An integrative dynamic model of brain energy metabolism using in vivo neurochemical measurements

Abstract

An integrative, systems approach to the modelling of brain energy metabolism is presented. Mechanisms such as glutamate cycling between neurons and astrocytes and glycogen storage in astrocytes have been implemented. A unique feature of the model is its calibration using in vivo data of brain glucose and lactate from freely moving rats under various stimuli. The model has been used to perform simulated perturbation experiments that show that glycogen breakdown in astrocytes is significantly activated during sensory (tail pinch) stimulation. This mechanism provides an additional input of energy substrate during high consumption phases. By way of validation, data from the perfusion of 50µM propranolol in the rat brain was compared with the model outputs. Propranolol affects the glucose dynamics during stimulation, and this was accurately reproduced in the model by a reduction in the glycogen breakdown in astrocytes. The model's predictive capacity was verified by using data from a sensory stimulation (restraint) that was not used for model calibration. Finally, a sensitivity analysis was conducted on the model parameters, this showed that the control of energy metabolism and transport processes are critical in the metabolic behaviour of cerebral tissue.

Resting state neural networks and energy metabolism

“…This stage of the cycle likely exacts a high-energy cost in that the increased firing rate in the population necessitates utilization of ATP from the Krebs cycle of the mitochondria to run the neurons' sodium-potassium pumps [1]. Such demand likely also drains the glycogen stores in the glia cells (astrocytes) that are closely associated with the neurons in the pool.…”

“…The energy utilization in stage four is also likely low as CBF serves to restore the glycogen stores, the oxygen debt is "repaid," and ATP production begins to crank up through the Krebs cycle in the mitochondria [1,15]. …”

“…The microscopic cellular level is based on the neuron-glia system using the ANLS shuttle [1]; see Fig. 3.…”

“…The excessive blood flow is necessary in the regions constituting the RSNs because a sustained cooperative activity between these regions demands high amount of energy even at rest. This demand is satisfied by the increased cerebral flow to the regions of the RSN in order to deliver an increase in O2 and glucose to not only the cooperatively interacting neurons, but also to the closely associated glia cells that intimately interact with the neurons in the metabolic cycle [1,15]. Furthermore, the increased cerebral blood flow (CBF) supplied to these RSN regions is likely required to remove the excessive CO2, waste products, as well as dissipate excess heat.…”

Mathematical Model of Cardiovascular and Metabolic Responses to Umbilical Cord Occlusions in Fetal Sheep

“…Another limitation pertains to the simplified metabolic process. A more detailed model will potentially improve predictions of impaired nutrient supply (Cloutier et al 2009). The transport equations are used with relatively simple kinetic reaction terms involving only O 2 , CO 2 , pyruvate, lactate, glucose and [H + ] in the systemic compartment.…”