Neurovascular coupling and oxygenation are decreased in hippocampus compared to neocortex because of microvascular differences.
Adenosine Triphosphate
/ biosynthesis
Alzheimer Disease
/ physiopathology
Animals
Cell Hypoxia
/ physiology
Dementia, Vascular
/ physiopathology
Female
Hippocampus
/ blood supply
Humans
Intravital Microscopy
Laser-Doppler Flowmetry
Male
Mice
Microcirculation
/ physiology
Microscopy, Fluorescence, Multiphoton
Microvessels
/ diagnostic imaging
Models, Animal
Neocortex
/ blood supply
Neurons
/ metabolism
Neurovascular Coupling
/ physiology
Oxidative Phosphorylation
Oxygen
/ analysis
Spatial Memory
/ physiology
Visual Cortex
/ blood supply
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
27 05 2021
27 05 2021
Historique:
received:
30
10
2019
accepted:
26
04
2021
entrez:
28
5
2021
pubmed:
29
5
2021
medline:
10
6
2021
Statut:
epublish
Résumé
The hippocampus is essential for spatial and episodic memory but is damaged early in Alzheimer's disease and is very sensitive to hypoxia. Understanding how it regulates its oxygen supply is therefore key for designing interventions to preserve its function. However, studies of neurovascular function in the hippocampus in vivo have been limited by its relative inaccessibility. Here we compared hippocampal and visual cortical neurovascular function in awake mice, using two photon imaging of individual neurons and vessels and measures of regional blood flow and haemoglobin oxygenation. We show that blood flow, blood oxygenation and neurovascular coupling were decreased in the hippocampus compared to neocortex, because of differences in both the vascular network and pericyte and endothelial cell function. Modelling oxygen diffusion indicates that these features of the hippocampal vasculature may restrict oxygen availability and could explain its sensitivity to damage during neurological conditions, including Alzheimer's disease, where the brain's energy supply is decreased.
Identifiants
pubmed: 34045465
doi: 10.1038/s41467-021-23508-y
pii: 10.1038/s41467-021-23508-y
pmc: PMC8160329
doi:
Substances chimiques
Adenosine Triphosphate
8L70Q75FXE
Oxygen
S88TT14065
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3190Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_15071
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S026495/1
Pays : United Kingdom
Commentaires et corrections
Type : ErratumIn
Références
Coughlan, G., Laczó, J., Hort, J., Minihane, A. M. & Hornberger, M. Spatial navigation deficits — overlooked cognitive marker for preclinical Alzheimer disease? Nat. Rev. Neurol. 14, 1–11 (2018).
doi: 10.1038/s41582-018-0031-x
Kisler, K., Nelson, A. R., Montagne, A. & Zlokovic, B. V. Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat. Rev. Neurosci. 18, 419–434 (2017).
pubmed: 28515434
pmcid: 5759779
doi: 10.1038/nrn.2017.48
Kanoski, S. E. & Davidson, T. L. Western diet consumption and cognitive impairment: links to hippocampal dysfunction and obesity. Physiol. Behav. 103, 59–68 (2011).
pubmed: 21167850
doi: 10.1016/j.physbeh.2010.12.003
Montagne, A. et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85, 296–302 (2015).
pubmed: 25611508
pmcid: 4350773
doi: 10.1016/j.neuron.2014.12.032
Montagne, A. et al. Brain imaging of neurovascular dysfunction in Alzheimer’s disease. Acta Neuropathol. 131, 687–707 (2016).
pubmed: 27038189
pmcid: 5283382
doi: 10.1007/s00401-016-1570-0
Wang, H., Golob, E. J. & Su, M. Y. Vascular volume and blood-brain barrier permeability measured by dynamic contrast enhanced MRI in hippocampus and cerebellum of patients with MCI and normal controls. J. Magn. Reson. Imaging 24, 695–700 (2006).
pubmed: 16878309
doi: 10.1002/jmri.20669
Perosa, V. et al. Hippocampal vascular reserve associated with cognitive performance and hippocampal volume. Brain 143, 622–634 (2020).
pubmed: 31994699
pmcid: 7009470
doi: 10.1093/brain/awz383
Michaelis, E. K. Selective Neuronal Vulnerability in the Hippocampus: Relationship to Neurological Diseases and Mechanisms for Differential Sensitivity of Neurons to Stress. in The Clinical Neurobiology of the Hippocampus, 54–76 (Oxford University Press, 2012).
