{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:33:32Z","timestamp":1771461212938,"version":"3.50.1"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T00:00:00Z","timestamp":1654819200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T00:00:00Z","timestamp":1654819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT081195MA"],"award-info":[{"award-number":["WT081195MA"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT081195MA"],"award-info":[{"award-number":["WT081195MA"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["RG\/12\/14\/29885"],"award-info":[{"award-number":["RG\/12\/14\/29885"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["RG\/12\/14\/29885"],"award-info":[{"award-number":["RG\/12\/14\/29885"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pflugers Arch - Eur J Physiol"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We recently demonstrated that the hypoxic ventilatory response (HVR) is facilitated by the AMP-activated protein kinase (AMPK) in catecholaminergic neural networks that likely lie downstream of the carotid bodies within the caudal brainstem. Here, we further subcategorise the neurons involved, by cross-comparison of mice in which the genes encoding the AMPK-\u03b11 (<jats:italic>Prkaa1<\/jats:italic>) and AMPK-\u03b12 (<jats:italic>Prkaa2<\/jats:italic>) catalytic subunits were deleted in catecholaminergic (TH-Cre) or adrenergic (PNMT-Cre) neurons. As expected, the HVR was markedly attenuated in mice with AMPK-\u03b11\/\u03b12 deletion in catecholaminergic neurons, but surprisingly was modestly augmented in mice with AMPK-\u03b11\/\u03b12 deletion in adrenergic neurons when compared against a variety of controls (TH-Cre, PNMT-Cre, AMPK-\u03b11\/\u03b12 floxed). Moreover, AMPK-\u03b11\/\u03b12 deletion in catecholaminergic neurons precipitated marked hypoventilation and apnoea during poikilocapnic hypoxia, relative to controls, while mice with AMPK-\u03b11\/\u03b12 deletion in adrenergic neurons entered relative hyperventilation with reduced apnoea frequency and duration. We conclude, therefore, that AMPK-dependent modulation of non-adrenergic networks may facilitate increases in ventilatory drive that shape the classical HVR, whereas AMPK-dependent modulation of adrenergic networks may provide some form of negative feedback or inhibitory input to moderate HVR, which could, for example, protect against hyperventilation-induced hypocapnia and respiratory alkalosis.<\/jats:p>","DOI":"10.1007\/s00424-022-02713-8","type":"journal-article","created":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T01:03:07Z","timestamp":1654822987000},"page":"89-99","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["AMPK facilitates the hypoxic ventilatory response through non-adrenergic mechanisms at the brainstem"],"prefix":"10.1007","volume":"475","author":[{"given":"Sandy","family":"MacMillan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. Mark","family":"Evans","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,6,10]]},"reference":[{"key":"2713_CR1","doi-asserted-by":"publisher","first-page":"5806","DOI":"10.1523\/JNEUROSCI.1106-09.2009","volume":"29","author":"SB Abbott","year":"2009","unstructured":"Abbott SB et al (2009) Photostimulation of retrotrapezoid nucleus phox2b-expressing neurons in vivo produces long-lasting activation of breathing in rats. J Neurosci\u202f: Off J Soc Neurosci 29:5806\u20135819","journal-title":"J Neurosci : Off J Soc Neurosci"},{"key":"2713_CR2","doi-asserted-by":"publisher","first-page":"3164","DOI":"10.1523\/JNEUROSCI.1046-12.2013","volume":"33","author":"SB Abbott","year":"2013","unstructured":"Abbott SB et al (2013) Selective optogenetic activation of rostral ventrolateral medullary catecholaminergic neurons produces cardiorespiratory stimulation in conscious mice. J Neurosci 33:3164\u20133177","journal-title":"J Neurosci"},{"key":"2713_CR3","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1620\/tjem.209.125","volume":"209","author":"T Adachi","year":"2006","unstructured":"Adachi T et al (2006) Mice with blunted hypoxic ventilatory response are susceptible to respiratory disturbance during hypoxia. Tohoku J Exp Med 209:125\u2013134","journal-title":"Tohoku J Exp Med"},{"key":"2713_CR4","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1523\/JNEUROSCI.2923-14.2015","volume":"35","author":"TM Basting","year":"2015","unstructured":"Basting TM et al (2015) Hypoxia silences retrotrapezoid nucleus respiratory chemoreceptors via alkalosis. J Neurosci: Off J Soc Neurosci 35:527\u2013543","journal-title":"J Neurosci: Off J Soc