Glial Cell Calcium Signaling Mediates Capillary Regulation of Blood Flow in the Retina

Biesecker, Kyle R.; Srienc, Anja I.; Shimoda, Angela M.; Agarwal, Amit; Bergles, Dwight E.; Kofuji, Paulo; Newman, Eric A.

doi:10.1523/jneurosci.1782-16.2016

Cited by 123 publications

(153 citation statements)

References 57 publications

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“…Adenosine, a potent vasodilator produced from ADP by ecto-nucleotidases, also contributes to the increase in CBF (Iadecola, 1993; Ko et al, 1990). In addition, a role for ATP acting on purinergic receptors has been postulated both in retina and neocortex (Biesecker et al, 2016; Mishra et al, 2016). Finally, ionic changes evoked by neural activity, in particular the increase in extracellular K + , a vasodilator at concentrations <12mM (Filosa et al, 2006), could also participate (see section on astrocytes and endothelium).…”

Section: Neurovascular Couplingmentioning

confidence: 99%

“…The role of astrocytes in neurovascular coupling may be restricted to capillaries and may not involve arterioles, and the signaling pathways regulating the response of these vascular segments may be distinct (Biesecker et al, 2016; Mishra et al, 2016). In brain slices, electrical stimulation increases the diameter of cerebral capillaries and astrocytic Ca 2+ , an effect suppressed by AMPA or P2X1 receptor inhibition, suggesting that ATP released from neurons acts on astrocytic P2X1 receptors leading to the Ca 2+ rise (Mishra et al, 2016).…”

Section: Neurovascular Couplingmentioning

confidence: 99%

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The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease

Iadecola

2017

Neuron

1,733

1,649

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The concept of neurovascular unit (NVU), formalized at the 2001 Stroke Progress Review Group meeting of the National Institute of Neurological Disorders and Stroke, emphasizes the intimate relationship between the brain and its vessels. Since then, the NVU has attracted the interest of the neuroscience community resulting in considerable advances in the field. Here the current state-of-knowledge of the NVU will be assessed, focusing on one of its most vital roles: the coupling between neural activity and blood flow. The evidence supports a conceptual shift in the mechanisms of neurovascular coupling, from a unidimensional process involving neuronal-astrocytic signaling to local blood vessels, to a multidimensional one in which mediators released from multiple cells engage distinct signaling pathways and effector systems across the entire cerebrovascular network in a highly orchestrated manner. The recently appreciated NVU dysfunction in neurodegenerative diseases, although still poorly understood, supports emerging concepts that maintaining neurovascular health promotes brain health.

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Section: Neurovascular Couplingmentioning

confidence: 99%

Section: Neurovascular Couplingmentioning

confidence: 99%

The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease

Iadecola

2017

Neuron

1,733

1,649

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“…Evoked neuronal activity as well as direct application of neurotransmitters results in pericyte relaxation and capillary dilation (Hamilton and others 2010). Measurements in the in vivo cortex (Hall and others 2014; Kisler and others 2017; Tian and others 2010) and retina (Biesecker and others 2016; Kornfield and Newman 2014) demonstrate that capillaries dilate in response to sensory stimulation.…”

Section: The Vessels That Actively Generate Functional Hyperemiamentioning

confidence: 99%

“…The rapid dilation of capillaries also suggests that capillaries might be the primary recipient of neurovascular coupling signals and that arteriole dilation results from the upstream propagation of dilatory signals from capillaries, which can travel through vascular endothelial cells. However, selective inhibition of capillary dilation in the in vivo retina demonstrates that arterioles are capable of dilating in response to sensory stimulation even when capillaries fail to respond (Biesecker and others 2016). …”

