LAUSR

Brain requires increased local cerebral blood flow (CBF) for as long as necessary during neuronal activation to match O2 and glucose supply with demand – termed functional hyperemia. Ca2+ elevation in astrocytes can drive arteriole dilation to increase CBF, yet affirmative evidence for the necessity of astrocytes in functional hyperemia in vivo is lacking. In awake and active mice, we discovered that functional hyperemia is bimodal with a distinct early and late component whereby arteriole dilation progresses as sensory stimulation is sustained. Clamping astrocyte Ca2+ signaling in vivo by expressing a high-affinity plasma membrane Ca2+ ATPase (CalEx) reduces sustained but not brief sensory-evoked arteriole dilation. Reciprocally, elevating astrocyte free Ca2+ using chemogenetics selectively augments sustained but not brief hyperemia. Neither locomotion, arousal, nor changes in neuronal signaling account for the selective effect of astrocyte Ca2+ on the late phase of the CBF response. Antagonizing NMDA-receptors or epoxyeicosatrienoic acid production reduces only the late component of functional hyperemia, leaving brief increases in CBF to sensory stimulation intact. We propose that a fundamental role of astrocyte Ca2+ is to amplify functional hyperemia when neuronal activation is prolonged.