Pub Date : 2023-05-01DOI: 10.1152/physiol.2023.38.s1.5731818
J. Furness, Farhad Dehkhoda, Emily A. Whitfield, L. Fothergill, Desye Misgenaw, M. Ringuet, Sebastian G.B. Furness
The typical action of dopamine at the dopamine 2 receptor (D2R) on CNS neurons is inhibition, an effect mediated via Gαi/o through GIRK channels. However, at two sites, autonomic preganglionic neurons in the lumbosacral spinal cord, and in the lateral hypothalamus, dopamine causes neuronal excitation through D2R. At both sites, dopamine neurons that are excited by dopamine express the ghrelin receptor, GHSR. Ghrelin is absent from the lateral hypothalamus and spinal cord, and it has been proposed that GHSR may modulate D2R signaling by the formation of heterodimers.In lumbrosacral spinal cord neurons of the defecation centre, D2R and GHSR agonists applied successively were both excitatory. Antagonism of GHSR at these neurons blocked the excitatory effect of DR2 stimulation, which was also blocked by depletion of intracellular calcium (iCa2+). We further investigated this interaction in recombinant cultured cells. In CHO cells expressing D2R, dopamine agonists had almost no effect on iCa2+, whereas in the presence of GHSR, D2R coupling to iCa2+ was observed in response to nanomolar dopamine. The elevation of iCa2+ by dopamine in D2R/GHSR cells was reduced by either D2R or GHSR antagonism, but the effect of a GHSR agonist was reduced only by GHSR antagonism. D2R coupling to iCa2+ in the presence of GHSR was dependent on both Gαq and Gαi/o, whereas ghrelin agonist coupling was dependent only on Gαq. D2R mediated effects on cAMP were dependent only on Gαi/o and were not effected by GHSR antagonism. D2R and GHSR in the membranes of CHO cells, revealed by fluorescent ligands, moved independently when tracked at high resolution in real time and, using fluorescent lifetime imaging, individual labelled DR2 sites were not in close enough proximity to detect resonance energy transfer (no detectable FRET). Consistent with coupling being via downstream crosstalk, no detectable DR2 dependent iCa2+ was evident in cells expressing the GHSR – A204E mutant, which lacks constitutive activity. The DR2-dependent iCa2+ increase was restored in these cells using subthreshold pre-stimulation with ghrelin. In native neurons of the defecation center, inward currents in response to D2R agonism were blocked by U73122, an inhibitor of PLCβ. Together this data indicates that dopamine-mediated excitation was dependent on GHSR, PLCβ and iCa2+, in both native and recombinant cells. We conclude that co-expression of GHSR causes augmentation of agonist-induced, D2R-mediated PLCβ activation and store Ca2+ release in recombinant cells and in a population of autonomic preganglionic neurons. D2R mediated excitation in D2R/GHSR cells is both Gαi/o and Gαq/11 dependent, but does not require receptor dimerisation. Our findings reveal a novel interaction between GPCRs, in a physiologically relevant system, that does not require direct receptor interaction and has broad implications for recoding of metabotropic neurotransmitter responses via modulation through other GPCRs. NHMRC grant, APP
{"title":"Modulation of dopamine's effect at dopamine 2 receptors (D2R) mediated by association with the ghrelin receptor, GHSR","authors":"J. Furness, Farhad Dehkhoda, Emily A. Whitfield, L. Fothergill, Desye Misgenaw, M. Ringuet, Sebastian G.B. Furness","doi":"10.1152/physiol.2023.38.s1.5731818","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5731818","url":null,"abstract":"The typical action of dopamine at the dopamine 2 receptor (D2R) on CNS neurons is inhibition, an effect mediated via Gαi/o through GIRK channels. However, at two sites, autonomic preganglionic neurons in the lumbosacral spinal cord, and in the lateral hypothalamus, dopamine causes neuronal excitation through D2R. At both sites, dopamine neurons that are excited by dopamine express the ghrelin receptor, GHSR. Ghrelin is absent from the lateral hypothalamus and spinal cord, and it has been proposed that GHSR may modulate D2R signaling by the formation of heterodimers.In lumbrosacral spinal cord neurons of the defecation centre, D2R and GHSR agonists applied successively were both excitatory. Antagonism of GHSR at these neurons blocked the excitatory effect of DR2 stimulation, which was also blocked by depletion of intracellular calcium (iCa2+). We further investigated this interaction in recombinant cultured cells. In CHO cells expressing D2R, dopamine agonists had almost no effect on iCa2+, whereas in the presence of GHSR, D2R coupling to iCa2+ was observed in response to nanomolar dopamine. The elevation of iCa2+ by dopamine in D2R/GHSR cells was reduced by either D2R or GHSR antagonism, but the effect of a GHSR agonist was reduced only by GHSR antagonism. D2R coupling to iCa2+ in the presence of GHSR was dependent on both Gαq and Gαi/o, whereas ghrelin agonist coupling was dependent only on Gαq. D2R mediated effects on cAMP were dependent only on Gαi/o and were not effected by GHSR antagonism. D2R and GHSR in the membranes of CHO cells, revealed by fluorescent ligands, moved independently when tracked at high resolution in real time and, using fluorescent lifetime imaging, individual labelled DR2 sites were not in close enough proximity to detect resonance energy transfer (no detectable FRET). Consistent with coupling being via downstream crosstalk, no detectable DR2 dependent iCa2+ was evident in cells expressing the GHSR – A204E mutant, which lacks constitutive activity. The DR2-dependent iCa2+ increase was restored in these cells using subthreshold pre-stimulation