Section: The Vessels That Actively Generate Functional Hyperemiamentioning

confidence: 99%

Mechanisms Mediating Functional Hyperemia in the Brain

2017

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Neuronal activity within the brain evokes local increases in blood flow, a response termed functional hyperemia. This response ensures that active neurons receive sufficient oxygen and nutrients to maintain tissue function and health. In this review, we discuss the functions of functional hyperemia, the types of vessels that generate the response, and the signaling mechanisms that mediate neurovascular coupling, the communication between neurons and blood vessels. Neurovascular coupling signaling is mediated primarily by the vasoactive metabolites of arachidonic acid (AA), by nitric oxide, and by K+. While much is known about these pathways, many contentious issues remain. We highlight two controversies, the role of glial cell Ca2+ signaling in mediating neurovascular coupling and the importance of capillaries in generating functional hyperemia. We propose signaling pathways that resolve these controversies. In this scheme, capillary dilations are generated by Ca2+ increases in astrocyte endfeet, leading to production of AA metabolites. In contrast, arteriole dilations are generated by Ca2+ increases in neurons, resulting in production of nitric oxide and AA metabolites. Arachidonic acid from neurons also diffuses into astrocyte endfeet where it is converted into additional vasoactive metabolites. While this scheme resolves several discrepancies in the field, many unresolved challenges remain and are discussed in the final section of the review.

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“…In this context the fact that the CBF/CMR O2 ratio varies between brain regions, as well with stimulus frequency (discussed in Buxton, 2010) and length (Lin et al, 2009), further suggests regulation of this ratio by notably neuronal activity-associated mechanisms (discussed in Buxton, 2010). Recent data further address this controversy in suggesting Ca 2+ -dependent signaling for modulation of capillary but not arteriolar diameter (Biesecker et al, 2016). Because CO 2 , one of the end products of oxidative metabolism, can diffuse out of the cells and is in rapid equilibrium with

{HCO}_{3}^{-}

, extracellular H + ions can also locally contribute to CBF regulation (Kuschinsky and Wahl, 1978).…”

Section: Functions Of Astrocytes In the Brainmentioning

confidence: 99%

How Energy Metabolism Supports Cerebral Function: Insights from 13C Magnetic Resonance Studies In vivo

2017

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Cerebral function is associated with exceptionally high metabolic activity, and requires continuous supply of oxygen and nutrients from the blood stream. Since the mid-twentieth century the idea that brain energy metabolism is coupled to neuronal activity has emerged, and a number of studies supported this hypothesis. Moreover, brain energy metabolism was demonstrated to be compartmentalized in neurons and astrocytes, and astrocytic glycolysis was proposed to serve the energetic demands of glutamatergic activity. Shedding light on the role of astrocytes in brain metabolism, the earlier picture of astrocytes being restricted to a scaffold-associated function in the brain is now out of date. With the development and optimization of non-invasive techniques, such as nuclear magnetic resonance spectroscopy (MRS), several groups have worked on assessing cerebral metabolism in vivo. In this context, 1H MRS has allowed the measurements of energy metabolism-related compounds, whose concentrations can vary under different brain activation states. 1H-[13C] MRS, i.e., indirect detection of signals from 13C-coupled 1H, together with infusion of 13C-enriched glucose has provided insights into the coupling between neurotransmission and glucose oxidation. Although these techniques tackle the coupling between neuronal activity and metabolism, they lack chemical specificity and fail in providing information on neuronal and glial metabolic pathways underlying those processes. Currently, the improvement of detection modalities (i.e., direct detection of 13C isotopomers), the progress in building adequate mathematical models along with the increase in magnetic field strength now available render possible detailed compartmentalized metabolic flux characterization. In particular, direct 13C MRS offers more detailed dataset acquisitions and provides information on metabolic interactions between neurons and astrocytes, and their role in supporting neurotransmission. Here, we review state-of-the-art MR methods to study brain function and metabolism in vivo, and their contribution to the current understanding of how astrocytic energy metabolism supports glutamatergic activity and cerebral function. In this context, recent data suggests that astrocytic metabolism has been underestimated. Namely, the rate of oxidative metabolism in astrocytes is about half of that in neurons, and it can increase as much as the rate of neuronal metabolism in response to sensory stimulation.

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Glial Cell Calcium Signaling Mediates Capillary Regulation of Blood Flow in the Retina

Cited by 123 publications

References 57 publications

The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease

The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease

Mechanisms Mediating Functional Hyperemia in the Brain

How Energy Metabolism Supports Cerebral Function: Insights from 13C Magnetic Resonance Studies In vivo

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