{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T07:06:49Z","timestamp":1791443209884,"version":"4.3.3"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"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\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Integr. Neurosci."],"abstract":"<jats:p>We report in a companion paper that in the mouse brain, in contrast to the 1,000-fold variation in local neuronal densities across sites, capillary density (measured both as capillary volume fraction and as density of endothelial cells) show very little variation, of the order of only fourfold. Here we confirm that finding in the rat brain and, using published rates of local blood flow and glucose use at rest, proceed to show that what small variation exists in capillary density across sites in the rat brain is strongly and linearly correlated to variations in local rates of brain metabolism at rest. Crucially, we show that such variations in local capillary density and brain metabolism are not correlated with local variations in neuronal density, which contradicts expectations that use-dependent self-organization would cause brain sites with more neurons to have higher capillary densities due to higher energetic demands. In fact, we show that the ratio of endothelial cells per neuron serves as a linear indicator of average blood flow and glucose use per neuron at rest, and both increase as neuronal density decreases across sites. In other words, because of the relatively tiny variation in capillary densities compared to the large variation in neuronal densities, the anatomical infrastructure of the brain is such that those sites with fewer neurons have more energy supplied per neuron, which matches a higher average rate of energy use per neuron, compared to sites with more neurons. Taken together, our data support the interpretation that resting brain metabolism is not demand-based, but rather limited by its capillary supply, and raise multiple implications for the differential vulnerability of diverse brain areas to disease and aging.<\/jats:p>","DOI":"10.3389\/fnint.2022.821850","type":"journal-article","created":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T05:54:11Z","timestamp":1654840451000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Resting Rates of Blood Flow and Glucose Use per Neuron Are Proportional to Number of Endothelial Cells Available per Neuron Across Sites in the Rat Brain"],"prefix":"10.3389","volume":"16","author":[{"given":"Lissa","family":"Ventura-Antunes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oisharya Moon","family":"Dasgupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzana","family":"Herculano-Houzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1124\/pr.111.004515","article-title":"Mechanisms of penile erection and basis for pharmacological treatment of erectile dysfunction.","volume":"63","author":"Andersson","year":"2011","journal-title":"Pharmacol. Rev."},{"key":"B2","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/0006-8993(96)00485-4","article-title":"Effects of dark-rearing on the vascularization of the developmental rat visual cortex.","volume":"732","author":"Argando\u00f1a","year":"1996","journal-title":"Brain Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1016\/j.cmet.2019.05.010","article-title":"Age mosaicism across multiple scales in adult tissues.","volume":"30","author":"Arrojo e Drigo","year":"2019","journal-title":"Cell Metab."},{"key":"B4","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1016\/S1474-4422(16)30029-1","article-title":"Relation of cerebral vessel disease to Alzheimer\u2019s disease dementia and cognitive function in elderly people: a cross-sectional study.","volume":"15","author":"Arvanitakis","year":"2016","journal-title":"Lancet Neurol."},{"key":"B5","author":"Aschoff","year":"1971","journal-title":"Energiehaushalt und Temperaturregulation."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1097\/00004647-200110000-00001","article-title":"An energy budget for signaling in the grey matter of the brain.","volume":"21","author":"Attwell","year":"2001","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"B7","doi-asserted-by":"publisher","first-page":"10506","DOI":"10.1073\/pnas.162216899","article-title":"Supply-demand balance and metabolic scaling","volume":"99","author":"Banavar","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B8","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1016\/0304-3940(87)90113-3","article-title":"Complex experience promotes capillary formation in young rat visual cortex.","volume":"83","author":"Black","year":"1987","journal-title":"Neurosci. Lett."},{"key":"B9","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1002\/cne.902880304","article-title":"Metabolic anatomy of brain: a comparison of regional capillary density, glucose metabolism, and enzyme activities.","volume":"288","author":"Borowsky","year":"1989","journal-title":"J. Comp. Neurol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1111\/j.1365-2990.2010.01139.x","article-title":"Cerebral microvascular pathology in aging and neurodegeneration.","volume":"37","author":"Brown","year":"2011","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1016\/j.neuroscience.2004.09.011","article-title":"Glucose transporter plasticity during memory processing.","volume":"130","author":"Choeiri","year":"2005","journal-title":"Neuroscience"},{"key":"B12","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1007\/0-387-26206-7_36","article-title":"The pathways of oxygen in brain I. Delivery and metabolism of oxygen.","volume":"566","author":"Gjedde","year":"2005","journal-title":"."