Ekstrom, A., Suthana, N., Millett, D., Fried, I. & Bookheimer, S. Correlation between BOLD fMRI and theta-band local field potentials in the human hippocampal area. J. Neurophysiol. 101, 2668–2678 (2009).
pubmed: 19244353
pmcid: 2681439
doi: 10.1152/jn.91252.2008
Schridde, U. et al. Negative BOLD with large increases in neuronal activity. Cereb. Cortex 18, 1814–27 (2008).
pubmed: 18063563
doi: 10.1093/cercor/bhm208
Dombeck, D. A., Harvey, C. D., Tian, L., Looger, L. L. & Tank, D. W. Functional imaging of hippocampal place cells at cellular resolution during virtual navigation. Nat. Neurosci. 13, 1433–1440 (2010).
pubmed: 20890294
pmcid: 2967725
doi: 10.1038/nn.2648
Kisler, K. et al. Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nat. Neurosci. 20, 406–416 (2017).
pubmed: 28135240
pmcid: 5323291
doi: 10.1038/nn.4489
Dana, H. et al. Thy1-GCaMP6 transgenic mice for neuronal population imaging in vivo. PLoS ONE 9, e108697 (2014).
pubmed: 25250714
pmcid: 4177405
doi: 10.1371/journal.pone.0108697
Cavaglia, M. et al. Regional variation in brain capillary density and vascular response to ischemia. Brain Res. 910, 81–93 (2001).
pubmed: 11489257
doi: 10.1016/S0006-8993(01)02637-3
Zhang, X. et al. High-resolution mapping of brain vasculature and its impairment in the hippocampus of Alzheimer’s disease mice. Natl. Sci. Rev. 6, 1223–1238 (2019).
pubmed: 34692000
pmcid: 8291402
doi: 10.1093/nsr/nwz124
Buxton, R. B. & Frank, L. R. A model for the coupling between cerebral blood flow and oxygen metabolism during neural stimulation. J. Cereb. Blood Flow. Metab. 17, 64–72 (1997).
pubmed: 8978388
doi: 10.1097/00004647-199701000-00009
Zeisel, A. et al. Molecular architecture of the mouse nervous system. Cell 174, 999–1014.e22 (2018).
pubmed: 30096314
pmcid: 6086934
doi: 10.1016/j.cell.2018.06.021
Grant, R. I. et al. Organizational hierarchy and structural diversity of microvascular pericytes in adult mouse cortex. J. Cereb. Blood Flow. Metab. 39, 411–425 (2019).
pubmed: 28933255
doi: 10.1177/0271678X17732229
Attwell, D., Mishra, A., Hall, C. N., O’Farrell, F. M. & Dalkara, T. What is a pericyte? J. Cereb. Blood Flow. Metab. 36, 451–455 (2016).
pubmed: 26661200
doi: 10.1177/0271678X15610340
Tsai, P. S. et al. Correlations of neuronal and microvascular densities in murine cortex revealed by direct counting and colocalization of nuclei and vessels. J. Neurosci. 29, 14553–70 (2009).
pubmed: 19923289
pmcid: 4972024
doi: 10.1523/JNEUROSCI.3287-09.2009
Nortley, R. et al. Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes. Science 365, eaav9518 (2019).
Garcia, V. et al. 20-HETE signals through G-protein-coupled receptor GPR75 (Gq) to affect vascular function and trigger hypertension. Circ. Res. 120, 1776–1788 (2017).
pubmed: 28325781
pmcid: 5446268
doi: 10.1161/CIRCRESAHA.116.310525
Park, S. K. et al. GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells. J. Biol. Chem. 293, 10675–10691 (2018).
pubmed: 29777058
pmcid: 6036206
doi: 10.1074/jbc.RA117.001297
Hogan-Cann, A. D., Lu, P. & Anderson, C. M. Endothelial NMDA receptors mediate activity-dependent brain hemodynamic responses in mice. Proc. Natl Acad. Sci. 116, 10229–10231 (2019).
