Neurovascular coupling and the influence of luminal agonists via the endothelium

Dormanns, Katharina; Disseldorp, van Emj Emiel; Brown, Richard G.; David, Tom

doi:10.1016/j.jtbi.2014.08.029

Cited by 24 publications

(22 citation statements)

References 53 publications

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“…NAAG is a neurotransmitter and appears to be involved in the activation of astrocytes, a component part of a complex "neurovascular" feedback mechanism 35 to supply sufficient oxygen and energy to neurons. Just how important this process is and what specific role NAAG plays in it remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Stimulation‐induced transient changes in neuronal activity, blood flow and N‐acetylaspartate content in rat prefrontal cortex: a chemogenetic fMRS‐BOLD study

et al. 2016

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Brain activation studies in humans have shown the dynamic nature of neuronal N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) based on changes in their magnetic resonance spectroscopy (MRS) signals in response to stimulation. These studies demonstrated that upon visual stimulation there was a focal increase in cerebral blood flow (CBF) and a decrease in NAA, or in the total of NAA and NAAG signals in the visual cortex, and that these changes were reversed upon cessation of stimulation. In the present study we have developed an animal model in order to explore the relationships between brain stimulation, neuronal activity, CBF and NAA. We use “Designer Receptors Exclusively Activated by Designer Drugs” (DREADDs) technology for site-specific neural activation, a local field potential electrophysiological method for measurement of changes in the rate of neuronal activity, functional MRS for measurement of changes in NAA, and a blood oxygenation level-dependent (BOLD) MR technique for evaluating changes in CBF. We show that stimulation of the rat prefrontal cortex using DREADDs results in (a) an increase in level of neuronal activity, (b) an increase in BOLD and (c) decrease in the NAA signal. These findings show for the first time the tightly coupled relationships between stimulation, neuron activity, CBF and NAA dynamics in brain, and also provide the first demonstration of the novel inverse stimulation-NAA phenomenon in an animal model.

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Section: Discussionmentioning

confidence: 99%

Stimulation‐induced transient changes in neuronal activity, blood flow and N‐acetylaspartate content in rat prefrontal cortex: a chemogenetic fMRS‐BOLD study

et al. 2016

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“…as shown in [7] fitting to the data of [11]. θ 141 shifts the conductance to the right for constant [K + ] P V S concentration in the perivascular space.…”

Section: Average Volumetric Flow Ratementioning

confidence: 90%

“…Previous work [30] has provided the construction of an experimentally validated numerical (in silico) model based on experimental data to simulate the functional magnetic resonance imaging (fMRI) bloodoxygen-level dependent (BOLD) signal associated with NVC along with the associated metabolic and blood volume responses. An existing neuron model [28,29] has been extended to include an additional transient sodium (Na + ) ion channel (NaT) expressed in the neuron, and integrated into a complex NVC model [7,8,19]. This present model is based on the hypothesis that the K + signaling mechanism of NVC is the primary contributor to the vascular response and the Na + /K + exchange pump in the neuron is the primary consumer of oxygen during neural activation.…”

Section: Physiological Model: Neurovascular Couplingmentioning

confidence: 99%

“…However, for this initial work, we constrain ourselves to the above subset. The numerical model outlined in sketch form in Figure 1 is fully defined in the Supplementary Material and has been developed over a number of years [7,8,10]. In order to induce a variation in radius of a vessel which perfuses the associated cerebral tissue following a neuronal stimulation, an input current is used.…”

Section: Physiological Model: Neurovascular Couplingmentioning

confidence: 99%

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Global Sensitivity Analysis of High-Dimensional Neuroscience Models: An Example of Neurovascular Coupling