},{"key":"B13","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1038\/jcbfm.1985.36","article-title":"Double-Tracer Study of the Fine Regional Blood\u2014Brain Glucose Transfer in the Rat by Computer-Assisted Autoradiography.","volume":"5","author":"Gjedde","year":"1985","journal-title":"J. Cerebr. Blood Flow Metab."},{"key":"B14","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1177\/0271678x16671146","article-title":"The capillary bed offers the largest hemodynamic resistance to the cortical blood supply.","volume":"37","author":"Gould","year":"2017","journal-title":"J. Cereb. Blood F low Metab."},{"key":"B15","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1111\/j.1365-2818.1987.tb02837.x","article-title":"The efficiency of systematic sampling in stereology and its prediction.","volume":"147","author":"Gundersen","year":"1987","journal-title":"J. Microscopy."},{"key":"B16","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1152\/jappl.2000.88.2.560","article-title":"Structural basis of muscle O(2) diffusing capacity: evidence from muscle function in situ.","volume":"88","author":"Hepple","year":"1985","journal-title":"J. Appl. Physiol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e17514","DOI":"10.1371\/journal.pone.0017514","article-title":"Scaling of brain metabolism with a fixed energy budget per neuron: implications for neuronal activity, plasticity and evolution.","volume":"6","author":"Herculano-Houzel","year":"2011","journal-title":"PLoS One"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.1002\/glia.22683","article-title":"The glia\/neuron ratio: how it varies uniformly across brain structures and species and what that means for brain physiology and evolution.","volume":"62","author":"Herculano-Houzel","year":"2014","journal-title":"Glia"},{"key":"B19","doi-asserted-by":"publisher","first-page":"12138","DOI":"10.1073\/pnas.0604911103","article-title":"Cellular scaling rules for rodent brains.","volume":"103","author":"Herculano-Houzel","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"B20","doi-asserted-by":"publisher","first-page":"818685","DOI":"10.3389\/fnint.2022.818685","article-title":"From a demand-based to a supply-limited framework of brain metabolism","volume":"16","author":"Herculano-Houzel","year":"2022","journal-title":"Front. Integr. Neurosci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.neuron.2017.07.030","article-title":"The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease.","volume":"96","author":"Iadecola","year":"2017","journal-title":"Neuron"},{"key":"B22","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1038\/jcbfm.1992.14","article-title":"Exercise and the brain: angiogenesis in the adult rat cerebellum after vigorous physical activity and motor skill learning.","volume":"12","author":"Isaacs","year":"1992","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"B23","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1038\/jcbfm.2011.153","article-title":"The roles of cerebral blood flow, capillary transit time heterogeneity, and oxygen tension in brain oxygenation and metabolism.","volume":"32","author":"Jesperson","year":"2012","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"B24","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1016\/0021-9681(56)90146-1","article-title":"Human cerebral blood flow and oxygen consumption as related to aging.","volume":"3","author":"Kety","year":"1956","journal-title":"J. Chron. Dis."},{"key":"B25","doi-asserted-by":"publisher","first-page":"H1333","DOI":"10.1152\/ajpheart.1986.251.6.H1333","article-title":"Interdependency of local capillary density, blood flow, and metabolism in rat brains.","volume":"251","author":"Klein","year":"1986","journal-title":"Am. J. Physiol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1113\/jphysiol.1919.sp001839","article-title":"The number and distribution of capillaries in muscles with calculations of the oxygen pressure head necessary for supplying the tissue.","volume":"52","author":"Krogh","year":"1919","journal-title":"J. Physiol."},{"key":"B27","first-page":"261","article-title":"Capillary circulation in the brain.","volume":"4","author":"Kuschinsky","year":"1992","journal-title":"Cerebrovasc. Brain Metab. Rev."},{"key":"B28","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1038\/jcbfm.2013.181","article-title":"The oxygen paradox of neurovascular coupling.","volume":"34","author":"Leithner","year":"2014","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"B29","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.brainres.2003.12.032","article-title":"Differential effects of ibogaine on local cerebral glucose utilization in drug-na\u00efve and morphine-dependent rats.","volume":"1003","author":"Levant","year":"2004","journal-title":"Brain Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e1001469","DOI":"10.1371\/journal.pbio.1001469","article-title":"Radial glial neural progenitors regulate nascent brain vascular network stabilization via inhibition of Wnt signaling.","volume":"11","author":"Ma","year":"2013","journal-title":"PLoS