Rapid stimulus-evoked astrocyte Ca2+ elevations and hemodynamic responses in mouse somatosensory cortex in vivo |
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Authors: | Barbara Lykke Lind Alexey R Brazhe Sanne Barsballe Jessen Florence C C Tan Martin J Lauritzen |
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Institution: | aDepartment of Neuroscience and Pharmacology and Center for Healthy Aging, University of Copenhagen, DK-2200 Copenhagen N, Denmark;;bBiophysics Department, Faculty of Biology, Moscow State University, Moscow 119234, Russia; and;cDepartment of Clinical Neurophysiology, Glostrup Hospital, DK-2600 Glostrup, Denmark |
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Abstract: | Increased neuron and astrocyte activity triggers increased brain blood flow, but controversy exists over whether stimulation-induced changes in astrocyte activity are rapid and widespread enough to contribute to brain blood flow control. Here, we provide evidence for stimulus-evoked Ca2+ elevations with rapid onset and short duration in a large proportion of cortical astrocytes in the adult mouse somatosensory cortex. Our improved detection of the fast Ca2+ signals is due to a signal-enhancing analysis of the Ca2+ activity. The rapid stimulation-evoked Ca2+ increases identified in astrocyte somas, processes, and end-feet preceded local vasodilatation. Fast Ca2+ responses in both neurons and astrocytes correlated with synaptic activity, but only the astrocytic responses correlated with the hemodynamic shifts. These data establish that a large proportion of cortical astrocytes have brief Ca2+ responses with a rapid onset in vivo, fast enough to initiate hemodynamic responses or influence synaptic activity.Brain function emerges from signaling in and between neurons and associated astrocytes, which causes fluctuations in cerebral blood flow (CBF) (1–5). Astrocytes are ideally situated for controlling activity-dependent increases in CBF because they closely associate with synapses and contact blood vessels with their end-feet (1, 6). Whether or not astrocytic Ca2+ responses develop often or rapidly enough to account for vascular signals in vivo is still controversial (7–10). Ca2+ responses are of interest because intracellular Ca2+ is a key messenger in astrocytic communication and because enzymes that synthesize the vasoactive substances responsible for neurovascular coupling are Ca2+-dependent (1, 4). Neuronal activity releases glutamate at synapses and activates metabotropic glutamate receptors on astrocytes, and this activation can be monitored by imaging cytosolic Ca2+ changes (11). Astrocytic Ca2+ responses are often reported to evolve on a slow (seconds) time scale, which is too slow to account for activity-dependent increases in CBF (8, 10, 12, 13). Furthermore, uncaging of Ca2+ in astrocytes triggers vascular responses in brain slices through specific Ca2+-dependent pathways with a protracted time course (14, 15). More recently, stimulation of single presynaptic neurons in hippocampal slices was shown to evoke fast, brief, local Ca2+ elevations in astrocytic processes that were essential for local synaptic functioning in the adult brain (16, 17). This work prompted us to reexamine the characteristics of fast, brief astrocytic Ca2+ signals in vivo with special regard to neurovascular coupling, i.e., the association between local increases in neural activity and the concomitant rise in local blood flow, which constitutes the physiological basis for functional neuroimaging.Here, we describe how a previously undescribed method of analysis enabled us to provide evidence for fast Ca2+ responses in a main fraction of astrocytes in mouse whisker barrel cortical layers II/III in response to somatosensory stimulation. The astrocytic Ca2+ responses were brief enough to be a direct consequence of synaptic excitation and correlated with stimulation-induced hemodynamic responses. Fast Ca2+ responses in astrocyte end-feet preceded the onset of dilatation in adjacent vessels by hundreds of milliseconds. This finding might suggest that communication at the gliovascular interface contributes considerably to neurovascular coupling. |
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Keywords: | neurovascular coupling Ca2+ imaging functional imaging sensory barrel cortex |
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