(A-3) Integrative Model of Astrocyte-Mediated Neurovascular Coupling

Introduction::
The role of astrocytes in neurovascular coupling (NVC) remains hotly contested with various proposed mechanisms of hemodynamic response. Accumulated evidence has linked glutamatergic activity in neuronal synapses with increase in astrocytic calcium activity, which constitutes the essential component in all astrocytic pathways of vascular control. Several theoretical models have tried to characterize these biochemical pathways [1-4]. However, these studies have failed to integrate all other known pathways by which astrocytic calcium activity regulate cerebral blood flow (CBF). We hypothesize that these astrocyte-governed pathways have unequal contributions and enact hemodynamic changes in a dynamic and non-linear fashion. We propose a novel model of astrocyte-mediated NVC that integrates all known pathways by which astrocytic calcium activity regulate vascular resistance and validated it using our own experimental data.




Materials and Methods::
We are developing a computational biophysical model of hemodynamic response encompassing all accepted pathways communicating astrocytes with contractile smooth muscle cells (SMC) and feedback from endothelial cells (EC). An extensive biochemical study and literature review was performed to determine the model equations, state variables, and physiological parameters [1-5]. We are using a tetracycline-based transgenic mice model, expressing ChR2-EYFP solely in astrocytes, to optogenetically stimulate astrocytic calcium activity in a localized section of the cortex where CBF changes are recorded using a Laser Doppler Flowmetry (LDF) modality. A theoretical model of optogenetically-induced calcium activity was also adopted from a previous study in our lab [7]. Simulated and experimental data are compared to characterize spatiotemporal features related to each specific biochemical pathway and fitted to estimate model parameters. Furthermore, subsequent pharmacological inhibition of voltage-gated potassium (BK) channels and phospholipase (PLA₂) governed pathways allowed us to characterize the contribution of each pathway to the vascular response.




Results, Conclusions, and Discussions::

Results and Discussion: A diagram comprising all biochemical pathways integrated in the model was obtained the literature review (Figure 1A). The diagram includes: a) the classical eicosanoid pathway and b) a K⁺ siphoning pathway. For the first time, we proposed the presence of a secreted phospholipase A2 (sPLA2) enzymes producing a vasoconstrictive effect on the microvasculature [6]. Results from the model corroborate differences in the temporal features (to the peak and to return to baseline) of the response depending on the dynamics of the molecules/ions characteristic to each biochemical pathway (Figure 1B). Model simulations shown in Figure 1C reproduced very well the experimental data from transgenic mice where an observed rapid increase in the signal is followed by a slow recovery to the baseline. The model fails to capture the shape of the experimental data in the first 25 seconds which might indicate the presence of another pathway also activated by astrocytic Ca²⁺.

Conclusions: An integrative theoretical model is proposed to characterize the role of astrocytic calcium activity in the neurovascular coupling. Our model reproduced very well most of the experimental hemodynamic response. Mismatch between experimental and simulated response suggests the possibility of another pathway that request further investigation. Our results proved that biochemical pathways impact the temporal features of the hemodynamic response differently and in a nonlinear fashion.








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References (Optional): :
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