with ghrelin. In native neurons of the defecation center, inward currents in response to D2R agonism were blocked by U73122, an inhibitor of PLCβ. Together this data indicates that dopamine-mediated excitation was dependent on GHSR, PLCβ and iCa2+, in both native and recombinant cells. We conclude that co-expression of GHSR causes augmentation of agonist-induced, D2R-mediated PLCβ activation and store Ca2+ release in recombinant cells and in a population of autonomic preganglionic neurons. D2R mediated excitation in D2R/GHSR cells is both Gαi/o and Gαq/11 dependent, but does not require receptor dimerisation. Our findings reveal a novel interaction between GPCRs, in a physiologically relevant system, that does not require direct receptor interaction and has broad implications for recoding of metabotropic neurotransmitter responses via modulation through other GPCRs. NHMRC grant, APP","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"1 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78987236","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}
Pub Date : 2023-05-01DOI: 10.1152/physiol.2023.38.s1.5732408
Steven Medarev, Madikay Faal, Andy Asher, Cole Smith, Muhammad Qasim, Jasen Belenko, D. Hendrickson, Logan Mitchell, Jayden Ojah-Maharaj, Victor Faynberg, Nicole Cannon, J. Muller-Delp
Adiponectin contributes to the regulation of vascular and metabolic functions in skeletal muscle. Although circulating adiponectin is known to increase with aerobic exercise training, a direct role for adiponectin in adaptation of microvasculature of skeletal muscle to aerobic exercise training has not been documented. We exercise trained young adult mice with normal circulating adiponectin (wild type, WT) and mice in which adiponectin was acutely deleted (Cre-Lox conditional knockout system induced with Tamoxifen chow, AdipoKO) before undergoing 8 weeks of exercise training. Sedentary WT and AdipoKO mice were housed under similar cage conditions for 8 weeks. We determined skeletal muscle oxidative capacity, exercise tolerance, lean and fat mass, and we assessed reactivity of 1A arterioles from the gastrocnemius muscle. Exercise training increased exercise tolerance in both WT and AdipoKO mice. Exercise training increased lean mass and reduced fat mass in both WT and AdipoKO mice. Myogenic constriction to intraluminal pressure changes was increased by exercise training in gastrocnemius muscle 1A arterioles from both WT and AdipoKO mice. In contrast, phenylephrine-induced contractile responses were increased by exercise training in WT, but not AdipoKO mice. These data suggest that adiponectin is an important contributor to adaptations of contractile function that occur in skeletal muscle in response to exercise training; however, the training-induced increase in exercise tolerance and muscle mass that occurred in both WT and AdipoKO mice suggests that loss of adiponectin impacts smooth muscle function independently of metabolic adaptations in skeletal muscle. NIH R56AG068156 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
{"title":"Microvascular Function in Skeletal Muscle of Acute Adiponectin Knockout Mice","authors":"Steven Medarev, Madikay Faal, Andy Asher, Cole Smith, Muhammad Qasim, Jasen Belenko, D. Hendrickson, Logan Mitchell, Jayden Ojah-Maharaj, Victor Faynberg, Nicole Cannon, J. Muller-Delp","doi":"10.1152/physiol.2023.38.s1.5732408","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5732408","url":null,"abstract":"Adiponectin contributes to the regulation of vascular and metabolic functions in skeletal muscle. Although circulating adiponectin is known to increase with aerobic exercise training, a direct role for adiponectin in adaptation of microvasculature of skeletal muscle to aerobic exercise training has not been documented. We exercise trained young adult mice with normal circulating adiponectin (wild type, WT) and mice in which adiponectin was acutely deleted (Cre-Lox conditional knockout system induced with Tamoxifen chow, AdipoKO) before undergoing 8 weeks of exercise training. Sedentary WT and AdipoKO mice were housed under similar cage conditions for 8 weeks. We determined skeletal muscle oxidative capacity, exercise tolerance, lean and fat mass, and we assessed reactivity of 1A arterioles from the gastrocnemius muscle. Exercise training increased exercise tolerance in both WT and AdipoKO mice. Exercise training increased lean mass and reduced fat mass in both WT and AdipoKO mice. Myogenic constriction to intraluminal pressure changes was increased by exercise training in gastrocnemius muscle 1A arterioles from both WT and AdipoKO mice. In contrast, phenylephrine-induced contractile responses were increased by exercise training in WT, but not AdipoKO mice. These data suggest that adiponectin is an important contributor to adaptations of contractile function that occur in skeletal muscle in response to exercise training; however, the training-induced increase in exercise tolerance and muscle mass that occurred in both WT and AdipoKO mice suggests that loss of adiponectin impacts smooth muscle function independently of metabolic adaptations in skeletal muscle. NIH R56AG068156 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"26 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79001107","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}
Pub Date : 2023-05-01DOI: 10.1152/physiol.2023.38.s1.5731242
Fabrice Dabertrand
