The Functional Role of Astrocyte Calcium Signaling in Cortical Blood Flow Regulation

Biesecker, Kyle R.; Srienc, Anja I.

doi:10.1523/jneurosci.4422-14.2015

Cited by 4 publications

(4 citation statements)

References 14 publications

(9 reference statements)

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“…Interestingly, a more recent study showed intact Ca 2+ responses in astrocyte processes in IP 3 R KO animals (Rungta et al, ; Srinivasan et al, ). In addition, other studies maintain that Ca 2+ in astrocyte processes and end‐feet plays a role in CBF regulation (Biesecker & Srienc, ; Dunn et al, ; Otsu et al, ), which our results tend to support. These conflicting results may have been conciliated by two recent studies showing how astrocytic Ca 2+ changes are essential for the dilation of capillaries, but not arterioles (Biesecker et al, ; Mishra et al, ).…”

Section: Discussionsupporting

confidence: 85%

Fast Ca²⁺ responses in astrocyte end‐feet and neurovascular coupling in mice

Lind

Jessen

Lønstrup

et al. 2017

Glia

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Cerebral blood flow (CBF) is regulated by the activity of neurons and astrocytes. Understanding how these cells control activity-dependent increases in CBF is crucial to interpreting functional neuroimaging signals. The relative importance of neurons and astrocytes is debated, as are the functional implications of fast Ca changes in astrocytes versus neurons. Here, we used two-photon microscopy to assess Ca changes in neuropil, astrocyte processes, and astrocyte end-feet in response to whisker pad stimulation in mice. We also developed a pixel-based analysis to improve the detection of rapid Ca signals in the subcellular compartments of astrocytes. Fast Ca responses were observed using both chemical and genetically encoded Ca indicators in astrocyte end-feet prior to dilation of arterioles and capillaries. A low dose of the NMDA receptor antagonist (5R,10s)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine-hydrogen-maleate (MK801) attenuated fast Ca responses in the neuropil and astrocyte processes, but not in astrocyte end-feet, and the evoked CBF response was preserved. In addition, a low dose of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), an agonist for the extrasynaptic GABA receptor (GABA R), increased CBF responses and the fast Ca response in astrocyte end-feet but did not affect Ca responses in astrocyte processes and neuropil. These results suggest that fast Ca increases in the neuropil and astrocyte processes are not necessary for an evoked CBF response. In contrast, as local fast Ca responses in astrocyte end-feet are unaffected by MK801 but increase via GABA R-dependent mechanisms that also increased CBF responses, we hypothesize that the fast Ca increases in end-feet adjust CBF during synaptic activity.

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Section: Discussionsupporting

confidence: 85%

Fast Ca²⁺ responses in astrocyte end‐feet and neurovascular coupling in mice

Lind

Jessen

Lønstrup

et al. 2017

Glia

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“…Petzold et al suggested that both pathways might converge upon increases in intracellular Ca 2+ , although through an unknown mechanism (Petzold and Murthy, 2011). Several different studies have examined the potential contributions of changes in astrocytic Ca 2+ to changes in arteriole diameter, and the results are somewhat varied (for discussions, see Biesecker and Srienc, 2015;Khakh and McCarthy, 2015;Munoz et al, 2015;Bazargani and Attwell, 2016;Lia et al, 2021). Takano and colleagues photouncaged Ca 2+ in astrocyte endfeet and found that this causes an increase in blood flow in vivo (Takano et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Activation of Glutamate Transport Increases Arteriole Diameter in vivo: Implications for Neurovascular Coupling

Jackson

Krizman

Takano

et al. 2022

Front. Cell. Neurosci.

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In order to meet the energetic demands of cell-to-cell signaling, increases in local neuronal signaling are matched by a coordinated increase in local blood flow, termed neurovascular coupling. Multiple different signals from neurons, astrocytes, and pericytes contribute to this control of blood flow. Previously, several groups demonstrated that inhibition/ablation of glutamate transporters attenuates the neurovascular response. However, it was not determined if glutamate transporter activation was sufficient to increase blood flow. Here, we used multiphoton imaging to monitor the diameter of fluorescently labeled cortical arterioles in anesthetized C57/B6J mice. We delivered vehicle, glutamate transporter substrates, or a combination of a glutamate transporter substrate with various pharmacologic agents via a glass micropipette while simultaneously visualizing changes in arteriole diameter. We developed a novel image analysis method to automate the measurement of arteriole diameter in these time-lapse analyses. Using this workflow, we first conducted pilot experiments in which we focally applied L-glutamate, D-aspartate, or L-threo-hydroxyaspartate (L-THA) and measured arteriole responses as proof of concept. We subsequently applied the selective glutamate transport substrate L-THA (applied at concentrations that do not activate glutamate receptors). We found that L-THA evoked a significantly larger dilation than that observed with focal saline application. This response was blocked by co-application of the potent glutamate transport inhibitor, L-(2S,3S)-3-[3-[4-(trifluoromethyl)-benzoylamino]benzyloxy]-aspartate (TFB-TBOA). Conversely, we were unable to demonstrate a reduction of this effect through co-application of a cocktail of glutamate and GABA receptor antagonists. These studies provide the first direct evidence that activation of glutamate transport is sufficient to increase arteriole diameter. We explored potential downstream mechanisms mediating this transporter-mediated dilation by using a Ca2+ chelator or inhibitors of reversed-mode Na+/Ca2+ exchange, nitric oxide synthetase, or cyclo-oxygenase. The estimated effects and confidence intervals suggested some form of inhibition for a number of these inhibitors. Limitations to our study design prevented definitive conclusions with respect to these downstream inhibitors; these limitations are discussed along with possible next steps. Understanding the mechanisms that control blood flow are important because changes in blood flow/energy supply are implicated in several neurodegenerative disorders and are used as a surrogate measure of neuronal activity in widely used techniques such as functional magnetic resonance imaging (fMRI).

