Journal of Physiology-London最新文献

{"title":"The place around me is (not) understood: Musings of an active single neurone.","authors":"Oscar Sacchi","doi":"10.1113/JP287796","DOIUrl":"https://doi.org/10.1113/JP287796","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015224","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":"Effects of patent foramen ovale in migraine: a metabolomics-based study.","authors":"Bosi Dong, Xin Li, Lu Zhang, Ge Liang, Wen Zheng, Luolan Gui, Shuming Ji, Yusha Tang, Hua Li, Wanling Li, Ruiqi Yang, Yajiao Li, Anjiao Peng, Yucheng Chen, Meng Gong, Lei Chen","doi":"10.1113/JP286772","DOIUrl":"https://doi.org/10.1113/JP286772","url":null,"abstract":"<p><p>Patent foramen ovale (PFO), a cardiac anatomical anomaly inducing abnormal haemodynamics, leads to a paradoxical bypass of the pulmonary circulation. PFO closure might alleviate migraines; however, clinical evidence and basic experiments for the relationship are lacking. To explore the effect of PFO on migraine, 371 migraineurs finishing blood tests and contrast transthoracic echocardiography for the detection of PFO were prospectively included. Multivariate regression analysis revealed that PFO was independently associated with aura, and lower cystatin-C (cys-C) and calcium levels. Among them, patients with PFO who underwent percutaneous PFO closure were continuously followed up 1 year after the operation. The intensity of migraine was significantly relieved and the levels of cys-C and calcium increased after PFO closure. Untargeted and targeted metabolomics of plasma from migraineurs before and after PFO closure revealed that 5-HT and glutathione (GSH) metabolites were differentially expressed after PFO closure. The differential metabolites were then validated in the plasma and brain tissues of PFO mouse models by LC-MS/MS analysis. Desorption electrospray ionization mass imaging demonstrated that these metabolic alterations occurred mainly in the posterior cerebral cortex. Collectively, aura, cys-C and calcium could be biomarkers of migraineurs with PFO. PFO might have an impact on the posterior head associated with the regulation of 5-HT and GSH. PFO closure might relieve migraine by improving 5-HT clearance metabolism and ameliorating redox reactions. Our results may provide evidence for an indication of PFO closure in migraine and support the related potential mechanism. KEY POINTS: Aura, and levels of cystatin-C and calcium are biomarkers of migraineurs with a patent foramen ovale (PFO). The clearance of pulmonary metabolism of 5-HT and deoxygenated blood might be the reason for the improvement of migraine symptoms in patients with PFO. The posterior region of the brain is the main area responsible for PFO-induced migraine.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015207","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 physiology of stroke neurorehabilitation","authors":"Richard G. Carson","doi":"10.1113/JP287848","DOIUrl":"10.1113/JP287848","url":null,"abstract":"&lt;p&gt;The Cochrane network, in its definition of rehabilitation, refers to “interventions targeting a person's” capacity (by addressing body structures, functions, and activities/participation) … with the goal of “optimizing” the “functioning” … of “persons with health conditions currently experiencing disability or likely to experience disability …” (Negrini et al., &lt;span&gt;2022&lt;/span&gt;). In respect of the significance accorded to ‘capacity’ and ‘functioning’, rehabilitation lies squarely within the purview of physiology, with its emphasis on the integration of molecular, cellular, systems and whole-body function. Neurorehabilitation (a.k.a. neurological rehabilitation) deals more specifically (e.g. National Institute for Health &amp; Care Excellence, &lt;span&gt;2021&lt;/span&gt;) with neurological impairments that arise from injury to the brain, spine or peripheral nerves, caused by disease, trauma, tumours, infections, metabolic insults and disorders of the blood supply – such as stroke. In terms of its ramifications, stroke ranks as the second highest cause of death (Roth et al., &lt;span&gt;2018&lt;/span&gt;), and follows only neonatal disorders and ischaemic heart disease as an agent of long-term disability (Kyu et al., &lt;span&gt;2018&lt;/span&gt;). Most notably, stroke has a disability impact – in terms of severity, greater than any other chronic disease (e.g. Adamson et al., &lt;span&gt;2004&lt;/span&gt;). It is estimated that approximately 15 million strokes occur worldwide every year (World Health Organization, &lt;span&gt;2024&lt;/span&gt;). Of those who survive, half will be left with a disability that demands neurorehabilitation. With the lethality of stroke falling, and the incidence of stroke rising – especially in low-income and middle-income countries (Prust et al., &lt;span&gt;2024&lt;/span&gt;), there is a renewed imperative to direct research towards life after stroke, particularly since targets for neurorehabilitation feature prominently among the priorities identified by stroke survivors and their carers (Pollock et al., &lt;span&gt;2012&lt;/span&gt;).