Arteries and arterioles exhibit myogenic tone, a partially constricted state that allows further constriction or dilation in response to moment-to-moment fluctuations in blood pressure. The vascular endothelium that lines the internal surface of all blood vessels controls a wide variety of essential functions, including the contractility of the adjacent smooth muscle cells by providing a tonic vasodilatory influence. Studies conducted on large (pial) arteries on the surface of the brain have shown that estrogen lowers myogenic tone in female mice by enhancing nitric oxide (NO) release from the endothelium, however, whether this difference extends to the intracerebral microcirculation remains ambiguous. The existing incomplete picture of sex differences in cerebrovascular physiology combined with a deficiency in treatments that fully restore cognitive function after cerebrovascular accidents places heavy emphasis on the necessity to investigate myogenic tone regulation in the microcirculation from both male and female mice. We hypothesized that sex-linked hormone regulation of myogenic tone extends its influence to the microcirculation level, and sought to characterize it in isolated arterioles from the hippocampus, a major cognitive brain area. Using diameter measurements in pressure myography experiments, we measured lower myogenic tone responses in hippocampal arterioles from female than male mice at physiologically relevant pressures. By using a combined surgical and pharmacological approach, we found myogenic tone in ovarectomized (OVX) female mice matches that of males, as well as in endothelium-denuded arterioles. Interestingly, eNOS inhibition induced a larger constriction in female arterioles but only partially abolished the difference in tone. We identified that the remnant difference was mediated by a higher activity of the small-conductance Ca2+-sensitive K+ (SK) channels. Collectively, these data indicate that eNOS and SK channels exert greater vasodilatory influence over myogenic tone in female mice at physiological pressures. R01HL136636; RF1NS129022 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
{"title":"Estrogen regulates myogenic tone in hippocampal arterioles by enhanced basal release of nitric oxide and endothelial SK channel activity","authors":"Fabrice Dabertrand","doi":"10.1152/physiol.2023.38.s1.5731242","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5731242","url":null,"abstract":"Arteries and arterioles exhibit myogenic tone, a partially constricted state that allows further constriction or dilation in response to moment-to-moment fluctuations in blood pressure. The vascular endothelium that lines the internal surface of all blood vessels controls a wide variety of essential functions, including the contractility of the adjacent smooth muscle cells by providing a tonic vasodilatory influence. Studies conducted on large (pial) arteries on the surface of the brain have shown that estrogen lowers myogenic tone in female mice by enhancing nitric oxide (NO) release from the endothelium, however, whether this difference extends to the intracerebral microcirculation remains ambiguous. The existing incomplete picture of sex differences in cerebrovascular physiology combined with a deficiency in treatments that fully restore cognitive function after cerebrovascular accidents places heavy emphasis on the necessity to investigate myogenic tone regulation in the microcirculation from both male and female mice. We hypothesized that sex-linked hormone regulation of myogenic tone extends its influence to the microcirculation level, and sought to characterize it in isolated arterioles from the hippocampus, a major cognitive brain area. Using diameter measurements in pressure myography experiments, we measured lower myogenic tone responses in hippocampal arterioles from female than male mice at physiologically relevant pressures. By using a combined surgical and pharmacological approach, we found myogenic tone in ovarectomized (OVX) female mice matches that of males, as well as in endothelium-denuded arterioles. Interestingly, eNOS inhibition induced a larger constriction in female arterioles but only partially abolished the difference in tone. We identified that the remnant difference was mediated by a higher activity of the small-conductance Ca2+-sensitive K+ (SK) channels. Collectively, these data indicate that eNOS and SK channels exert greater vasodilatory influence over myogenic tone in female mice at physiological pressures. R01HL136636; RF1NS129022 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"33 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79053485","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}
Pub Date : 2023-05-01DOI: 10.1152/physiol.2023.38.s1.5795558
K. Schweitzer, N. Egersdorf, T. Rivera, B. Dubois, C. Cornell, Alexander Borowiec, J. Poczobutt, J. Matsuda, E. Berdyshev, R. Bowen, I. Petrache
RATIONALE: IGSF3, a transmembrane tetraspanin interacting protein, is required for lung epithelial scratch wound repair and migration via inhibition of glucosyl ceramide synthase. However, as a result, a decrease in glycosphingolipids such as lactosylceramide may decrease cell proliferation and impair lung recovery from infections such as SARS-CoV-2 (CoV2). We hypothesized that recovery from CoV2 is associated with downregulation of lung IGSF3, increased glycosphingolipid synthesis, and enhanced lung cell proliferation. METHODS: Lung IGSF3, sphingolipid levels, and cell proliferation were measured in Golden Syrian hamsters harvested during the early recovery (at 7 days) following a single intranasal exposure to CoV2 (strain WA01; 10E4 pfu). Lung cell proliferation was measured in mice with constitutive deletion of IGSF3 (KO). Immunofluorescence (IF) was performed for cell-specific markers CD11b and CD11c, as