pubmed: 31061120
pmcid: 6535036
doi: 10.1073/pnas.1902647116
Tselnicker, I., Tsemakhovich, V. A., Dessauer, C. W. & Dascal, N. Stargazin modulates neuronal voltage-dependent Ca2+ channel Cav2.2 by a Gβγ-dependent mechanism. J. Biol. Chem. 285, 20462–20471 (2010).
pubmed: 20435886
pmcid: 2898357
doi: 10.1074/jbc.M110.121277
Longden, T. A. et al. Capillary K(+)-sensing initiates retrograde hyperpolarization to increase local cerebral blood flow. Nat. Neurosci. 20, 717–726 (2017).
pubmed: 28319610
pmcid: 5404963
doi: 10.1038/nn.4533
Parpaleix, A., Goulam Houssen, Y. & Charpak, S. Imaging local neuronal activity by monitoring PO
pubmed: 23314058
doi: 10.1038/nm.3059
Sakadžić, S. et al. Two-photon microscopy measurement of cerebral metabolic rate of oxygen using periarteriolar oxygen concentration gradients. Neurophotonics 3, 045005 (2016).
pubmed: 27774493
pmcid: 5066455
doi: 10.1117/1.NPh.3.4.045005
Gould, I. G., Tsai, P., Kleinfeld, D. & Linninger, A. The capillary bed offers the largest hemodynamic resistance to the cortical blood supply. J. Cereb. Blood Flow. Metab. 37, 52–68 (2017).
pubmed: 27780904
doi: 10.1177/0271678X16671146
Shulman, R. G., Hyder, F. & Rothman, D. L. Insights from neuroenergetics into the interpretation of functional neuroimaging: an alternative empirical model for studying the brain’s support of behavior. J. Cereb. Blood Flow. Metab. 34, 1721–35 (2014).
pubmed: 25160670
pmcid: 4269754
doi: 10.1038/jcbfm.2014.145
Schmid, F., Tsai, P. S., Kleinfeld, D., Jenny, P. & Weber, B. Depth-dependent flow and pressure characteristics in cortical microvascular networks. PLoS Comput. Biol. 13, 1–22 (2017).
doi: 10.1371/journal.pcbi.1005392
Rungta, R. L., Chaigneau, E., Osmanski, B.-F. & Charpak, S. Vascular compartmentalization of functional hyperemia from the synapse to the Pia. Neuron 99, 362–375.e4 (2018).
pubmed: 29937277
pmcid: 6069674
doi: 10.1016/j.neuron.2018.06.012
Hall, C. N. et al. Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508, 55–60 (2014).
pubmed: 24670647
pmcid: 3976267
doi: 10.1038/nature13165
Fernández-Klett, F., Offenhauser, N., Dirnagl, U., Priller, J. & Lindauer, U. Pericytes in capillaries are contractile in vivo, but arterioles mediate functional hyperemia in the mouse brain. Proc. Natl Acad. Sci. USA 107, 22290–5 (2010).
pubmed: 21135230
pmcid: 3009761
doi: 10.1073/pnas.1011321108
Hill, R. A. et al. Regional blood flow in the normal and ischemic brain is controlled by arteriolar smooth muscle cell contractility and not by capillary pericytes. Neuron 87, 95–110 (2015).
pubmed: 26119027
pmcid: 4487786
doi: 10.1016/j.neuron.2015.06.001
Alarcon-Martinez, L. et al. Capillary pericytes express α-smooth muscle actin, which requires prevention of filamentous-actin depolymerization for detection. Elife 7, 1–17 (2018).
doi: 10.7554/eLife.34861
Chen, B. R., Kozberg, M. G., Bouchard, M. B., Shaik, M. A. & Hillman, E. M. C. A critical role for the vascular endothelium in functional neurovascular coupling in the brain. J. Am. Heart Assoc. 3, e000787 (2014).
pubmed: 24926076
pmcid: 4309064
doi: 10.1161/JAHA.114.000787
Galeffi, F., Degan, S., Britz, G. & Turner, D. A. Dysregulation of oxygen hemodynamic responses to synaptic train stimulation in a rat hippocampal model of subarachnoid hemorrhage. J. Cereb. Blood Flow. Metab. 36, 696–701 (2015).
pubmed: 26721394
pmcid: 4821025
doi: 10.1177/0271678X15624699
Erecińska, M. & Silver, I. A. Tissue oxygen tension and brain sensitivity to hypoxia. Respir. Physiol. 128, 263–276 (2001).
