Astrocytes provide structural and metabolic support for neuronal networks, but direct evidence demonstrating their active role in complex behaviors is limited. Central respiratory chemosensitivity is an essential mechanism which, via regulation of breathing, maintains constant levels of blood and brain PCO 2 /pH. We found that astrocytes of the brainstem chemoreceptor areas are highly chemosensitive. They responded to physiological decreases in pH with vigorous elevations in intracellular Ca 2+ and release of ATP. ATP propagated astrocytic Ca 2+ excitation, activated chemoreceptor neurons, and induced adaptive increases in breathing. Mimicking pHevoked Ca 2+ responses by optogenetic stimulation of astrocytes expressing channelrhodopsin-2 activated chemoreceptor neurons via ATP-dependent mechanism and triggered robust respiratory responses in vivo. This demonstrates a potentially crucial role for brain glial cells in mediating a fundamental physiological reflex.The role of astrocytes in the brain is by no means limited to just providing structural and metabolic support to neurons. Astrocytes are closely associated with cerebral blood vessels and are thought to regulate cerebrovascular tone adjusting blood supply to match local metabolic demands(1-6). A single astrocyte may enwrap several neuronal somata(7) and make contact with thousands of synapses(8), potentially regulating synaptic strength and information processing (4,(9)(10)(11)(12)(13)(14). However, direct evidence demonstrating the functional role of astrocytes in complex behaviors is only starting to emerge(15).Astrocytes provide a vascular-neuronal interface and are in a position to quickly relay bloodborne stimuli to the activities of neuronal networks. Does this have a functional significance for the detection of the relevant stimuli by brain chemosensors which monitor key homeostatic parameters including glucose concentration, pH and PCO 2 ? Here we tested the * This manuscript has been accepted for publication in Science. This version has not undergone final editing. Please refer to the complete version of record at http://www.sciencemag.org/. The manuscript may not be reproduced or used in any manner that does not fall within the fair use provisions of the Copyright Act without the prior, written permission of AAAS. Fig 1a). Subsequent histological examination of the chemoresponsive areas confirmed contacts of transduced astrocytes with pia mater and penetrating arterioles ( fig. S3). Supporting Online MaterialPropagating Ca 2+ excitation of ventral medullary astrocytes in response to acidification was also observed in different in vitro preparations such as acute horizontal brainstem slices of adult rats (n = 56 slices; Fig In brainstem slices of adult rats, in which blood vessels were visualized with lectin, many pH-sensitive astrocytes were found to be located adjacent to the VS vasculature (Fig. 1f).Acidification-induced Ca 2+ excitation of VS astrocytes is unlikely to be secondary to increased activity of local neurons. To minimize ne...

In terrestrial mammals, the oxygen storage capacity of the CNS is limited, and neuronal function is rapidly impaired if oxygen supply is interrupted even for a short period of time. However, oxygen tension monitored by the peripheral (arterial) chemoreceptors is not sensitive to regional CNS differences in partial pressure of oxygen (P O 2 ) that reflect variable levels of neuronal activity or local tissue hypoxia, pointing to the necessity of a functional brain oxygen sensor. This experimental animal (rats and mice) study shows that astrocytes, the most numerous brain glial cells, are sensitive to physiological changes in P

Astrocytes might function as brain interoceptors capable of detecting different (chemo)sensory modalities and transmitting sensory information to the relevant neural networks controlling vital functions. For example, astrocytes that reside near the ventral surface of the brainstem (central respiratory chemosensitive area) respond to physiological decreases in pH with vigorous elevations in intracellular Ca 2ϩ and release of ATP. ATP transmits astroglial excitation to the brainstem respiratory network and contributes to adaptive changes in lung ventilation. Here we show that in terms of pH-sensitivity, ventral brainstem astrocytes are clearly distinct from astrocytes residing in the cerebral cortex. We monitored vesicular fusion in cultured rat brainstem astrocytes using total internal reflection fluorescence microscopy and found that ϳ35% of them respond to acidification with an increased rate of exocytosis of ATP-containing vesicular compartments. These fusion events require intracellular Ca 2ϩ signaling and are independent of autocrine ATP actions. In contrast, the rate of vesicular fusion in cultured cortical astrocytes is not affected by changes in pH. Compared to cortical astrocytes, ventral brainstem astrocytes display higher levels of expression of genes encoding proteins associated with ATP vesicular transport and fusion, including vesicle-associated membrane protein-3 and vesicular nucleotide transporter. These results suggest that astrocytes residing in different parts of the rat brain are functionally specialized. In contrast to cortical astrocytes, astrocytes of the brainstem chemosensitive area(s) possess signaling properties that are functionally relevant-they are able to sense changes in pH and respond to acidification with enhanced vesicular release of ATP.

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Fragments of mitochondrial DNA are released from mitochondria upon opening of the mitochondrial permeability transition pore. Cyclosporin A, an inhibitor of pore opening, completely prevented the release of mitochondrial fragments. Induction of mitochondrial permeability transition and subsequent release of the fragments of mitochondrial DNA could be one cause of genomic instability in the cell.