Tightly coupled brain activity and cerebral ATP metabolic rate

Abstract

A majority of ATP in the brain is formed in the mitochondria through oxidative phosphorylation of ADP with the F(1)F(0)-ATP (ATPase) enzyme. This ATP production rate plays central roles in brain bioenergetics, function and neurodegeneration. In vivo (31)P magnetic resonance spectroscopy combined with magnetization transfer (MT) is the sole approach able to noninvasively determine this ATP metabolic rate via measuring the forward ATPase reaction flux (F(f,ATPase)). However, previous studies indicate lack of quantitative agreement between F(f,ATPase) and oxidative metabolic rate in heart and liver. In contrast, recent work has shown that F(f,ATPase) might reflect oxidative phosphorylation rate in resting human brains. We have conducted an animal study, using rats under varied brain activity levels from light anesthesia to isoelectric state, to examine whether the in vivo (31)P MT approach is suitable for measuring the oxidative phosphorylation rate and its change associated with varied brain activity. Our results conclude that the measured F(f,ATPase) reflects the oxidative phosphorylation rate in resting rat brains, that this flux is tightly correlated to the change of energy demand under varied brain activity levels, and that a significant amount of ATP energy is required for "housekeeping" under the isoelectric state. These findings reveal distinguishable characteristics of ATP metabolism between the brain and heart, and they highlight the importance of in vivo (31)P MT approach to potentially provide a unique and powerful neuroimaging modality for noninvasively studying the cerebral ATP metabolic network and its central role in bioenergetics associated with brain function, activation, and diseases.

Fig. 1.

In vivo ³¹P MT and EEG measurements from a representative rat brain under IsoF (SEI = 0.75) (A), low-Pen (SEI = 0.65) (B), and high-Pen (isoelectric; SEI = 0.50) (C) anesthesia conditions, respectively. (Left and Center) ³¹P spectra acquired in the absence (control) (Left) and presence (Center) of γ-ATP saturation. The magnetization ratio quantified by the NMR signals obtained at steady-state saturation versus control was 56%, 59%, and 63% for PCr and 59%, 67%, and 78% for Pi at IsoF, low-Pen, and high-Pen anesthesia conditions, respectively. The ratio changes indicate reduction in the measured ATP metabolic rates with increased anesthesia depth. (Right) EEG time courses recorded at three anesthesia conditions.

Fig. 2.

Correlations between the averaged ATP metabolic rates of CK (F_f,CK and full diamonds) and ATPase (F_f,ATPase and open circles) reactions versus the averaged spectral entropy index of EEG measured under varied brain activity levels in the rat brain with four anesthesia conditions as labeled. Both F_f,CK and F_f,ATPase were normalized to the values measured under the IsoF condition.