&lt;/p&gt;&lt;p&gt;It seems self-evident that physiological knowledge should inform stroke neurorehabilitation, particularly when there is an aspiration to increase the efficacy and efficiency of its delivery. In this context, such knowledge might extend to mechanisms that mediate adaptation to, or recovery from, brain damage. It may also encompass means through which a neurorehabilitation technique exerts an effect. Writing in this collection, Carson and Hayward (&lt;span&gt;2025&lt;/span&gt;) point out that these strands of knowledge are integrated less frequently than one might suppose. In addition, and unlike in many other areas of clinical science, knowledge of the relevant physiology is frequently sought (if at all) following the concoction of a novel neurorehabilitation therapy, rather than as a precursor. Perhaps this is due to lack of appreciation of an existing corpus of physiological knowledge that is directly relevant to stroke neurorehabilitation. This special issue of &lt;i&gt;T","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 3","pages":"611-615"},"PeriodicalIF":4.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP287848","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Does exercise truly affect brain-wide glucose metabolism?","authors":"Laust Vind Knudsen, Tanja Maria Michel, Abigail Jane Sheldrick-Michel, Manouchehr Seyedi Vafaee","doi":"10.1113/JP288329","DOIUrl":"https://doi.org/10.1113/JP288329","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015206","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":"Inhibition of diacylglycerol lipase α induced blood-brain barrier breach in female Sprague-Dawley rats.","authors":"Erika Liktor-Busa, Aidan A Levine, Sally J Young, Colin Bader, Seph M Palomino, Felipe D Polk, Sarah A Couture, Paulo W Pires, Trent Anderson, Tally M Largent-Milnes","doi":"10.1113/JP287680","DOIUrl":"https://doi.org/10.1113/JP287680","url":null,"abstract":"<p><p>The endocannabinoid system's significance in maintaining blood-brain barrier (BBB) integrity under physiological and pathological conditions is suggested by several reports, but the underlying molecular mechanisms are not well understood. In this paper, we investigated the effects of depletion of 2-arachidonoylglycerol (2-AG), one of the main endocannabinoids in the central nervous system, on BBB integrity using pharmacological tools. Female Sprague-Dawley rats were injected with the diacylglycerol lipase α (DAGLα) inhibitor LEI-106 (40 mg/kg, i.p.), followed by assessment of BBB integrity via in situ brain perfusion. Liquid chromatography-mass spectrometry, western immunoblotting, light transmittance experiments and pressure myography were also used to further examine the results of DAGLα blockade on the BBB and vascular reactivity. We found that DAGLα inhibition caused BBB opening in cortical brain areas, manifesting as increased sucrose transport measured by in situ brain perfusion. This was accompanied by reduced levels of 2-AG and decreased detection of the tight junction protein zonula occludens-1 (ZO-1). The protein level in cortical areas of neuronal PAS domain protein 4 (NPAS4), encoded by an activity-dependent immediate early gene, was increased without the presence of cortical spreading depression after LEI-106 administration. We also observed a significant increase in pressure-induced constriction within the parenchymal microcirculation after inhibition of DAGLα, possibly altering shear stress in the microcirculation. These results support the role of endogenous 2-AG in maintaining normal tight junction function. This improved understanding of the molecular mechanisms of endocannabinoid system function at the neurovascular unit can help to unlock the therapeutic potentials of cannabinoids in central nervous system disorders associated with BBB dysfunction. KEY POINTS: The administration of the diacylglycerol lipase α (DAGLα) inhibitor LEI-106 (40 mg/kg, i.p.) induced blood-brain barrier (BBB) opening of cortical brain areas in female Sprague-Dawley rats. This BBB disruption was accompanied by reduced levels of 2-arachidonoylglycerol (2-AG) and decreased detection of the tight junction protein zonula occludens-1 (ZO-1). The protein level in cortical areas of neuronal PAS domain protein 4 (NPAS4), encoded by an activity-dependent immediate early gene, was increased without the presence of cortical spreading depression after LEI-106 administration. A significant increase in pressure-induced constriction within the parenchymal microcirculation was also observed after inhibition of DAGLα, possibly altering shear stress. These results support the role of endogenous 2-AG in maintaining normal tight junction function.