Neurosci"},{"key":"2713_CR5","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.1164\/rccm.201407-1262OC","volume":"190","author":"PG Burke","year":"2014","unstructured":"Burke PG et al (2014) Optogenetic stimulation of adrenergic C1 neurons causes sleep state-dependent cardiorespiratory stimulation and arousal with sighs in rats. Am J Respir Crit Care Med 190:1301\u20131310","journal-title":"Am J Respir Crit Care Med"},{"issue":"118","key":"2713_CR6","doi-asserted-by":"publisher","first-page":"1491","DOI":"10.1152\/japplphysiol.00164.2015","volume":"1985","author":"PG Burke","year":"2015","unstructured":"Burke PG, Kanbar R, Viar KE, Stornetta RL, Guyenet PG (2015) Selective optogenetic stimulation of the retrotrapezoid nucleus in sleeping rats activates breathing without changing blood pressure or causing arousal or sighs. J Appl Physiol 1985(118):1491\u20131501","journal-title":"J Appl Physiol"},{"issue":"88","key":"2713_CR7","doi-asserted-by":"publisher","first-page":"1840","DOI":"10.1152\/jappl.2000.88.5.1840","volume":"1985","author":"AK Curran","year":"2000","unstructured":"Curran AK et al (2000) Ventilatory responses to specific CNS hypoxia in sleeping dogs. J Appl Physiol 1985(88):1840\u20131852","journal-title":"J Appl Physiol"},{"key":"2713_CR8","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1113\/jphysiol.2006.119594","volume":"578","author":"TA Day","year":"2007","unstructured":"Day TA, Wilson RJ (2007) Brainstem PCO2 modulates phrenic responses to specific carotid body hypoxia in an in situ dual perfused rat preparation. J Physiol 578:843\u2013857","journal-title":"J Physiol"},{"key":"2713_CR9","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1113\/expphysiol.2004.028985","volume":"90","author":"JA Dempsey","year":"2005","unstructured":"Dempsey JA (2005) Crossing the apnoeic threshold: causes and consequences. Exp Physiol 90:13\u201324","journal-title":"Exp Physiol"},{"key":"2713_CR10","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1002\/dvdy.20188","volume":"231","author":"SN Ebert","year":"2004","unstructured":"Ebert SN et al (2004) Targeted insertion of the Cre-recombinase gene at the phenylethanolamine n-methyltransferase locus: a new model for studying the developmental distribution of adrenergic cells. Dev Dyn: an off Publ Am Assoc Anatomists 231:849\u2013858","journal-title":"Dev Dyn: an off Publ Am Assoc Anatomists"},{"key":"2713_CR11","doi-asserted-by":"publisher","first-page":"2561","DOI":"10.1042\/BCJ20160002","volume":"473","author":"AM Evans","year":"2016","unstructured":"Evans AM, Mahmoud AD, Moral-Sanz J, Hartmann S (2016) The emerging role of AMPK in the regulation of breathing and oxygen supply. Biochem J 473:2561\u20132572","journal-title":"Biochem J"},{"key":"2713_CR12","first-page":"384","volume":"46","author":"GT Foster","year":"2001","unstructured":"Foster GT, Vaziri ND, Sassoon CS (2001) Respiratory alkalosis. Respir Care 46:384\u2013391","journal-title":"Respir Care"},{"key":"2713_CR13","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1016\/j.cmet.2013.08.019","volume":"18","author":"GJ Gowans","year":"2013","unstructured":"Gowans GJ, Hawley SA, Ross FA, Hardie DG (2013) AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell Metab 18:556\u2013566","journal-title":"Cell Metab"},{"key":"2713_CR14","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/S0034-5687(00)00125-0","volume":"121","author":"PG Guyenet","year":"2000","unstructured":"Guyenet PG (2000) Neural structures that mediate sympathoexcitation during hypoxia. Respir Physiol 121:147\u2013162","journal-title":"Respir Physiol"},{"key":"2713_CR15","doi-asserted-by":"publisher","first-page":"R187","DOI":"10.1152\/ajpregu.00054.2013","volume":"305","author":"PG Guyenet","year":"2013","unstructured":"Guyenet PG et al (2013) C1 neurons: the body\u2019s EMTs. Am J Physiol Regul Integr Comp Physiol 305:R187-204","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"2713_CR16","doi-asserted-by":"publisher","first-page":"R187","DOI":"10.1152\/ajpregu.00054.2013","volume":"305","author":"PG Guyenet","year":"2013","unstructured":"Guyenet PG et al (2013) C1 neurons: the body\u2019s EMTs. Am J Phys - Regul, Integr Comp Physiol 305:R187\u2013R204","journal-title":"Am J Phys - Regul, Integr Comp Physiol"},{"key":"2713_CR17","doi-asserted-by":"publisher","first-page":"1511","DOI":"10.1002\/cphy.c140004","volume":"4","author":"PG Guyenet","year":"2014","unstructured":"Guyenet PG (2014) Regulation of breathing and autonomic outflows by chemoreceptors. Compr Physiol 4:1511\u20131562","journal-title":"Compr