well as CD31. Lipids were quantified using LC-MS/MS. RESULTS: CoV2 infection was associated with decreased Igsf3 [log2FC (fold change) -0.914; p<0.01] expression and immunostaining in the lung tissue and increased glucosylceramide (FC 11, p<0.001), lactosylceramide (FC 5, p<0.01), and lysophosphatidic acid (FC 6, p<0.001) in the BALF. Lung cell proliferation was increased, with high Proliferation Marker Protein Ki-67 expression (Ki-67; log2FC 2.17; p<0.0001). In mice, compared to control, IGSF3 KO mice exhibited increased lung Proliferating Cell Nuclear Antigen (PCNA; FC 2.44; p=0.03) and Ki-67 (FC 1.71; p=0.03) IF and enhanced EdU incorporation (in female mice only, FC 1.9; p=0.007), predominantly in the lung epithelium. Of the Ki-67+ cells in the IGSF3 KO lung parenchyma, the populations of cells that had higher proliferation rates than in control mice were alveolar epithelial (>70% of all proliferating cells) followed by recruited monocytes/macrophages, and vascular cells. CONCLUSIONS: Inhibition of IGSF3 may accelerate lung epithelial cell proliferation and lung repair during recovery from respiratory viral infections such as with CoV2 by a mechanism that may involve enhanced glycosphingolipid production. DOD W81XWH-21-PRMRP-IIRA, ALA ETRA736704 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
{"title":"IGSF3 (immunoglobulin superfamily 3) and glycosphingolipids associated with lung cell proliferation during recovery from respiratory SARS-CoV-2 infection","authors":"K. Schweitzer, N. Egersdorf, T. Rivera, B. Dubois, C. Cornell, Alexander Borowiec, J. Poczobutt, J. Matsuda, E. Berdyshev, R. Bowen, I. Petrache","doi":"10.1152/physiol.2023.38.s1.5795558","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5795558","url":null,"abstract":"RATIONALE: IGSF3, a transmembrane tetraspanin interacting protein, is required for lung epithelial scratch wound repair and migration via inhibition of glucosyl ceramide synthase. However, as a result, a decrease in glycosphingolipids such as lactosylceramide may decrease cell proliferation and impair lung recovery from infections such as SARS-CoV-2 (CoV2). We hypothesized that recovery from CoV2 is associated with downregulation of lung IGSF3, increased glycosphingolipid synthesis, and enhanced lung cell proliferation. METHODS: Lung IGSF3, sphingolipid levels, and cell proliferation were measured in Golden Syrian hamsters harvested during the early recovery (at 7 days) following a single intranasal exposure to CoV2 (strain WA01; 10E4 pfu). Lung cell proliferation was measured in mice with constitutive deletion of IGSF3 (KO). Immunofluorescence (IF) was performed for cell-specific markers CD11b and CD11c, as well as CD31. Lipids were quantified using LC-MS/MS. RESULTS: CoV2 infection was associated with decreased Igsf3 [log2FC (fold change) -0.914; p<0.01] expression and immunostaining in the lung tissue and increased glucosylceramide (FC 11, p<0.001), lactosylceramide (FC 5, p<0.01), and lysophosphatidic acid (FC 6, p<0.001) in the BALF. Lung cell proliferation was increased, with high Proliferation Marker Protein Ki-67 expression (Ki-67; log2FC 2.17; p<0.0001). In mice, compared to control, IGSF3 KO mice exhibited increased lung Proliferating Cell Nuclear Antigen (PCNA; FC 2.44; p=0.03) and Ki-67 (FC 1.71; p=0.03) IF and enhanced EdU incorporation (in female mice only, FC 1.9; p=0.007), predominantly in the lung epithelium. Of the Ki-67+ cells in the IGSF3 KO lung parenchyma, the populations of cells that had higher proliferation rates than in control mice were alveolar epithelial (>70% of all proliferating cells) followed by recruited monocytes/macrophages, and vascular cells. CONCLUSIONS: Inhibition of IGSF3 may accelerate lung epithelial cell proliferation and lung repair during recovery from respiratory viral infections such as with CoV2 by a mechanism that may involve enhanced glycosphingolipid production. DOD W81XWH-21-PRMRP-IIRA, ALA ETRA736704 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"5 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79507435","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}
Pub Date : 2023-05-01DOI: 10.1152/physiol.2023.38.s1.5733877
Steven Wu, L. Anderson, Joseph Metzger, Vincent Barnett
The Department of Integrative Biology and Physiology at the University of Minnesota is committed to supporting outstanding physiology majors interested in research and gaining research experience. We have created a program, UPRIME (Undergraduate Physiology Research In Medicine and Education), which has: 1) Foster young and aspiring undergraduates interested in physiology and biomedical research, and 2) Create unfettered opportunities for students that are both underrepresented in research and have strong interests in physiology research and education. UPRIME (Undergraduate Physiology Research In Medicine and Education) is a 10-week summer program hosted by the Department of Integrative Biology and Physiology at the University of Minnesota and sponsored by an American Heart Association award. Students (“UPRIME Scholars”) were either juniors or seniors that had just started working in physiology labs. They were selected on the basis of: 1) Scientific merit of their projects, 2) If they were underrepresented in research (as defined by NIH and/or especially in Minnesota), and 3) If they were from low socio-economic status. To meet our goals, UPRIME Scholars met once a week to discuss research and scientific methods. As the UPRIME Scholars were relatively inexperienced in research, we designed our meetings to be safe and open spaces for encouraging discussion, especially about their