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015209","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":"Cortical coding of gustatory and thermal signals in active licking mice.","authors":"Audrey N Nash, Morgan Shakeshaft, Cecilia G Bouaichi, Katherine E Odegaard, Tom Needham, Martin Bauer, Richard Bertram, Roberto Vincis","doi":"10.1113/JP287499","DOIUrl":"10.1113/JP287499","url":null,"abstract":"<p><p>Eating behaviours are influenced by the integration of gustatory, olfactory and somatosensory signals, which all contribute to the perception of flavour. Although extensive research has explored the neural correlates of taste in the gustatory cortex (GC), less is known about its role in encoding thermal information. This study investigates the encoding of oral thermal and chemosensory signals by GC neurons compared to the oral somatosensory cortex. In this study we recorded the spiking activity of more than 900 GC neurons and 500 neurons from the oral somatosensory cortex in mice allowed to freely lick small drops of gustatory stimuli or deionized water at varying non-nociceptive temperatures. We then developed and used a Bayesian-based analysis technique to assess neural classification scores based on spike rate and phase timing within the lick cycle. Our results indicate that GC neurons rely predominantly on rate information, although phase information is needed to achieve maximum accuracy, to effectively encode both chemosensory and thermosensory signals. GC neurons can effectively differentiate between thermal stimuli, excelling in distinguishing both large contrasts (14 vs. 36°C) and, although less effectively, more subtle temperature differences. Finally a direct comparison of the decoding accuracy of thermosensory signals between the two cortices reveals that whereas the somatosensory cortex exhibited higher overall accuracy, the GC still encodes significant thermosensory information. These findings highlight the GC's dual role in processing taste and temperature, emphasizing the importance of considering temperature in future studies of taste processing. KEY POINTS: Flavour perception relies on gustatory, olfactory and somatosensory integration, with the gustatory cortex (GC) central to taste processing. GC neurons also respond to temperature, but the specifics of how the GC processes taste and oral thermal stimuli remain unclear. The focus of this study is on the role of GC neurons in the encoding of oral thermal information, particularly compared to the coding functions of the oral somatosensory cortex. We found that whereas the somatosensory cortex shows a higher classification accuracy for distinguishing water temperature, the GC still encodes a substantial amount of thermosensory information. These results emphasize the importance of including temperature as a key factor in future studies of cortical taste coding.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015205","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":"Mouse models for metabolic health research: molecular mechanism of exercise effects on health improvement through adipose tissue remodelling.","authors":"Hye Jin Kim, Youn Ju Kim, Je Kyung Seong","doi":"10.1113/JP285975","DOIUrl":"https://doi.org/10.1113/JP285975","url":null,"abstract":"<p><p>Exercise provides health benefits to multiple metabolic tissues through complex biological pathways and interactions between organs. However, investigating these complex mechanisms in humans is still limited, making mouse models extremely useful for exploring exercise-induced changes in whole-body metabolism and health. In this review, we focus on gaining a broader understanding of the metabolic phenotypes and molecular mechanisms induced by exercise in mouse models. We first discuss the differences in adaptations induced by aerobic and resistance exercise, and compare voluntary wheel running and forced treadmill exercise, the two main methods of aerobic exercise research in mice, to show the