2019

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The complexity and size of state-of-the-art cell models have significantly increased in part due to the requirement that these models possess complex cellular functions which are thought-but not necessarily proven-to be important. Modern cell models often involve hundreds of parameters; the values of these parameters come, more often than not, from animal experiments whose relationship to the human physiology is weak with very little information on the errors in these measurements. The concomitant uncertainties in parameter values result in uncertainties in the model outputs or Quantities of Interest (QoIs). Global Sensitivity Analysis (GSA) aims at apportioning to individual parameters (or sets of parameters) their relative contribution to output uncertainty thereby introducing a measure of influence or importance of said parameters. New GSA approaches are required to deal with increased model size and complexity; a three stage methodology consisting of screening (dimension reduction), surrogate modeling, and computing Sobol' indices, is presented. The methodology is used to analyze a physiologically validated numerical model of neurovascular coupling which possess 160 uncertain parameters. The sensitivity analysis investigates three quantities of interest (QoIs), the average value of K + in the extracellular space, the average volumetric flow rate through the perfusing vessel, and the minimum value of the J.actin/myosin complex in the smooth muscle cell. GSA provides a measure of the influence of each parameter, for each of the three QoIs, giving insight into areas of possible physiological dysfunction and areas of further investigation.

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“…Investigating the relationship between neuronal activity and the resulting variation in the radius of the perfusing arteriole in addition to the role of EC/SMC connectivity and the resulting effects of flowing blood is crucial to the further understanding of NVC and how it interacts over the larger scale elucidated by non-invasive measurement techniques such as fMRI; our current multi-scale model provides a framework for investigating both scales simultaneously. The complex NVU model used is that described in Dormanns et al ( 2015 ). The model is based on experimentally validated ion channel parameters providing the model with the ability to describe the full NVC phenomenon.…”

Section: Introductionmentioning

confidence: 99%

Neurovascular coupling: a parallel implementation

Dormanns

Brown

Todem

2015

Front. Comput. Neurosci.

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A numerical model of neurovascular coupling (NVC) is presented based on neuronal activity coupled to vasodilation/contraction models via the astrocytic mediated perivascular K+ and the smooth muscle cell (SMC) Ca2+ pathway termed a neurovascular unit (NVU). Luminal agonists acting on P2Y receptors on the endothelial cell (EC) surface provide a flux of inositol trisphosphate (IP3) into the endothelial cytosol. This concentration of IP3 is transported via gap junctions between EC and SMC providing a source of sarcoplasmic derived Ca2+ in the SMC. The model is able to relate a neuronal input signal to the corresponding vessel reaction (contraction or dilation). A tissue slice consisting of blocks, each of which contain an NVU is connected to a space filling H-tree, simulating a perfusing arterial tree (vasculature) The model couples the NVUs to the vascular tree via a stretch mediated Ca2+ channel on both the EC and SMC. The SMC is induced to oscillate by increasing an agonist flux in the EC and hence increased IP3 induced Ca2+ from the SMC stores with the resulting calcium-induced calcium release (CICR) oscillation inhibiting NVC thereby relating blood flow to vessel contraction and dilation following neuronal activation. The coupling between the vasculature and the set of NVUs is relatively weak for the case with agonist induced where only the Ca2+ in cells inside the activated area becomes oscillatory however, the radii of vessels both inside and outside the activated area oscillate (albeit small for those outside). In addition the oscillation profile differs between coupled and decoupled states with the time required to refill the cytosol with decreasing Ca2+ and increasing frequency with coupling. The solution algorithm is shown to have excellent weak and strong scaling. Results have been generated for tissue slices containing up to 4096 blocks.

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Neurovascular coupling and the influence of luminal agonists via the endothelium

Cited by 24 publications

References 53 publications

Stimulation‐induced transient changes in neuronal activity, blood flow and N‐acetylaspartate content in rat prefrontal cortex: a chemogenetic fMRS‐BOLD study

Stimulation‐induced transient changes in neuronal activity, blood flow and N‐acetylaspartate content in rat prefrontal cortex: a chemogenetic fMRS‐BOLD study

Global Sensitivity Analysis of High-Dimensional Neuroscience Models: An Example of Neurovascular Coupling

Neurovascular coupling: a parallel implementation

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