research projects. Discussion topics included techniques (e.g. qPCR, histology, and cell culture), experimental design (e.g. animal models, use of controls), and developing a hypothesis. In addition, we had UPRIME Scholars attend weekly “Graduate Student Colloquia” where our graduate students give formal presentations and chalk talks about their research. Here, UPRIME Scholars were tasked to identify and discuss the hypotheses tested, animal or experimental models used, and interpretation of results. In our first two years, UPRIME Scholars reported very positive experiences in their summer research and in the usefulness of the weekly meetings. They were able to better understand why they were doing their projects, how their projects were an important part of their mentor’s research, and how to troubleshoot the techniques they used. Taken together, the UPRIME program has been successful in the fostering of undergraduates in physiology research. The UPRIME program serves as our basis for future programs for undergraduates interested in research. American Heart Association This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
{"title":"A summer physiology research program directed toward underrepresented students, UPRIME (Undergraduate Physiology Research In Medicine and Education), fosters and engages students into physiology research","authors":"Steven Wu, L. Anderson, Joseph Metzger, Vincent Barnett","doi":"10.1152/physiol.2023.38.s1.5733877","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5733877","url":null,"abstract":"The Department of Integrative Biology and Physiology at the University of Minnesota is committed to supporting outstanding physiology majors interested in research and gaining research experience. We have created a program, UPRIME (Undergraduate Physiology Research In Medicine and Education), which has: 1) Foster young and aspiring undergraduates interested in physiology and biomedical research, and 2) Create unfettered opportunities for students that are both underrepresented in research and have strong interests in physiology research and education. UPRIME (Undergraduate Physiology Research In Medicine and Education) is a 10-week summer program hosted by the Department of Integrative Biology and Physiology at the University of Minnesota and sponsored by an American Heart Association award. Students (“UPRIME Scholars”) were either juniors or seniors that had just started working in physiology labs. They were selected on the basis of: 1) Scientific merit of their projects, 2) If they were underrepresented in research (as defined by NIH and/or especially in Minnesota), and 3) If they were from low socio-economic status. To meet our goals, UPRIME Scholars met once a week to discuss research and scientific methods. As the UPRIME Scholars were relatively inexperienced in research, we designed our meetings to be safe and open spaces for encouraging discussion, especially about their research projects. Discussion topics included techniques (e.g. qPCR, histology, and cell culture), experimental design (e.g. animal models, use of controls), and developing a hypothesis. In addition, we had UPRIME Scholars attend weekly “Graduate Student Colloquia” where our graduate students give formal presentations and chalk talks about their research. Here, UPRIME Scholars were tasked to identify and discuss the hypotheses tested, animal or experimental models used, and interpretation of results. In our first two years, UPRIME Scholars reported very positive experiences in their summer research and in the usefulness of the weekly meetings. They were able to better understand why they were doing their projects, how their projects were an important part of their mentor’s research, and how to troubleshoot the techniques they used. Taken together, the UPRIME program has been successful in the fostering of undergraduates in physiology research. The UPRIME program serves as our basis for future programs for undergraduates interested in research. American Heart Association This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"215 3 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79594490","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}
Pub Date : 2023-05-01DOI: 10.1152/physiol.2023.38.s1.5794369
Yuki Tamura
The purpose of this study was to understand the effect of increased lactate accumulation in skeletal muscle by MCT4 deficiency on the adaptation of skeletal muscle to high-intensity interval training. To address this challenge, we first developed MCT4-deficient mice with a genetic background of the Jcl:ICR strain which is capable of performing high-intensity exercise. We found that MCT4 deficiency enhances high-intensity interval training-induced improvement of endurance exercise capacity at high intensity. Furthermore, it was also shown that the combination of MCT4 deficiency and high-intensity interval training, coupled with the physiological context of such adaptation, increases enzyme activity of the glycolysis and the mitochondrial oxidative capacity of pyruvate. The findings of this study would help us understand the physiological significance of lactate accumulation in skeletal muscle with high-intensity exercise. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