similarities and differences between the same aerobic exercise but different methods, and their impact on experimental outcomes. The effects of exercise on metabolic phenotypes, including alleviation of obesity and metabolic disorders, and the mechanisms involved in adipose tissue remodelling and browning are explored, as well as the role of the gut microbiota in mediating the physiological responses and metabolic effects of exercise. Understanding these molecular mechanisms and methodological aspects of exercise experiments in mouse models can serve as a valuable template for the design of future basic research in exercise physiology and will provide a strong scientific evidence base for optimizing the design of exercise intervention programmes for metabolic health.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015220","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":"Skin disease-associated GJB4 variants differentially influence connexin stability, cell viability and channel function.","authors":"Sergiu A Lucaciu, Stephanie E Leighton, Robert S Wong, Varun Sekar, Alexandra Hauser, Nhu-An Lai, Danielle Johnston, Peter B Stathopulos, Donglin Bai, Dale W Laird","doi":"10.1113/JP286367","DOIUrl":"https://doi.org/10.1113/JP286367","url":null,"abstract":"<p><p>Here we characterize seven Cx30.3 gene variants (R22H, S26Y, P61R, C86S, E99K, T130M and M190L) clinically associated with the rare skin disorder erythrokeratodermia variabilis et progressiva (EKVP) in tissue-relevant and differentiation-competent rat epidermal keratinocytes (REKs). We found that all variants, when expressed alone or together with wildtype (WT) Cx30.3, had the capacity to traffic and form gap junctions with an efficiency like WT Cx30.3. Cx30.3 was found to have a slower relative turnover than Cx43. However, turnover was more rapid for the R22H and P61R variants relative to Cx30.3. Furthermore, REKs that expressed the P61R variant exhibited reduced viability and were more permeable to fluorescent dyes, indicative of leaky hemichannels and/or the loss of membrane integrity associated with cell death. In connexin-null AD-293 cells, dual patch clamp studies revealed that the variants had either reduced (C86S) or no (S26Y and T130M) gap junction channel function. The remaining variants formed functional gap junction channels with enhanced transjunctional voltage (V_j)-dependent gating. Moreover, WT Cx30.3 and functional variant gap junction channels had similar unitary conductance of ∼34-42 pS, though variant channels appeared to have lower open probability than WT Cx30.3 channels at high V_js. In conclusion, EKVP-associated Cx30.3 variants each alter one or more Cx30.3 characteristics although the molecular changes identified for E99K were limited to enhanced V_j gating. The breadth of molecular changes identified may all be sufficient to cause EKVP, but this remains to be firmly established as more familial patients are genotyped for these variants. KEY POINTS: Here we characterize seven Cx30.3 variants (R22H, S26Y, P61R, C86S, E99K, T130M and M190L) that have been clinically associated with the rare skin disorder erythrokeratodermia variabilis et progressiva (EKVP). We discovered human Cx30.3 undergoes relatively slow turnover compared with Cx43 and exhibits kinetically slow and limited voltage gating. Wildtype Cx30.3 and all variants localized to intracellular compartments and gap junctions in rat epidermal keratinocytes. Each EKVP-associated Cx30.3 variant altered one or more Cx30.3 characteristics related to protein stability, cell viability and/or channel function. The breadth of molecular changes identified for each Cx30.3 variant may independently be sufficient to cause EKVP, but this remains to be firmly established through additional genetic and molecular analysis.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015221","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":"In vivo calcium imaging reveals directional sensitivity of C-low threshold mechanoreceptors.","authors":"Evangelia Semizoglou, Laure Lo Re, Steven J Middleton, Jimena Perez-Sanchez, Tommaso Tufarelli, David L Bennett, Kim I Chisholm","doi":"10.1113/JP286631","DOIUrl":"https://doi.org/10.1113/JP286631","url":null,"abstract":"<p><p>C-low threshold mechanoreceptors (C-LTMRs) in animals (termed C-tactile (CT) fibres in humans) are a subgroup of C-fibre primary afferents, which innervate hairy skin and respond to low-threshold punctate indentations and brush stimuli. These afferents respond to gentle touch stimuli and are implicated in mediating pleasant/affective touch. These afferents