title: Mitochondrial functional state impacts spontaneous neocortical activity and resting state FMRI.
abstract: Mitochondrial Ca(2+) 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 Ca(2+) uptake capacities on intrinsic brain activity using clinically relevant markers. From a multi-compartment estimate of probable baseline Ca(2+) ranges in the brain, we hypothesized that reduced or enhanced mitochondrial Ca(2+) 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 Ca(2+) 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 Ca(2+) uptake capacity was perturbed by pharmacologically inhibiting or enhancing the mitochondrial Ca(2+) 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 Ca(2+) uptake capacities lead to diminished resting state modes of brain functional connectivity.
authors: Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut, United States of America. P30NS052519
authors: Basavaraju G
authors: BG
authors: Sanganahalli
authors: Peter
authors: P
authors: Herman
authors: Fahmeed
authors: F
authors: Hyder
authors: Sridhar S
authors: SS
authors: Kannurpatti
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D005071:Evoked Potentials / Q000187:drug effects; D044949:Kaempferols / Q000494:pharmacology; D008279:Magnetic Resonance Imaging; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D019579:Neocortex / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012146:Rest / Q000502:physiology; D017975:Ruthenium Compounds / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D044949:Kaempferols; C112020:Ru 360; D017975:Ruthenium Compounds; C034703:mitochondrial calcium uniporter; C006552:kaempferol; D002118:Calcium
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