pubmed: 11718758
doi: 10.1016/S0034-5687(01)00306-1
Mikat, M., Peters, J., Zindler, M. & Arndt, J. O. Whole body oxygen consumption in awake, sleeping, and anesthetized dogs. Anesthesiology 60, 220–7 (1984).
pubmed: 6696256
doi: 10.1097/00000542-198403000-00009
Lyons, D. G., Parpaleix, A., Roche, M. & Charpak, S. Mapping oxygen concentration in the awake mouse brain. Elife 5, 1–16 (2016).
doi: 10.7554/eLife.12024
Sakadžić, S. et al. Large arteriolar component of oxygen delivery implies a safe margin of oxygen supply to cerebral tissue. Nat. Commun. 5, 5734 (2014).
pubmed: 25483924
doi: 10.1038/ncomms6734
Le Feber, J., Pavlidou, S. T., Erkamp, N., Van Putten, M. J. A. M. & Hofmeijer, J. Progression of neuronal damage in an in vitro model of the ischemic penumbra. PLoS ONE 11, 1–19 (2016).
doi: 10.1371/journal.pone.0147231
Hofmeijer, J., Mulder, A. T. B., Farinha, A. C., Van Putten, M. J. A. M. & Le Feber, J. Mild hypoxia affects synaptic connectivity in cultured neuronal networks. Brain Res. 1557, 180–189 (2014).
pubmed: 24560899
doi: 10.1016/j.brainres.2014.02.027
de Jong, D. L. K. et al. Effects of nilvadipine on cerebral blood flow in patients With Alzheimer disease. Hypertension 74, 413–420 (2019).
pubmed: 31203725
doi: 10.1161/HYPERTENSIONAHA.119.12892
Lawlor, B. et al. Nilvadipine in mild to moderate Alzheimer disease: a randomised controlled trial. PLoS Med. 15, 1–20 (2018).
doi: 10.1371/journal.pmed.1002660
Berens, S. C., Horst, J. S. & Bird, C. M. Cross-situational learning is supported by propose-but-verify hypothesis testing. Curr. Biol. 28, 1132–1136.e5 (2018).
pubmed: 29551416
doi: 10.1016/j.cub.2018.02.042
Hall, C. N., Howarth, C., Kurth-Nelson, Z. & Mishra, A. Interpreting BOLD: towards a dialogue between cognitive and cellular neuroscience. Philos. Trans. R. Soc. B Biol. Sci. 371, 1–12 (2016).
doi: 10.1098/rstb.2015.0348
Zhu, X., Hill, R. A. & Nishiyama, A. NG2 cells generate oligodendrocytes and gray matter astrocytes in the spinal cord. Neuron Glia Biol. 4, 19–26 (2008).
pubmed: 19006598
doi: 10.1017/S1740925X09000015
Goldey, G. J. et al. Removable cranial windows for long-term imaging in awake mice. Nat. Protoc. 9, 2515–2538 (2014).
pubmed: 25275789
pmcid: 4442707
doi: 10.1038/nprot.2014.165
Aronov, D. & Tank, D. W. Engagement of neural circuits underlying 2D spatial navigation in a rodent virtual reality system. Neuron 84, 442–456 (2014).
pubmed: 25374363
pmcid: 4454359
doi: 10.1016/j.neuron.2014.08.042
Royl, G. et al. Hypothermia effects on neurovascular coupling and cerebral metabolic rate of oxygen. Neuroimage 40, 1523–1532 (2008).
pubmed: 18343160
doi: 10.1016/j.neuroimage.2008.01.041
Fagrell, B. & Nilsson, G. Advantages and limitations of one-point laser Doppler perfusion monitoring in clinical practice. Vasc. Med. Rev. 6, 97–101 (1995).
doi: 10.1177/1358863X9500600202
Fabricius, M., Akgören, N., Dirnagl, U. & Lauritzen, M. Laminar analysis of cerebral blood flow in cortex of rats by laser-Doppler flowmetry: a pilot study. J. Cereb. Blood Flow. Metab. 17, 1326–36 (1997).
pubmed: 9397032
doi: 10.1097/00004647-199712000-00008
Dombeck, D. A., Harvey, C. D., Tian, L., Looger, L. L. & Tank, D. W. Functional imaging of hippocampal place cells at cellular resolution during virtual navigation. Nat. Neurosci. 13, 1433–1440 (2010).