{"title":"MCT4 Deficiency Enhances High-intensity Interval Training-induced Metabolic Adaptations in Skeletal Muscle","authors":"Yuki Tamura","doi":"10.1152/physiol.2023.38.s1.5794369","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5794369","url":null,"abstract":"The purpose of this study was to understand the effect of increased lactate accumulation in skeletal muscle by MCT4 deficiency on the adaptation of skeletal muscle to high-intensity interval training. To address this challenge, we first developed MCT4-deficient mice with a genetic background of the Jcl:ICR strain which is capable of performing high-intensity exercise. We found that MCT4 deficiency enhances high-intensity interval training-induced improvement of endurance exercise capacity at high intensity. Furthermore, it was also shown that the combination of MCT4 deficiency and high-intensity interval training, coupled with the physiological context of such adaptation, increases enzyme activity of the glycolysis and the mitochondrial oxidative capacity of pyruvate. The findings of this study would help us understand the physiological significance of lactate accumulation in skeletal muscle with high-intensity exercise. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"37 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76468490","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}
Pub Date : 2023-05-01DOI: 10.1152/physiol.2023.38.s1.5732732
Zhichao Fan, Wei Liu, Chunxia G. Cronin, Lai Wen, K. Ley, Bruce T Liang
Leukocyte recruitment and their mediated inflammatory responses are critical for cardiovascular diseases, including myocardial ischemia-reperfusion (I/R) injury, which accounts for 9% mortality and 10% morbidity rates in ischemic heart disease patients. Blocking leukocyte recruitment in mouse knockouts (KO) of beta2 integrin (CD18) or blocking beta2 integrin with anitibodies in multiple animals significantly reduced infarct size after myocardial I/R injury. However, the cell-specific contribution of leukocyte beta2 integrin to I/R injury is unknown. In this study, we used the newly established CD18flox/flox (hITGB2 KI) mouse strain to address this knowledge gap. We crossed them to CSF1R-cre (CD115) and MRP8-cre (S100A8) and tested the KO of beta2 integrins in different leukocyte populations. Interestingly, CSF1R-cre CD18flox/flox unexpectedly deleted beta2 integrins in all peripheral blood leukocyte populations, including blood neutrophils, monocytes, CD4 T cells, CD8 T cells, B cells, and NK cells. It also elevated the cell number of these leukocyte populations in peripheral blood. In MRP8-cre CD18flox/flox mice, beta2 integrins were only knocked out in neutrophils but not other peripheral blood leukocytes. And only neutrophil number was elevated in peripheral blood. After 35 minutes of myocardial ischemia and 24 hours of reperfusion, we found both CSF1R-cre CD18flox/flox and MRP8-cre CD18flox/flox mice have significantly reduced infarct size compared to cre- controls. However, if we distinguish the sex in analysis, we only found a significant alleviation in female but not male CSF1R-cre CD18flox/flox mice. In contrast, we observed a significant alleviation only in male but not female MRP8-cre CD18flox/flox mice. These results suggested sex-specific and immune-cell-specific contributions of beta2 integrins in myocardial ischemia-reperfusion injury and provided new insights into beta2 integrin targeting therapies. This research was supported by grants from the National Institutes of Health, National Heart, Lung, and Blood Institute, USA (R01HL145454, R41HL156322, and R44HL152710) and a startup fund from UConn Health. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
{"title":"Sex-specific and immune-cell-specific contributions of beta2 integrins in myocardial ischemia-reperfusion injury","authors":"Zhichao Fan, Wei Liu, Chunxia G. Cronin, Lai Wen, K. Ley, Bruce T Liang","doi":"10.1152/physiol.2023.38.s1.5732732","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5732732","url":null,"abstract":"Leukocyte recruitment and their mediated inflammatory responses are critical for cardiovascular diseases, including myocardial ischemia-reperfusion (I/R) injury, which accounts for 9% mortality and 10% morbidity rates in ischemic heart disease patients. Blocking leukocyte recruitment in mouse knockouts (KO) of beta2 integrin (CD18) or blocking beta2 integrin with anitibodies in multiple animals significantly reduced infarct size after myocardial I/R injury. However, the cell-specific contribution of leukocyte beta2 integrin to I/R injury is unknown. In this study, we used the newly established CD18flox/flox (hITGB2 KI) mouse strain to address this knowledge gap. We crossed them to CSF1R-cre (CD115) and MRP8-cre (S100A8) and tested the KO of beta2 integrins in different leukocyte populations. Interestingly, CSF1R-cre CD18flox/flox unexpectedly deleted beta2 integrins in all peripheral blood leukocyte populations, including blood neutrophils, monocytes, CD4 T cells, CD8 T cells, B cells, and NK cells. It also elevated the cell number of these leukocyte populations in peripheral blood. In MRP8-cre CD18flox/flox mice, beta2 integrins were only knocked out in neutrophils but not other peripheral blood leukocytes. And only neutrophil number was elevated in peripheral blood. After 35 minutes of myocardial ischemia and 24 hours of reperfusion, we found both CSF1R-cre CD18flox/flox and MRP8-cre CD18flox/flox mice have significantly reduced infarct size compared to cre- controls. However, if we distinguish the sex in analysis, we only found a significant alleviation in female but not male CSF1R-cre CD18flox/flox mice. In contrast, we observed a significant alleviation only in male but not female MRP8-cre CD18flox/flox mice. These results suggested sex-specific and immune-cell-specific contributions of beta2 integrins in myocardial ischemia-reperfusion injury and provided new insights into beta2 integrin targeting therapies. This research was supported by grants from the National Institutes of Health, National Heart, Lung, and Blood Institute, USA (R01HL145454, R41HL156322, and R44HL152710) and a startup fund from UConn Health. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"47 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78420185","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}
