothalamic neurons influence the transformation of tactile stimuli into neuronal discharge characteristics. Our findings reveal that increasing cortical dynamics enhances thalamic response magnitude at low stimulus intensities but decreases it at high intensities, whereas reducing cortical dynamics produces the opposite effect. Moreover, we observe bidirectional cortical influence on thalamic neurons extending to stimulus magnitude-dependent sensory adaptation and burst propensity modulation by Layer 6 dynamics. Specifically, increased cortical dynamics reduce thalamic sensory adaptation and increase burst propensity at low stimulus intensities, with no observed change at high intensities, whereas decreased cortical dynamics elicit opposite effects. We show that thalamic neurons can discriminate between stimuli, with cortical influence varying by stimulus intensity. Increased cortical dynamics enhances discrimination at low intensities, whereas reduced dynamics has the opposite effect. Our findings suggest that cortical control of ventral posteromedial nucleus tactile transformation is not a binary switch but a dynamic modulator, adjusting thalamic transformations in real time based on cortical dynamics. This mechanism finely tunes sensory processing to meet environmental and behavioural demands. KEY POINTS: The study investigates touch processing in the brain by examining interactions between brain regions. Specifically, we study how cortical Layer 6 influences sensory signal processing in the thalamus. We manipulated Layer 6 activity with drugs and observed resulting changes in thalamic touch responses. Increased cortical activity enhanced weak touch signals but dampened strong ones in the thalamus; lower activity had the opposite effect. Increased cortical dynamics reduced thalamic sensory adaptation and increased burst propensity at low stimulus intensities, with no change at high intensities. The study shows that the brain's control over how it processes sensory information is not just an on/off switch but a dynamic system that adjusts in real time to different situations.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143773577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The complex nature of blood pressure control during rest and exercise in humans: The role of the carotid chemoreflex.","authors":"Jason H Mateika","doi":"10.1113/JP288705","DOIUrl":"https://doi.org/10.1113/JP288705","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143773962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vestibular contribution to motor output is also suppressed by voluntary action of the arm.","authors":"Angelo Bartsch-Jiménez, Francisco J Valero-Cuevas","doi":"10.1113/JP287077","DOIUrl":"https://doi.org/10.1113/JP287077","url":null,"abstract":"&lt;p&gt;&lt;p&gt;The vestibular sensory system is among the oldest and most fundamental contributors to motor behaviour as it is critical to maintaining posture and balance. However such low-level motor responses could interfere with cortically mediated voluntary behaviour that naturally involves posture and balance. Consequently, it has been proposed that - much like the inhibition of reflex responses - vestibular contributions to motor output are 'gated' (dubbed vestibular suppression) to avoid undesirable self-perturbations during voluntary head movements. Here we demonstrate that such suppression also occurs for unperturbed voluntary arm function. Our evidence comes from comparing coherence at baseline (No Stimulation) and after Sham and Galvanic Vestibular Stimulation (GVS). Specifically neck muscles showed shared neural drive (intermuscular coherence [IMC]), which increased with GVS - but not Sham - at Rest. This GVS-mediated increased coherence in neck muscles, however, was suppressed during voluntary isometric contractions and reaching movements of the arm on the same side as the GVS was applied. No changes were found in pairwise IMC during Sham (compared with No stimulation) or in arm muscles either at rest or during voluntary movement during GVS in neurotypical adults. In addition to extending vestibular suppression to unperturbed voluntary arm function, these results provide support for the common (yet unproven to our knowledge) notion that arm muscles do not receive vestibular neural drive during unperturbed voluntary movement. Moreover, these results shed light on the mechanisms that mediate competing descending outputs for voluntary function and serve as a baseline against which to compare potential task-dependent dysregulation of vestibular-mediated output to the neck and arms in stroke and neurological conditions. KEY POINTS: The vestibular system is critical for correcting perturbations during voluntary movement. During voluntary head movements, vestibular suppression occurs to avoid undesirable self-perturbations. However, the contribution of the vestibular system to unperturbed voluntary arm movement remains unclear. We used intermuscular coherence (IMC) to measure vestibulospinal drive to neck and arm muscles while applying Galvanic Vestibular Stimulation (GVS), Sham and No Stimulation. We compared IMC at Rest and unperturbed voluntary movement of the arm in neurotypical adults. Neck muscles showed increased shared neural drive at rest, only when GVS was applied. However, vestibular drive was suppressed during unperturbed voluntary isometric contractions and reaching movements of the arm. Vestibular drive to arm muscles did not increase