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“…Other roles have been suggested for astrocytes in NVC, such as extending the late vasoconstrictive phase of (Mulligan and MacVicar 2004, Metea and Newman 2006, Gordon, Choi et al 2008, Girouard, Bonev et al 2010) or amplifying the response (Gu, Chen et al 2018, Institoris, Vandal et al 2022). It has also been suggested that the astrocytic contribution to NVC is capillary-specific (Biesecker and Srienc 2015, Mishra, Reynolds et al 2016). Hence, we focused our investigation on the vascular inflow tract where a 1 st order capillary branch from the penetrating arteriole (PA).…”

Section: Introductionmentioning

confidence: 99%

Localised Astrocyte Ca2+ Activity Regulates Neurovascular Coupling Responses to Active Sensing

Stelzner,

Krogsgaard,

Kulkoviene

et al. 2024

Preprint

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The process of neurovascular coupling (NVC) is the regulation of sufficient and targeted blood flow during energy-consuming cerebral processes. Astrocyte participation in NVC has long been debated. The lack of clear answers is likely based on the diversity of astrocyte intracellular Ca2+ activities and the multitude of ways astrocytes may regulate cerebral blood flow. We focused our investigation on NVC responses to sensory input actively reached for by freely behaving mice. To do so, we studied the cellular and vascular activity in the sensory whisker barrel cortex of awake head-fixed mice and aligned this activity to the volitional whisking events. We compared the NVC initiated by the whisking event in the resting mouse to the whisking evoked by the experimenter and the whisking prior to locomotion. We did this comparison because astrocyte signaling is known to be sensitive to brain state transitions. In the NVC response to all three, we found that both neuronal and astrocytic activity corresponded to vascular activity. When we repeated this investigation after depletion of NA release from locus coeruleus projections, we identified that the three NVC responses did not equally depend on NA delivery or astrocytic activity. Though we found the expected effect on astrocytic Ca2+ surges, the whisking-dependent astrocytic Ca2+ activity was only moderately reduced by the reduced NA levels in the resting mouse and only in cells near the vessels. On the vascular side, we found that the dilation of the 1st order capillary to volitional whisking was much reduced. This suggests a disturbance in the precision regulation of the cerebral blood flow that may limit the appropriate delivery of blood to the region of activated neurons. Finally, this disturbance might partially account for the extended period of exploratory whisking prior to the initiation of locomotion that we saw in the NA-depleted mice. Our study reveals an astrocytic contribution to NVC in the natural shifts in the attention directed toward the sensory input received during volitional whisking.

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The Functional Role of Astrocyte Calcium Signaling in Cortical Blood Flow Regulation

Cited by 4 publications

References 14 publications

Fast Ca²⁺ responses in astrocyte end‐feet and neurovascular coupling in mice

Fast Ca²⁺ responses in astrocyte end‐feet and neurovascular coupling in mice

Activation of Glutamate Transport Increases Arteriole Diameter in vivo: Implications for Neurovascular Coupling

Localised Astrocyte Ca2+ Activity Regulates Neurovascular Coupling Responses to Active Sensing

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The Functional Role of Astrocyte Calcium Signaling in Cortical Blood Flow Regulation

Cited by 4 publications

References 14 publications

Fast Ca2+ responses in astrocyte end‐feet and neurovascular coupling in mice

Fast Ca2+ responses in astrocyte end‐feet and neurovascular coupling in mice

Activation of Glutamate Transport Increases Arteriole Diameter in vivo: Implications for Neurovascular Coupling

Localised Astrocyte Ca2+ Activity Regulates Neurovascular Coupling Responses to Active Sensing

Contact Info

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Fast Ca²⁺ responses in astrocyte end‐feet and neurovascular coupling in mice

Fast Ca²⁺ responses in astrocyte end‐feet and neurovascular coupling in mice