Pub Date : 2023-05-01DOI: 10.1152/physiol.2023.38.s1.5733304
Pieter Koopmans, Ronald G. Jones, F. von Walden, I. Vechetti, Kevin A. Murach
Skeletal muscle adaptation during conditions of dynamic muscle loading such as resistance-type exercise occurs in conjunction with pronounced changes in gene expression. The objective of this study was to comprehensively evaluate gene expression at the onset of rapid muscle hypertrophy in mice. We analyzed the global, nascent, stable, and myonuclear transcriptome utilizing RNA-sequencing. C57BL6/J mice were treated with 5-ethenyl uridine at the end of 72 hours of synergist ablation mechanical overload of the plantaris muscle to assess transcriptional dynamics; sham mice served as controls. Mice with in vivo fluorescent myonuclear labeling were used to obtain RNA-sequencing in exclusively myonuclei from overloaded and sham mice. In these analyses, RUNX family transcription factor 1 ( Runx1, or Aml1) was significantly elevated in all conditions (adj. p<0.05x10-15) and was among the most induced genes across datasets. These findings allude to Runx1 as a highly regulated mediator of muscle hypertrophy that is enriched specifically in muscle fibers during loading. Myonucleus-specific global DNA methylome analysis also report exon and intron CpG hypomethylation in the Runx1 gene after overload. As gene body methylation can mediate alternative splicing, we subsequently hypothesized Runx1 may be subject to alternative splicing and conducted preliminary analyses of RNA splice isoforms present after acute overload. We found that a non-canonical isoform of Runx1 ( Runx1-202, coding for a 387 amino acid protein) was relatively more induced than the Runx1-201 transcript that codes for the full-length 465 amino acid protein (30- versus 17-fold induction, respectively), while Runx1 is essentially not expressed in sham muscle. Ongoing analysis will validate Runx1 splice variant expression during overload in muscle, the potential influence of DNA methylation, and the impact of the Runx1 short isoform on muscle hypertrophy. This work is supported by the National Institutes of Health under grant R00 AG063994 to Kevin A. Murach. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
在动态肌肉负荷条件下，如阻力型运动，骨骼肌的适应与基因表达的显著变化同时发生。本研究的目的是全面评估小鼠快速肌肉肥大发病时的基因表达。我们利用rna测序分析了全局的、新生的、稳定的和我的核转录组。C57BL6/J小鼠在增效剂消融72小时后给予5-乙基尿苷处理，以评估足底肌肉机械过载的转录动力学;假小鼠作为对照。采用体内肌核荧光标记的小鼠对超载小鼠和假小鼠的肌核进行特异性rna测序。在这些分析中，RUNX家族转录因子1 (Runx1，或Aml1)在所有条件下都显著升高(adj. p<0.05x10-15)，并且是所有数据集中最受诱导的基因之一。这些发现暗示Runx1是一种高度调控的肌肉肥大介质，在负荷期间在肌肉纤维中特异性富集。myonuclear -specific global DNA甲基组分析也报道了Runx1基因过载后外显子和内含子CpG低甲基化。由于基因体甲基化可以介导选择性剪接，我们随后假设Runx1可能受到选择性剪接的影响，并对急性过载后存在的RNA剪接异构体进行了初步分析。我们发现Runx1的非规范异构体(Runx1-202，编码387个氨基酸的蛋白)比编码全长465个氨基酸蛋白的Runx1-201转录本(诱导率分别为30倍和17倍)相对更强，而Runx1在假肌中基本上不表达。正在进行的分析将验证Runx1剪接变异体在肌肉过载时的表达，DNA甲基化的潜在影响，以及Runx1短异构体对肌肉肥大的影响。这项工作由美国国立卫生研究院资助，拨款R00 AG063994给Kevin A. Murach。这是在2023年美国生理学峰会上发表的完整摘要，仅以HTML格式提供。此摘要没有附加版本或附加内容。生理学没有参与同行评议过程。
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Pub Date : 2023-05-01DOI: 10.1152/physiol.2023.38.s1.5731689
Caroline M Grady, Soumya Khanna, Bryan K. Becker
The modern lifestyle can lead to many circadian rhythm and sleep disturbances through factors such as artificial lighting and shiftwork. Central fluid flow follows a strong circadian rhythm with increased CSF flow and interstitial clearance during sleep. Disruption of this rhythm in central fluid flow has been implicated in numerous neurodegenerative diseases. However, how circadian central fluid homeostasis is regulated is incompletely understood. The essential clock gene, Bmal1, regulates many circadian processes. Whole body knockout of Bmal1 in mice increases blood brain barrier (BBB) permeability and eliminates many 24-hour rhythms. The recently developed Bmal1 knockout (Bmal1KO) rat has preserved activity and blood pressure rhythms, but central fluid regulation has not been explored. We hypothesized that Bmal1KO rats have altered central fluid control and blunted circadian rhythms of genes involved in central fluid homeostasis. We harvested brains from male and female Bmal1KO and wildtype (WT) littermate control rats and subtracted the dry weight from the wet weight to determine brain water content. Bmal1KO had elevated brain water compared to WT (1.54 ± 0.03 vs 1.44 ± 0.03 g, n = 8-11; p = 0.04). We then evaluated BBB permeability by injecting FITC-dextran (3-5 kDa) intravenously followed by transcardiac perfusion of saline after 30 minutes. Brain sections were dissected and homogenized, and the amount of FITC-dextran was measured by spectrometry. Bmal1KO rats had more FITC-dextran in the brain stem (261.3 ± 18.8 vs 196.4 ± 10.6 ng/mg tissue, n = 4-5; p = 0.03) and in the spinal cord (331.9 ± 17.1 vs 239.2 ± 31.7 ng/mg, p = 0.03) indicating increased BBB permeability. We measured gene expression via RT-qPCR from prefrontal cortex samples collected every four hours throughout the day. We then fit a Cosinor curve to the results in order to evaluate the circadian rhythmicity, and differences were established by extra sum-of-squares F test. We measured aquaporin 4 (aqp4) expression because it is a key component of BBB permeability and glymphatic flux in the brain. Bmal1KO had a blunted aqp4 amplitude (1.2 ± 0.2 vs 0.8 ± 0.2 Ct; p = 0.004 comparison of fit). Bmal1 is also known to contribute to endothelin-1 (edn1) expression rhythms, and we found a dramatic blunting of edn1 amplitude in Bmal1KO rats (0.41 ± 0.19 vs 1.31 ± 0.39 Ct; p < 0.001 comparison of fit) and a phase shift in peak edn1 expression (10.71 ± 0.48 vs 19.72 ± 0.30 zeitgeber time). These data indicate that loss of the circadian gene Bmal1 in rats causes increased BBB permeability and disrupted circadian rhythms of genes involved in central fluid homeostasis. These results suggest that circadian genes are integral in maintaining proper central fluid dynamics and that alterations in these rhythms may play a role in neurodegenerative diseases linked with circadian disruption. NIH K01HL159047 This is the full abstract presented at the American Physiology Summit 2023 meeting and is onl