when GVS was applied. We provide evidence that arm muscles do not receive vestibulospinal drive, excluding its contribution to unperturbed voluntary movement. These results could provide valuable insights into the vestibular contribution to motor impairments following neurological conditions such as strok","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143773979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sensory deception during cycling: The truth prevails in a virtual world.","authors":"Nathan E Bartman, Georgia Charachousou, Eric E Corrêa Rodrigues, Mohamed B Amara","doi":"10.1113/JP288674","DOIUrl":"https://doi.org/10.1113/JP288674","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"7 Tesla magnetic resonance spectroscopy estimates of GABA concentration relate to physiological measures of tonic inhibition in the human motor cortex.","authors":"Ilenia Paparella, Paolo Cardone, Benedetta Zanichelli, Laurent Lamalle, Fabienne Collette, Siya Sherif, Mikhail Zubkov, William T Clarke, Charlotte J Stagg, Pierre Maquet, Gilles Vandewalle","doi":"10.1113/JP287311","DOIUrl":"https://doi.org/10.1113/JP287311","url":null,"abstract":"<p><p>GABAergic neurotransmission within the cortex plays a key role in learning and is altered in several brain diseases. Quantification of bulk GABA in the human brain is typically obtained by magnetic resonance spectroscopy (MRS). However, the interpretation of MRS-GABA is still debated. A recent mathematical simulation contends that MRS detects extrasynaptic GABA, mediating tonic inhibition. Nevertheless, no empirical data have yet confirmed this hypothesis. Here we collected ultra-high-field 7 Tesla MRS and transcranial magnetic stimulation coupled with high-density electroencephalography (TMS-hdEEG) from the motor cortex of 20 healthy participants (age 23.95 ± 6.4 years), while they were at rest. We first applied a neural mass model (NMM) to TMS-evoked potentials to disentangle the contribution of different GABAergic pools. We then assessed to which of these different pools MRS-GABA was related to by means of parametric empirical Bayesian (PEB) analysis. We found that MRS-GABA was mostly positively related to the NMM-derived measures of tonic inhibition and overall functionality of the GABAergic synapse. This relationship was reliable enough to predict MRS-GABA from NMM-GABA. These findings clarify the mesoscopic underpinnings of GABA levels measured by MRS. Our work will help fulfil the promises of MRS-GABA, enhancing our understanding of human behaviour, brain physiology and pathophysiology. KEY POINTS: GABA neurotransmission is essential for synaptic plasticity and learning (especially motor learning) and is altered in several brain disorders, such as epilepsy and stroke. Quantification of GABA in the human brain is typically obtained by magnetic resonance spectroscopy (MRS). However, the interpretation of MRS-GABA is still debated. By using a biophysical neural mass model, here we show that MRS-GABA relates to physiological measures of tonic inhibition in the human cortex.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143774709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of TRPA1 and TRPM3 triggers Ca²⁺ waves in central terminals of sensory neurons and facilitates synaptic activity in the spinal dorsal horn.","authors":"Yaroslav E Andrianov, Alex L Keyes, Charles A Warwick, Miriam C McDonough, Leonid P Shutov, Kavita S Solanki, Jon M Resch, Alexander G Bassuk, Nana Voitenko, Pavel Belan, Yuriy M Usachev","doi":"10.1113/JP286407","DOIUrl":"https://doi.org/10.1113/JP286407","url":null,"abstract":"<p><p>Transient receptor potential ankyrin 1 (TRPA1) and melastatin 3 (TRPM3) are transduction channels of sensory neurons that play major roles in peripheral mechanisms of somatosensation, including thermosensation, chemosensation and nociception. Recent studies suggest that both channels also contribute to central mechanisms of pain processing at the spinal cord level. TRPA1 and TRPM3 are highly permeable for Ca²⁺, suggesting that they could regulate Ca²⁺ signalling at spinal synapses. However, information about TRPA1- and TRPM3-induced Ca²⁺ signalling in the dorsal horn (DH) of the spinal cord is lacking. Here, we describe a dual-colour technique for simultaneously measuring Ca²⁺ concentration ([Ca²⁺]_i) in central terminals of sensory neurons and in spinal DH neurons by green (GCaMP3) and red (jRGECO1a) Ca²⁺ indicators, using two-photon imaging in isolated mouse spinal cord with attached dorsal roots (DR). DR stimulation elicited [Ca²⁺]_i transients in axonal boutons of primary afferents and in cell bodies of DH neurons. The antagonists of AMPA and NMDA glutamate receptors, CNQX and AP5, inhibited [Ca²⁺]_i transients in DH neurons, but not in sensory axonal boutons. Selective agonists of TRPA1 and TRPM3, ASP7663 and CIM0216, induced complex [Ca²⁺]_i responses in distinct but partially overlapping subsets of sensory axonal boutons. Concomitant [Ca²⁺]_i elevations were observed in DH neurons, which were blocked by CNQX and AP5. Patch clamp recordings from DH neurons showed that ASP7663 and CIM0216 markedly enhanced excitatory synaptic activity. In summary, our findings suggest that TRPA1 and TRPM3 on central terminals of sensory neurons regulate presynaptic [Ca²⁺]_i and synaptic transmission in the spinal DH. KEY POINTS: Transient receptor potential ankyrin 1 (TRPA1) and melastatin 3 (TRPM3) are transduction channels of sensory neurons that play