Physiol"},{"key":"2713_CR18","doi-asserted-by":"publisher","first-page":"18132","DOI":"10.1073\/pnas.1106201108","volume":"108","author":"N Ikematsu","year":"2011","unstructured":"Ikematsu N et al (2011) Phosphorylation of the voltage-gated potassium channel Kv2.1 by AMP-activated protein kinase regulates membrane excitability. Proc Natl Acad Sci U S A 108:18132\u201318137","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2713_CR19","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.resp.2016.10.012","volume":"235","author":"CM Ivy","year":"2017","unstructured":"Ivy CM, Scott GR (2017) Ventilatory acclimatization to hypoxia in mice: methodological considerations. Respir Physiol Neurobiol 235:95\u2013103","journal-title":"Respir Physiol Neurobiol"},{"key":"2713_CR20","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1002\/cne.902330305","volume":"233","author":"M Kalia","year":"1985","unstructured":"Kalia M, Woodward DJ, Smith WK, Fuxe K (1985) Rat medulla oblongata. IV. Topographical distribution of catecholaminergic neurons with quantitative three-dimensional computer reconstruction. J Comp Neurol 233:350\u2013364","journal-title":"J Comp Neurol"},{"key":"2713_CR21","doi-asserted-by":"publisher","first-page":"3211","DOI":"10.1096\/fj.14-250449","volume":"28","author":"L Lantier","year":"2014","unstructured":"Lantier L et al (2014) AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity. FASEB J 28:3211\u20133224","journal-title":"FASEB J"},{"key":"2713_CR22","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1002\/gene.20065","volume":"40","author":"J Lindeberg","year":"2004","unstructured":"Lindeberg J et al (2004) Transgenic expression of Cre recombinase from the tyrosine hydroxylase locus. Genesis 40:67\u201373","journal-title":"Genesis"},{"key":"2713_CR23","doi-asserted-by":"publisher","first-page":"1032","DOI":"10.1164\/rccm.201508-1667OC","volume":"193","author":"AD Mahmoud","year":"2016","unstructured":"Mahmoud AD et al (2016) AMPK deficiency blocks the hypoxic ventilatory response and thus precipitates hypoventilation and apnea. Am J Respir Crit Care Med 193:1032\u20131043","journal-title":"Am J Respir Crit Care Med"},{"key":"2713_CR24","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/0165-1838(90)90252-E","volume":"30","author":"J Minson","year":"1990","unstructured":"Minson J, Llewellyn-Smith I, Neville A, Somogyi P, Chalmers J (1990) Quantitative analysis of spinally projecting adrenaline-synthesising neurons of C1, C2 and C3 groups in rat medulla oblongata. J Auton Nerv Syst 30:209\u2013220","journal-title":"J Auton Nerv Syst"},{"key":"2713_CR25","doi-asserted-by":"publisher","first-page":"3419","DOI":"10.1113\/jphysiol.2013.269829","volume":"592","author":"CA Nurse","year":"2014","unstructured":"Nurse CA (2014) Synaptic and paracrine mechanisms at carotid body arterial chemoreceptors. J Physiol 592:3419\u20133426","journal-title":"J Physiol"},{"key":"2713_CR26","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1111\/j.1440-1681.2008.04906.x","volume":"35","author":"PM Pilowsky","year":"2008","unstructured":"Pilowsky PM et al (2008) Metabotropic neurotransmission and integration of sympathetic nerve activity by the rostral ventrolateral medulla in the rat. Clin Exp Pharmacol Physiol 35:508\u2013511","journal-title":"Clin Exp Pharmacol Physiol"},{"key":"2713_CR27","doi-asserted-by":"publisher","first-page":"2987","DOI":"10.1111\/febs.13698","volume":"283","author":"FA Ross","year":"2016","unstructured":"Ross FA, MacKintosh C, Hardie DG (2016) AMP-activated protein kinase: a cellular energy sensor that comes in 12 flavours. FEBS J 283:2987\u20133001","journal-title":"FEBS J"},{"key":"2713_CR28","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1113\/jphysiol.1993.sp019490","volume":"460","author":"CA Smith","year":"1993","unstructured":"Smith CA, Engwall MJ, Dempsey JA, Bisgard GE (1993) Effects of specific carotid body and brain hypoxia on respiratory muscle control in the awake goat. J Physiol 460:623\u2013640","journal-title":"J Physiol"},{"key":"2713_CR29","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.tins.2012.11.004","volume":"36","author":"JC Smith","year":"2013","unstructured":"Smith JC, Abdala AP, Borgmann A, Rybak IA, Paton JF (2013) Brainstem respiratory networks: building blocks and microcircuits. Trends Neurosci 36:152\u2013162","journal-title":"Trends Neurosci"},{"key":"2713_CR30","doi-asserted-by":"publisher","first-page":"9725","DOI":"10.1523\/JNEUROSCI.1268-19.2019","volume":"39","author":"G Souza","year":"2019","unstructured":"Souza G, Stornetta RL, Stornetta DS, Abbott SBG, Guyenet PG (2019) Contribution