pubmed: 20890294
pmcid: 2967725
doi: 10.1038/nn.2648
Sun, W., Tan, Z., Mensh, B. D. & Ji, N. Thalamus provides layer 4 of primary visual cortex with orientation- and direction-tuned inputs. Nat. Neurosci. 19, 308–315 (2016).
pubmed: 26691829
doi: 10.1038/nn.4196
Mukamel, E. A., Nimmerjahn, A. & Schnitzer, M. J. Automated analysis of cellular signals from large-scale calcium imaging data. Neuron 63, 747–60 (2009).
pubmed: 19778505
pmcid: 3282191
doi: 10.1016/j.neuron.2009.08.009
Drew, P. J., Blinder, P., Cauwenberghs, G., Shih, A. Y. & Kleinfeld, D. Rapid determination of particle velocity from space-time images using the Radon transform. J. Comput. Neurosci. 29, 5–11 (2010).
pubmed: 19459038
doi: 10.1007/s10827-009-0159-1
Dix, S. L. & Aggleton, J. P. Extending the spontaneous preference test of recognition: evidence of object-location and object-context recognition. Behav. Brain Res. 99, 191–200 (1999).
pubmed: 10512585
doi: 10.1016/S0166-4328(98)00079-5
Preibisch, S., Saalfeld, S. & Tomancak, P. Globally optimal stitching of tiled 3D microscopic image acquisitions. Bioinformatics 25, 1463–1465 (2009).
pubmed: 19346324
pmcid: 2682522
doi: 10.1093/bioinformatics/btp184
Uchida, K., Reilly, M. P. & Asakura, T. Molecular stability and function of mouse hemoglobins. Zool. Sci. 15, 703–706 (2006).
doi: 10.2108/zsj.15.703
Sander, R. Compilation of Henry’s law constants (version 4.0) for water as solvent. Atmos. Chem. Phys. 15, 4399–4981 (2015).
doi: 10.5194/acp-15-4399-2015
Ganfield, R. A., Nair, P. & Whalen, W. J. Mass transfer, storage, and utilization of O2 in cat cerebral cortex. Am. J. Physiol. 219, 814–821 (1970).
pubmed: 5450892
doi: 10.1152/ajplegacy.1970.219.3.814
Cooper, C. E. Competitive, reversible, physiological? Inhibition of mitochondrial cytochrome oxidase by nitric oxide. IUBMB Life 55, 591–597 (2003).
pubmed: 14711004
doi: 10.1080/15216540310001628663
Colom, A., Galgoczy, R., Almendros, I., Xaubet, A. & Farr, R. Oxygen diffusion and consumption in extracellular matrix gels: Implications for designing three-dimensional cultures. J. Biomed. Mater. Res. A 102, 2776–2784 (2014).
Thomsen, M. S., Routhe, L. J. & Moos, T. The vascular basement membrane in the healthy and pathological brain. J. Cereb. Blood Flow Metab. 37, 3300–3317 (2017).
Zhu, X. H., Zhang, Y., Zhang, N., Ugurbil, K. & Chen, W. Noninvasive and three-dimensional imaging of CMRO2 in rats at 9.4 T: Reproducibility test and normothermia/hypothermia comparison study. J. Cereb. Blood Flow. Metab. 27, 1225–1234 (2007).
pubmed: 17133228
doi: 10.1038/sj.jcbfm.9600421
Xu, F., Ge, Y. & Lu, H. Noninvasive quantification of whole-brain cerebral metabolic rate of oxygen (CMRO2) by MRI. Magn. Reson. Med. 62, 141–148 (2009).
pubmed: 19353674
pmcid: 2726987
doi: 10.1002/mrm.21994
Shaw, K.; Hall, C. N. Data for figures in the paper ‘Neurovascular coupling and oxygenation are decreased in hippocampus compared to neocortex because of microvascular differences’. Figshare https://figshare.com/s/af41650f9277cec99c20 (2021).
Brain Energy Lab (Kira Shaw and Catherine Hall). BrainEnergyLab/HCvsV1_NVC_Manuscript: NVCinHCmanuscript_March2021_release1. Zenodo https://zenodo.org/record/4593010#.YFIfFC2l1R0 (2021).