The Bimodal Nature of Neurovascular Coupling

Neurons, by virtue of their complex and continuously changing signaling roles in brain, must be able to regulate access to energy in order to maintain their ability to communicate meaningful frequency-encoded information. This is accomplished by release of neurotransmitters to astrocytes that in turn signal the vascular system to increase cerebral blood flow (CBF). This process has been termed “neurovascular coupling” (NVC). It has also been observed that NVC is bimodal in that there are two separate mechanisms for control of CBF. One type is rapid [phasic] in response to changes in glutamatergic synaptic activity and release of glutamate (Glu), K and nitric oxide (NO). Uptake of free Glu and K by astrocytes induces Ca2 waves activating regional astrocyte syncytium’s to liberate prostaglandins which in turn dilate capillaries by relaxing surrounding pericytes. The NO dilates arterioles by relaxing surrounding smooth muscle cells. These agents acting in concert sharply increase CBF within 1-3 seconds. The other type is slow [tonic] reflecting ongoing neuronal metabolic activity of all neuron types independent of changes in synaptic activity or astrocyte Ca2 waves and eliciting modest oscillations in CBF in 10’s of seconds. In this review, we describe two neuronal signaling mechanisms that match the criteria for phasic and for tonic regulation of CBF. The difference being the nature of the “Glu” released by neurons and of their targeted astrocyte receptors. Dependence on synaptic activity limits phasic responses to gray matter, but tonic responses can regulate CBF in both gray matter and white matter and may be the primary regulator of CBF in white matter.