现代生活方式会因人工照明和倒班等因素导致许多昼夜节律和睡眠紊乱。中枢液体流动遵循强烈的昼夜节律，睡眠时脑脊液流量增加和间隙清除。许多神经退行性疾病都与中枢流体流动节律的中断有关。然而，昼夜节律中枢流体稳态是如何调节的尚不完全清楚。重要的时钟基因Bmal1调节许多昼夜节律过程。小鼠全身敲除Bmal1可增加血脑屏障(BBB)的通透性，消除许多24小时节律。最近开发的Bmal1敲除(Bmal1KO)大鼠保留了活动和血压节律，但尚未探索中枢液体调节。我们假设Bmal1KO大鼠改变了中枢液体控制，并使参与中枢液体稳态的基因的昼夜节律变钝。我们采集了雄性和雌性Bmal1KO和野生型(WT)同胎对照大鼠的大脑，并从湿重中减去干重来测定脑含水量。与WT相比，Bmal1KO脑水升高(1.54±0.03 g vs 1.44±0.03 g, n = 8-11;P = 0.04)。然后，我们通过静脉注射fitc -葡聚糖(3-5 kDa)，并在30分钟后经心灌注生理盐水来评估血脑屏障的通透性。脑切片解剖匀浆，分光光度法测定fitc -葡聚糖含量。Bmal1KO大鼠脑干中fitc -葡聚糖含量更高(261.3±18.8 vs 196.4±10.6 ng/mg, n = 4-5;p = 0.03)和脊髓(331.9±17.1 vs 239.2±31.7 ng/mg, p = 0.03)表明血脑屏障通透性增加。我们通过RT-qPCR从全天每四小时收集一次的前额皮质样本中测量基因表达。然后我们对结果拟合余弦曲线以评估昼夜节律性，并通过额外的平方和F检验确定差异。我们测量了水通道蛋白4 (aqp4)的表达，因为它是脑内血脑屏障通透性和淋巴通量的关键组成部分。Bmal1KO aqp4振幅减弱(1.2±0.2 vs 0.8±0.2 Ct);P = 0.004比较拟合)。Bmal1也参与内皮素-1 (edn1)表达节律，我们发现Bmal1KO大鼠的edn1振幅显著减弱(0.41±0.19 vs 1.31±0.39 Ct;P < 0.001(拟合比较)和edn1峰值表达相移(10.71±0.48 vs 19.72±0.30授时数时间)。这些数据表明，大鼠昼夜节律基因Bmal1的缺失会导致血脑屏障通透性增加，并破坏与中枢流体稳态有关的基因的昼夜节律。这些结果表明，昼夜节律基因在维持适当的中枢流体动力学中是不可或缺的，这些节律的改变可能在与昼夜节律中断相关的神经退行性疾病中发挥作用。这是在2023年美国生理学峰会会议上发表的全文摘要，仅以HTML格式提供。此摘要没有附加版本或附加内容。生理学没有参与同行评议过程。
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Pub Date : 2023-05-01DOI: 10.1152/physiol.2023.38.s1.5735271
Christian Valtierra
Nociception is the neural process of encoding and processing noxious stimuli; this sensation is transduced by specialized sensory neurons called nociceptors. Activation of nociceptors typically evoke so called “nocifensive behavioral responses,” that are generally aimed at decreasing exposure to the noxious stimulus. Intense activation of nociceptors can result in long lasting changes in the nervous system, as well as a subsequent decrease in the threshold for perceiving and acting upon stimuli as if it were harmful—this persistent change in the organism is nociceptive sensitization. The hornworm, Manduca sexta, displays rapid defensive “striking” behavior that accurately targets the cite of noxious stimulation of the abdominal body wall. Nociceptive sensitization of the defensive strike response has been induced behaviorally and recapitulated in vitro through extracellular electrophysiology, where it appears to be encoded by an increase in the firing frequency occurring within the central nervous system, rather than changes in peripheral nociceptor signaling. The current model proposed by Tabuena et al. (2017), argues that central neural alterations are responsible for the neural correlate of nociceptive sensitization (Tabuena et al., 2017), rather than changes in spiking activity of the primary sensory neurons. While the changes in firing frequency centrally are undisputed, relegating sensitization to the CNS alone may be overly simplistic, as the model is based on the comparison of threshold crossings of purported multiunit activity, rather than of single cell activity of known populations of sensory and/or higher order neurons. Moreover, studies in the vertebrate and invertebrate literature alike have reported retrograde sensitization of primary nociceptors (Parada et al., 2003; Xie et al., 2022; Babcock et al., 2000), mediated by inflammatory signals from the cite of injury, thus complicating the question of central versus peripheral sensitization. Therefore, it is worth re-examining the possibility of presynaptic plasticity as an added contribution to nociceptive sensitization. In this work, we propose leveraging available neuroanatomical data to re-analyze the Tabuena et al. dataset, by performing spike sorting and spike train analyses to tease apart the signals originating from the peripheral sensory neurons to obtain input/output relationships between the identified sensory units and VNC spiking during stimulation. Distinguishing the nociceptor and tracking its stimulus dependent firing is expected to elucidate the contribution of nociceptor activity in nociceptive sensitization. Genentech Scholars Foundation This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
伤害感觉是对有害刺激进行编码和加工的神经过程;这种感觉是由称为伤害感受器的特殊感觉神经元传导的。伤害感受器的激活通常会引起所谓的“有害行为反应”，这种反应通常旨在减少对有害刺激的暴露。痛觉感受器的强烈激活会导致神经系统长期持续的变化，以及随后感知刺激和对刺激做出有害反应的阈值的降低——这种持续的变化就是痛觉敏化。这种名为Manduca sexta的角虫表现出快速的防御性“攻击”行为，准确地瞄准了对腹壁的有害刺激。防御性打击反应的伤害性敏化已经在行为上被诱导，并在体外通过细胞外电生理学重现，其中它似乎是由中枢神经系统内发生的放电频率增加编码的，而不是外周伤害感受器信号的变化。Tabuena等人(2017)提出的当前模型认为，中枢神经的改变是造成伤害性敏化的神经关联的原因(Tabuena等人，2017)，而不是主要感觉神经元尖峰活动的变化。虽然中心放电频率的变化是无可争议的，但将致敏性单独归于中枢神经系统可能过于简单，因为该模型是基于对所谓的多单元活动的阈值交叉的比较，而不是基于已知的感觉和/或高阶神经元群体的单细胞活动。此外，脊椎动物和无脊椎动物的研究文献都报道了初级伤害感受器的逆行致敏(Parada et al.， 2003;谢等，2022;Babcock等人，2000)，由来自损伤的炎症信号介导，从而使中枢与外周致敏的问题复杂化。因此，值得重新研究突触前可塑性作为伤害敏感化的额外贡献的可能性。在这项工作中，我们建议利用现有的神经解剖学数据来重新分析Tabuena等人的数据集，通过执行尖峰排序和尖峰序列分析来梳理来自周围感觉神经元的信号，以获得在刺激期间识别的感觉单元和VNC尖峰之间的输入/输出关系。区分伤害感受器并追踪其刺激依赖性放电有望阐明伤害感受器活动在伤害致敏中的作用。这是在2023年美国生理学峰会上发表的全文摘要，仅以HTML格式提供。此摘要没有附加版本或附加内容。生理学没有参与同行评议过程。
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