Mitochondrial calcium homeostasis: Implications for neurovascular and neurometabolic coupling

Mitochondrial function is critical to maintain high rates of oxidative metabolism supporting energy demands of both spontaneous and evoked neuronal activity in the brain. Mitochondria not only regulate energy metabolism, but also influence neuronal signaling. Regulation of “energy metabolism” and “neuronal signaling” (i.e. neurometabolic coupling), which are coupled rather than independent can be understood through mitochondria’s integrative functions of calcium ion (Ca2+) uptake and cycling. While mitochondrial Ca2+ do not affect hemodynamics directly, neuronal activity changes are mechanistically linked to functional hyperemic responses (i.e. neurovascular coupling). Early in vitro studies lay the foundation of mitochondrial Ca2+ homeostasis and its functional roles within cells. However, recent in vivo approaches indicate mitochondrial Ca2+ homeostasis as maintained by the role of mitochondrial Ca2+ uniporter (mCU) influences system-level brain activity as measured by a variety of techniques. Based on earlier evidence of subcellular cytoplasmic Ca2+ microdomains and cellular bioenergetic states, a mechanistic model of Ca2+ mobilization is presented to understand systems-level neurovascular and neurometabolic coupling. This integrated view from molecular and cellular to the systems level, where mCU plays a major role in mitochondrial and cellular Ca2+ homeostasis, may explain the wide range of activation-induced coupling across neuronal activity, hemodynamic, and metabolic responses.

Patterned Optogenetic Modulation of Neurovascular and Metabolic Signals

The hemodynamic and metabolic response of the cortex depends spatially and temporally on the activity of multiple cell types. Optogenetics enables specific cell types to be modulated with high temporal precision and is therefore an emerging method for studying neurovascular and neurometabolic coupling. Going beyond temporal investigations, we developed a microprojection system to apply spatial photostimulus patterns in vivo. We monitored vascular and metabolic fluorescence signals after photostimulation in Thy1-channelrhodopsin-2 mice. Cerebral arteries increased in diameter rapidly after photostimulation, while nearby veins showed a slower smaller response. The amplitude of the arterial response was depended on the area of cortex stimulated. The fluorescence signal emitted at 450/100 nm and excited with ultraviolet is indicative of reduced nicotinamide adenine dinucleotide, an endogenous fluorescent enzyme involved in glycolysis and the citric acid cycle. This fluorescence signal decreased quickly and transiently after optogenetic stimulation, suggesting that glucose metabolism is tightly locked to optogenetic stimulation. To verify optogenetic stimulation of the cortex, we used a transparent substrate microelectrode array to map cortical potentials resulting from optogenetic stimulation. Spatial optogenetic stimulation is a new tool for studying neurovascular and neurometabolic coupling.