Figure 1.

Neurovascular and neurometabolic coupling mechanisms. Schematic illustrating neuronal and astrocytic mechanisms responsible for activity-related blood flow and metabolic changes. (a) NMDA receptors (NMDA-R) are linked to neuronal nitric oxide synthase (nNOS) through post-synaptic density protein 95 (PSD-95) and neurovascular coupling during activity is thought to be triggered through the neuronally-produced vasodilator •NO, which can diffuse rapidly and freely through membranes to act on arterioles. (b) Vasodilation is also thought to be controlled at the capillary level through astrocytic Ca⁺ signaling acting on contractile perictyes. (c) In the glutamine-glutamate cycle, glutamate (Glu) released into the synaptic cleft is cleared by Na⁺-dependent astrocytic uptake, primarily through GLT-1. Glutamate is converted to glutamine (Gln) and returned to neurons to replenish neurotransmitter stores. (d,e) The astrocyte-neuron lactate shuttle (ANLS) hypothesis suggests associated increases in astrocytic Na⁺ concentration triggers activation of Na⁺/K⁺ ATPase pumps, promoting glucose uptake and glycolysis. Glycolytically-generated lactate is released and utilized as a substrate for oxidative phosphorylation in neurons during periods of activity. LDH, lactate dehydrogenase; MCT, monocarboxylate transporter. Solid lines indicate enzymatic activity, dashed lines indicate solute movement.