of the retrotrapezoid nucleus and carotid bodies to hypercapnia- and hypoxia-induced arousal from sleep. J Neurosci 39:9725\u20139737","journal-title":"J Neurosci"},{"key":"2713_CR31","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1002\/(SICI)1096-9861(19991227)415:4<482::AID-CNE5>3.0.CO;2-4","volume":"415","author":"RL Stornetta","year":"1999","unstructured":"Stornetta RL, Akey PJ, Guyenet PG (1999) Location and electrophysiological characterization of rostral medullary adrenergic neurons that contain neuropeptide Y mRNA in rat medulla. J Comp Neurol 415:482\u2013500","journal-title":"J Comp Neurol"},{"key":"2713_CR32","doi-asserted-by":"crossref","first-page":"R1371","DOI":"10.1152\/ajpcell.1994.267.5.C1371","volume":"267","author":"CG Tankersley","year":"1994","unstructured":"Tankersley CG, Fitzgerald RS, Kleeberger SR (1994) Differential control of ventilation among inbred strains of mice. Am J Physiol 267:R1371-1377","journal-title":"Am J Physiol"},{"issue":"88","key":"2713_CR33","doi-asserted-by":"publisher","first-page":"2310","DOI":"10.1152\/jappl.2000.88.6.2310","volume":"1985","author":"CG Tankersley","year":"2000","unstructured":"Tankersley CG, Elston RC, Schnell AH (2000) Genetic determinants of acute hypoxic ventilation: patterns of inheritance in mice. J Appl Physiol 1985(88):2310\u20132318","journal-title":"J Appl Physiol"},{"key":"2713_CR34","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1152\/physrev.00012.2009","volume":"90","author":"LJ Teppema","year":"2010","unstructured":"Teppema LJ, Dahan A (2010) The ventilatory response to hypoxia in mammals: mechanisms, measurement, and analysis. Physiol Rev 90:675\u2013754","journal-title":"Physiol Rev"},{"issue":"102","key":"2713_CR35","doi-asserted-by":"publisher","first-page":"1927","DOI":"10.1152\/japplphysiol.00909.2006","volume":"1985","author":"NL Ward","year":"2007","unstructured":"Ward NL et al (2007) Cerebral angiogenic factors, angiogenesis, and physiological response to chronic hypoxia differ among four commonly used mouse strains. J Appl Physiol 1985(102):1927\u20131935","journal-title":"J Appl Physiol"},{"key":"2713_CR36","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1002\/cphy.c140040","volume":"6","author":"RJ Wilson","year":"2016","unstructured":"Wilson RJ, Teppema LJ (2016) Integration of central and peripheral respiratory chemoreflexes. Compr Physiol 6:1005\u20131041","journal-title":"Compr Physiol"},{"key":"2713_CR37","doi-asserted-by":"publisher","unstructured":"Evans AM, Hardie DG (2020) AMPK and the Need to Breathe and Feed: What's the Matter with Oxygen? Int J Mol Sci 21(10):3518. https:\/\/doi.org\/10.3390\/ijms21103518","DOI":"10.3390\/ijms21103518"},{"key":"2713_CR38","unstructured":"Mahmoud AD (2014) Thesis: The loss of LKB1 and the AMP-activated protein kinase in catecholaminergic cells and the effect on the ventilatory response to hypoxia and hypercapnia. (University of Edinburgh, University of Edinburgh) 1\u2013273."},{"key":"#cr-split#-2713_CR39.1","unstructured":"Franklin KBJ, Paxinos G (2008) The mouse brain in stereotaxic coordinates (Elsevier, Amsterdam"},{"key":"#cr-split#-2713_CR39.2","unstructured":"London, ed. 3rd, 2008), pp. xxviii, 325"}],"container-title":["Pfl\u00fcgers Archiv - European Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00424-022-02713-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00424-022-02713-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00424-022-02713-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T03:10:14Z","timestamp":1672974614000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00424-022-02713-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,10]]},"references-count":40,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2023,1]]}},"alternative-id":["2713"],"URL":"https:\/\/doi.org\/10.1007\/s00424-022-02713-8","relation":{},"ISSN":["0031-6768","1432-2013"],"issn-type":[{"value":"0031-6768","type":"print"},{"value":"1432-2013","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,10]]},"assertion":[{"value":"13 April 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 May 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 June 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ethical approval was given by the Ethics Committee, College of Medicine, University of Edinburgh.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All experimental procedures were covered by the UK Home Office Project Licence PBA4DCF9D.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human and Animal Ethics"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}