Mitochondrial Functional State Impacts Spontaneous Neocortical Activity and Resting State fMRI

Mitochondrial Ca²⁺ uptake, central to neural metabolism and function, is diminished in aging whereas enhanced after acute/sub-acute traumatic brain injury. To develop relevant translational models for these neuropathologies, we determined the impact of perturbed mitochondrial Ca²⁺ uptake capacities on intrinsic brain activity using clinically relevant markers. From a multi-compartment estimate of probable baseline Ca²⁺ ranges in the brain, we hypothesized that reduced or enhanced mitochondrial Ca²⁺ uptake capacity would decrease or increase spontaneous neuronal activity respectively. As resting state fMRI-BOLD fluctuations and stimulus-evoked BOLD responses have similar physiological origins [1] and stimulus-evoked neuronal and hemodynamic responses are modulated by mitochondrial Ca²⁺ uptake capacity [2,3] respectively, we tested our hypothesis by measuring hemodynamic fluctuations and spontaneous neuronal activities during normal and altered mitochondrial functional states. Mitochondrial Ca²⁺ uptake capacity was perturbed by pharmacologically inhibiting or enhancing the mitochondrial Ca²⁺ uniporter (mCU) activity. Neuronal electrical activity and cerebral blood flow (CBF) fluctuations were measured simultaneously and integrated with fMRI-BOLD fluctuations at 11.7T. mCU inhibition reduced spontaneous neuronal activity and the resting state functional connectivity (RSFC), whereas mCU enhancement increased spontaneous neuronal activity but reduced RSFC. We conclude that increased or decreased mitochondrial Ca²⁺ uptake capacities lead to diminished resting state modes of brain functional connectivity.