have traditionally been studied using low-throughput, technically challenging approaches, including microneurography in humans and teased fibre electrophysiology in other mammals. Here we suggest a new approach to studying genetically labelled C-LTMRs using in vivo calcium imaging. We used an automated rotating brush stimulus and von Frey filaments, applied to the hairy skin of anaesthetized mice to mirror light and affective touch. Simultaneously we visualized changes in C-LTMR activity and confirmed that these neurons are sensitive to low-threshold punctate mechanical stimuli and brush stimuli with a strong preference for slow brushing speeds. We also reveal that C-LMTRs are directionally sensitive, showing more activity when brushed against the natural orientation of the hair. We present in vivo calcium imaging of genetically labelled C-LTMRs as a useful approach that can reveal new aspects of C-LTMR physiology. KEY POINTS: C-low threshold mechanoreceptors are sensitive to the directionality of a brush stimulus, being preferentially activated by brushing against the grain of the hair, compared with brushing with the grain of the hair. This is surprising as brushing against the grain of the hair is considered less pleasant. In vivo calcium imaging is a useful approach to the study of C-low threshold mechanoreceptors. While viral transfection, using systemic AAV9, is effective in labelling most sensory neuron populations in the dorsal root ganglion, it fails to label C-low threshold mechanoreceptors.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142985260","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":"Cognitive impairment caused by compromised hepatic ketogenesis is prevented by endurance exercise.","authors":"Taylor J Kelty, Nathan R Kerr, Chih H Chou, Grace E Shryack, Christopher L Taylor, Alexa A Krause, Alexandra R Knutson, Josh Bunten, Tom E Childs, Grace M Meers, Ryan J Dashek, Patrycja Puchalska, Peter A Crawford, John P Thyfault, Frank W Booth, R Scott Rector","doi":"10.1113/JP287573","DOIUrl":"https://doi.org/10.1113/JP287573","url":null,"abstract":"<p><p>Extensive research has demonstrated endurance exercise to be neuroprotective. Whether these neuroprotective benefits are mediated, in part, by hepatic ketone production remains unclear. To investigate the role of hepatic ketone production on brain health during exercise, healthy 6-month-old female rats underwent viral knockdown of the rate-limiting enzyme in the liver that catalyses the first reaction in ketogenesis: 3-hydroxymethylglutaryl-CoA synthase 2 (HMGCS2). Rats were then subjected to either a bout of acute exercise or 4 weeks of chronic treadmill running (5 days/week) and cognitive behavioural testing. Acute exercise elevated ketone plasma concentration 1 h following exercise. Hepatic HMGCS2 knockdown, verified by protein expression, reduced ketone plasma concentration 1 h after acute exercise and 48 h after chronic exercise. Proteomic analysis and enrichment of the frontal cortex revealed hepatic HMGCS2 knockdown reduced markers of mitochondrial function 1 h after acute exercise. HMGCS2 knockdown significantly reduced state 3 complex I + II respiration in isolated mitochondria from the frontal cortex after chronic exercise. Spatial memory and protein markers of synaptic plasticity were significantly reduced by HMGCS2 knockdown. These deficiencies were prevented by chronic endurance exercise training. In summary, these are the first data to propose that hepatic ketogenesis is required to maintain cognition and mitochondrial function, irrespective of training status, and that endurance exercise can overcome neuropathology caused by insufficient hepatic ketogenesis. These results establish a mechanistic link between liver and brain health that enhance our understanding of how peripheral tissue metabolism influences brain health. KEY POINTS: Decades of literature demonstrate endurance exercise to be neuroprotective. Whether neuroprotective benefits are mediated, in part, by hepatic ketone production remains unclear. This study provides the first set of data that suggest hepatic ketogenesis is required to maintain cognition, synaptic plasticity and mitochondrial function. These data indicate endurance exercise can protect against cognitive decline caused by compromised hepatic ketogenesis. These results establish a mechanistic link between liver and brain function, prompting further investigation of how hepatic metabolism influences brain health.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142985258","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}