Biol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1093\/cercor\/6.1.50","article-title":"Cellular bases of brain energy metabolism and their relevance to functional brain imaging: evidence for a prominent role of astrocytes.","volume":"6","author":"Magistretti","year":"1996","journal-title":"Cereb. Cx"},{"key":"B32","doi-asserted-by":"publisher","first-page":"H416","DOI":"10.1152\/ajpheart.1982.243.3.H416","article-title":"Local cerebral circulatory and metabolic effects of indomethacin.","volume":"243","author":"McCulloch","year":"1982","journal-title":"Am. J. Physiol. -Heart Circulat. Physiol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1006\/nimg.2002.1114","article-title":"Time-related increase of oxygen utilization in continuously activated human visual cortex.","volume":"16","author":"Mintun","year":"2002","journal-title":"NeuroImage"},{"key":"B34","doi-asserted-by":"publisher","first-page":"127","DOI":"10.3389\/fnana.2014.00127","article-title":"All brains are made of this: a fundamental building block of brain matter with matching neuronal and glial masses.","volume":"8","author":"Mota","year":"2014","journal-title":"Front. Neuroanat."},{"key":"B35","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1242\/dev.116.1.201","article-title":"NeuN, a neuronal specific nuclear protein in vertebrates.","volume":"116","author":"Mullen","year":"1992","journal-title":"Develop"},{"key":"B36","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/0006-8993(83)90762-x","article-title":"Electrical stimulation of cerebellar fastigial nucleus increases cerebral cortical blood flow without change in local metabolism: Evidence for an intrinsic system in brain for primary vasodilation.","volume":"260","author":"Nakai","year":"1983","journal-title":"Brain Res."},{"key":"B37","author":"Paxinos","year":"2006","journal-title":"The rat brain in stereotaxic coordinates: hardcover edition."},{"key":"B38","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1002\/cne.901450105","article-title":"Mode of cell migration to superficial layers of fetal monkey neocortex","volume":"145","author":"Rakic","year":"1972","journal-title":"J. Comp. Neurol."},{"key":"B39","doi-asserted-by":"crossref","DOI":"10.1093\/oso\/9780195074017.001.0001","author":"Ram\u00f3n y Cajal","year":"1995","journal-title":"Histology of the nervous system of man and vertebrates (trans. Swanson N, Swanson LW)."},{"key":"B40","doi-asserted-by":"publisher","first-page":"G435","DOI":"10.1152\/ajpgi.1982.242.5.G435","article-title":"Role of capillary recruitment in the regulation of intestinal oxygenation.","volume":"242","author":"Shepherd","year":"1982","journal-title":"Am. J. Physiol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/0165-3806(88)90107-1","article-title":"Direct evidence that complex experience increases capillary branching and surface area in visual cortex of young rats.","volume":"43","author":"Sirevaag","year":"1988","journal-title":"Dev. Brain Res."},{"key":"B42","doi-asserted-by":"crossref","first-page":"e13486","DOI":"10.1111\/apha.13486","article-title":"Contribution of oxygen extraction fraction to maximal oxygen uptake in healthy young men.","volume":"230","author":"Skattebo","year":"2020","journal-title":"Acta Physiol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1111\/j.1471-4159.1977.tb10649.x","article-title":"The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat.","volume":"28","author":"Sokoloff","year":"1977","journal-title":"J. Neurochem."},{"key":"B44","doi-asserted-by":"publisher","first-page":"4493","DOI":"10.1523\/jneurosci.3199-16.2017","article-title":"SOX9 is an astrocyte-specific marker in the adult brain outside the neurogenic regions.","volume":"37","author":"Sun","year":"2017","journal-title":"J. Neurosci."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1318","DOI":"10.1038\/s41593-018-0234-x","article-title":"The role of brain vasculature in neurodegenerative disorders.","volume":"21","author":"Sweeney","year":"2018","journal-title":"Nat.eurosci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/0165-3806(87)90242-2","article-title":"The metabolic consequence of visual deprivation in the rat.","volume":"37","author":"Toga","year":"1987","journal-title":"Dev. Brain Res."},{"key":"B47","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1046\/j.1365-201x.2000.00712.x","article-title":"Diffusive resistance to O2 transport in muscle.","volume":"168","author":"Wagner","year":"2000","journal-title":"Acta Physiol. Scand"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1312","DOI":"10.1097\/00004647-199611000-00028","article-title":"Brain capillary perfusion during sleep.","volume":"16","author":"Zoccoli","year":"1996","journal-title":"J. Cereb. Blood Flow Metab."}],"container-title":["Frontiers in Integrative Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnint.2022.821850\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,22]],"date-time":"2023-11-22T22:39:24Z","timestamp":1700692764000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnint.2022.821850\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,10]]},"references-count":48,"alternative-id":["10.3389\/fnint.2022.821850"],"URL":"https:\/\/doi.org\/10.3389\/fnint.2022.821850","relation":{},"ISSN":["1662-5145"],"issn-type":[{"value":"1662-5145","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,10]]},"article-number":"821850"}}