TY - JOUR
T1 - Computational singular perturbation analysis of brain lactate metabolism
AU - Patsatzis, Dimitris G.
AU - Tingas, Efstathios Al
AU - Goussis, Dimitris A.
AU - Mani Sarathy, S.
N1 - Copyright: © 2019 Patsatzis et al.
PY - 2019/12/17
Y1 - 2019/12/17
N2 - Lactate in the brain is considered an important fuel and signalling molecule for neuronal activity, especially during neuronal activation. Whether lactate is shuttled from astrocytes to neurons or from neurons to astrocytes leads to the contradictory Astrocyte to Neuron Lactate Shuttle (ANLS) or Neuron to Astrocyte Lactate Shuttle (NALS) hypotheses, both of which are supported by extensive, but indirect, experimental evidence. This work explores the conditions favouring development of ANLS or NALS phenomenon on the basis of a model that can simulate both by employing the two parameter sets proposed by Simpson et al. (J Cereb. Blood Flow Metab., 27:1766, 2007) and Mangia et al. (J of Neurochemistry, 109:55, 2009). As most mathematical models governing brain metabolism processes, this model is multi-scale in character due to the wide range of time scales characterizing its dynamics. Therefore, we utilize the Computational Singular Perturbation (CSP) algorithm, which has been used extensively in multi-scale systems of reactive flows and biological systems, to identify components of the system that (i) generate the characteristic time scale and the fast/slow dynamics, (ii) participate to the expressions that approximate the surfaces of equilibria that develop in phase space and (iii) control the evolution of the process within the established surfaces of equilibria. It is shown that a decisive factor on whether the ANLS or NALS configuration will develop during neuronal activation is whether the lactate transport between astrocytes and interstitium contributes to the fast dynamics or not. When it does, lactate is mainly generated in astrocytes and the ANLS hypothesis is realised, while when it doesn’t, lactate is mainly generated in neurons and the NALS hypothesis is realised. This scenario was tested in exercise conditions.
AB - Lactate in the brain is considered an important fuel and signalling molecule for neuronal activity, especially during neuronal activation. Whether lactate is shuttled from astrocytes to neurons or from neurons to astrocytes leads to the contradictory Astrocyte to Neuron Lactate Shuttle (ANLS) or Neuron to Astrocyte Lactate Shuttle (NALS) hypotheses, both of which are supported by extensive, but indirect, experimental evidence. This work explores the conditions favouring development of ANLS or NALS phenomenon on the basis of a model that can simulate both by employing the two parameter sets proposed by Simpson et al. (J Cereb. Blood Flow Metab., 27:1766, 2007) and Mangia et al. (J of Neurochemistry, 109:55, 2009). As most mathematical models governing brain metabolism processes, this model is multi-scale in character due to the wide range of time scales characterizing its dynamics. Therefore, we utilize the Computational Singular Perturbation (CSP) algorithm, which has been used extensively in multi-scale systems of reactive flows and biological systems, to identify components of the system that (i) generate the characteristic time scale and the fast/slow dynamics, (ii) participate to the expressions that approximate the surfaces of equilibria that develop in phase space and (iii) control the evolution of the process within the established surfaces of equilibria. It is shown that a decisive factor on whether the ANLS or NALS configuration will develop during neuronal activation is whether the lactate transport between astrocytes and interstitium contributes to the fast dynamics or not. When it does, lactate is mainly generated in astrocytes and the ANLS hypothesis is realised, while when it doesn’t, lactate is mainly generated in neurons and the NALS hypothesis is realised. This scenario was tested in exercise conditions.
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U2 - 10.1371/journal.pone.0226094
DO - 10.1371/journal.pone.0226094
M3 - Article
C2 - 31846455
AN - SCOPUS:85076669084
SN - 1932-6203
VL - 14
JO - PLoS ONE
JF - PLoS ONE
IS - 12
M1 - e0226094
ER -