major roles in peripheral mechanisms of somatosensation and central mechanisms of pain processing. These two receptors are highly permeable for Ca²⁺, suggesting that they could regulate Ca²⁺ signalling at spinal synapses. This study uses a dual-colour technique to simultaneously measure Ca²⁺ changes in response to electrical and chemical stimulation in the central terminals of sensory neurons and in spinal dorsal horn neurons in an intact, ex vivo spinal cord with attached dorsal roots. Selective agonists of TRPA1 and TRPM3 induced complex Ca²⁺ responses in sensory boutons and evoked synaptically-driven Ca²⁺ changes in dorsal horn neurons. These results help us to better understand TRPA1 and TRPM3 mediated synaptic transmission in the spinal cord, potentially explaining the role of these channels in pain processing.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143765598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise-induced signalling in alleviating neuronal insulin resistance.","authors":"Ishitha Reddy, Chinmoy Sankar Dey","doi":"10.1113/JP287750","DOIUrl":"https://doi.org/10.1113/JP287750","url":null,"abstract":"<p><p>Exercise contributes to a multitude of positive changes within the body and brain with regard to glucose homeostasis, insulin sensitivity, synaptic plasticity, neuroprotection and neurogenesis, among other effects. It provides a non-pharmaceutical alternative for addressing metabolic disorders in individuals with type 2 diabetes, who also face an increased risk of developing Alzheimer's disease. A number of molecules are evoked upon exercise and circulate through the bloodstream, transmitting the wide-reaching advantages of exercise. The ensuing cross-talk has been shown to improve conditions associated with Alzheimer's disease. The vast signalling network mediated by exercise is currently being studied extensively and its implications in improving neuronal insulin resistance, especially as a bypass mechanism, are of major interest. Taking into account sirtuin 1/peroxisome proliferator-activated receptor γ co-activator 1-α, AMP-activated protein kinase, phosphoinositide 3-kinase/AKT, phospholipase C-γ and brain-derived neurotrophic factor/tropomyosin receptor kinase B among many pathways and cross-interactions involved, researching the molecular characteristics of brain exercise signalling and the mechanisms by which it compensates for hampered signalling is crucial for future research.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143773960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin: a lifeline for cardiac dysfunction in hypoxic pregnancy.","authors":"Salman Ahmad","doi":"10.1113/JP288323","DOIUrl":"https://doi.org/10.1113/JP288323","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise-induced plasma mature brain-derived neurotrophic factor elevation in children, adolescents and adults: influence of age, maturity and physical activity.","authors":"Sebastian Edman, Julia Starck, Linnéa Corell, William Hangasjärvi, Amelie von Finckenstein, Mikael Reimeringer, Stefan Reitzner, Jessica Norrbom, Marcus Moberg, Ferdinand von Walden","doi":"10.1113/JP288170","DOIUrl":"https://doi.org/10.1113/JP288170","url":null,"abstract":"<p><p>Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a central role in neuronal health. BDNF exists in two primary isoforms, the mature form (mBDNF) and its precursor (proBDNF), with opposing downstream effects on neuronal function. The positive effect of exercise on plasma levels of the BDNF isoforms has been extensively studied in adults. However, equivalent investigations are lacking in children and adolescents. Twenty healthy children (9-12 years old), 19 adolescents (13-17 years old) and 39 adults (23-49 years old) donated venous blood before and after a 45-minute run. Platelet-poor plasma was analysed for pro- and mBDNF using an enzyme-linked immunosorbent assay. Maximal oxygen uptake and anthropometric data were assessed in all participants, while Tanner stage, circulating sex hormones and accelerometry-based activity level were assessed in children and adolescents only. We found that children, adolescents and adults have similar circulating levels of plasma pro- and mBDNF at rest. For children and adolescents, resting levels of mBDNF correlated with average time spent in vigorous activity. In response to the acute endurance exercise intervention, mBDNF increased in all age groups, but the greatest rise in mBDNF was seen in adults. The acute endurance exercise did not affect proBDNF levels. Our results demonstrate that plasma mBDNF levels, but not proBDNF, increase following endurance exercise in all age groups, with a greater effect in adults. We also show that high-intensity physical activity, but not underlying fitness, is contributing to sustained elevated mBDNF levels. KEY POINTS: We show that in children and adolescents, regular vigorous physical activity is key to increased basal levels of plasma mature brain-derived neurotrophic factor (mBDNF), a factor linked to neuroplasticity and brain health. The ability to elevate mBDNF through exercise is present across all age groups, with the greatest increase in adults. The mBDNF response to physical exercise seems to be independent of underlying physical fitness. Our findings suggest that basal plasma mBDNF levels may reflect the cumulative effects of repeated exercise rather than an individual's overall physical fitness.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}