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      Astrocytes monitor cerebral perfusion and control systemic circulation to maintain brain blood flow

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          Abstract

          Astrocytes provide neurons with essential metabolic and structural support, modulate neuronal circuit activity and may also function as versatile surveyors of brain milieu, tuned to sense conditions of potential metabolic insufficiency. Here we show that astrocytes detect falling cerebral perfusion pressure and activate CNS autonomic sympathetic control circuits to increase systemic arterial blood pressure and heart rate with the purpose of maintaining brain blood flow and oxygen delivery. Studies conducted in experimental animals (laboratory rats) show that astrocytes respond to acute decreases in brain perfusion with elevations in intracellular [Ca 2+]. Blockade of Ca 2+-dependent signaling mechanisms in populations of astrocytes that reside alongside CNS sympathetic control circuits prevents compensatory increases in sympathetic nerve activity, heart rate and arterial blood pressure induced by reductions in cerebral perfusion. These data suggest that astrocytes function as intracranial baroreceptors and play an important role in homeostatic control of arterial blood pressure and brain blood flow.

          Abstract

          The brain receives 20% of cardiac output, but in accord with the current knowledge lacks a specialized sensor of its own blood flow. Here, the authors show that brain astrocytes detect drops in perfusion and trigger compensatory increases in arterial pressure and heart rate to preserve brain blood flow and oxygen delivery.

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          Most cited references20

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          Integrative regulation of human brain blood flow.

          Herein, we review mechanisms regulating cerebral blood flow (CBF), with specific focus on humans. We revisit important concepts from the older literature and describe the interaction of various mechanisms of cerebrovascular control. We amalgamate this broad scope of information into a brief review, rather than detailing any one mechanism or area of research. The relationship between regulatory mechanisms is emphasized, but the following three broad categories of control are explicated: (1) the effect of blood gases and neuronal metabolism on CBF; (2) buffering of CBF with changes in blood pressure, termed cerebral autoregulation; and (3) the role of the autonomic nervous system in CBF regulation. With respect to these control mechanisms, we provide evidence against several canonized paradigms of CBF control. Specifically, we corroborate the following four key theses: (1) that cerebral autoregulation does not maintain constant perfusion through a mean arterial pressure range of 60-150 mmHg; (2) that there is important stimulatory synergism and regulatory interdependence of arterial blood gases and blood pressure on CBF regulation; (3) that cerebral autoregulation and cerebrovascular sensitivity to changes in arterial blood gases are not modulated solely at the pial arterioles; and (4) that neurogenic control of the cerebral vasculature is an important player in autoregulatory function and, crucially, acts to buffer surges in perfusion pressure. Finally, we summarize the state of our knowledge with respect to these areas, outline important gaps in the literature and suggest avenues for future research.
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            Glial regulation of the cerebral microvasculature.

            The brain is a heterogeneous organ with regionally varied and constantly changing energetic needs. Blood vessels in the brain are equipped with control mechanisms that match oxygen and glucose delivery through blood flow with the local metabolic demands that are imposed by neural activity. However, the cellular bases of this mechanism have remained elusive. A major advance has been the demonstration that astrocytes, cells with extensive contacts with both synapses and cerebral blood vessels, participate in the increases in flow evoked by synaptic activity. Their organization in nonoverlapping spatial domains indicates that they are uniquely positioned to shape the spatial distribution of the vascular responses that are evoked by neural activity. Astrocytic calcium is an important determinant of microvascular function and may regulate flow independently of synaptic activity. The involvement of astrocytes in neurovascular coupling has broad implications for the interpretation of functional imaging signals and for the understanding of brain diseases that are associated with neurovascular dysfunction.
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              Three-dimensional Ca(2+) imaging advances understanding of astrocyte biology.

              Astrocyte communication is typically studied by two-dimensional calcium ion (Ca(2+)) imaging, but this method has not yielded conclusive data on the role of astrocytes in synaptic and vascular function. We developed a three-dimensional two-photon imaging approach and studied Ca(2+) dynamics in entire astrocyte volumes, including during axon-astrocyte interactions. In both awake mice and brain slices, we found that Ca(2+) activity in an individual astrocyte is scattered throughout the cell, largely compartmented between regions, preponderantly local within regions, and heterogeneously distributed regionally and locally. Processes and endfeet displayed frequent fast activity, whereas the soma was infrequently active. In awake mice, activity was higher than in brain slices, particularly in endfeet and processes, and displayed occasional multifocal cellwide events. Astrocytes responded locally to minimal axonal firing with time-correlated Ca(2+) spots.
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                Author and article information

                Contributors
                n.marina@ucl.ac.uk
                a.gourine@ucl.ac.uk
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                9 January 2020
                9 January 2020
                2020
                : 11
                : 131
                Affiliations
                [1 ]ISNI 0000000121901201, GRID grid.83440.3b, Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, , University College London, ; London, WC1E 6BT UK
                [2 ]ISNI 0000000121901201, GRID grid.83440.3b, Division of Medicine, , University College London, ; London, WC1E 6BT UK
                [3 ]ISNI 0000 0001 2192 9124, GRID grid.4886.2, Department of Molecular Neurobiology, Institute of Bioorganic Chemistry, , Russian Academy of Sciences, ; Moscow, 117997 Russian Federation
                [4 ]ISNI 0000 0001 2342 9668, GRID grid.14476.30, Faculty of Biology, , Lomonosov Moscow State University, ; Moscow, 119234 Russian Federation
                [5 ]ISNI 0000000121901201, GRID grid.83440.3b, Centre for Advanced Biomedical Imaging, Division of Medicine, , University College London, ; London, WC1E 6DD UK
                [6 ]ISNI 0000 0004 0372 3343, GRID grid.9654.e, Department of Physiology, , University of Auckland, ; Auckland, 1023 New Zealand
                [7 ]ISNI 0000 0004 1936 7603, GRID grid.5337.2, Physiology, Neuroscience and Pharmacology, , University of Bristol, ; Bristol, BS8 1TD UK
                [8 ]Baltic Federal University, Kaliningrad, 236041 Russian Federation
                Author information
                http://orcid.org/0000-0002-3048-9455
                http://orcid.org/0000-0003-4119-9979
                http://orcid.org/0000-0003-3068-491X
                Article
                13956
                10.1038/s41467-019-13956-y
                6952443
                31919423
                9cd41185-ff76-459b-a29f-c53838afeb62
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 14 December 2018
                : 6 December 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100000274, British Heart Foundation (BHF);
                Award ID: FS/13/5/29927
                Award ID: RG/14/4/30736
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100002261, Russian Foundation for Basic Research (RFBR);
                Award ID: 17-00-00407
                Award ID: 17-00-00412(K)
                Award ID: 17-00-00409
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100004440, Wellcome Trust (Wellcome);
                Award ID: 200893
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2020

                Uncategorized
                neuro-vascular interactions,circulation
                Uncategorized
                neuro-vascular interactions, circulation

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