ASTROCYTES REGULATE PHASIC ACTIVATION OF LOCUS COERULEUS NOREPINEPHRINE NEURONS VIA NMDA RECEPTOR-DEPENDENT PLASTICITY

The LC is composed primarily of NE neurons. Due to their widespread axonal projections throughout the brain, these neurons play an important role in regulating brain function and behavior. LC-NE neurons are known to regulate wakefulness levels by firing tonically at different frequencies. They also respond to salient environmental stimuli with phasic activation to promote adaptive behaviors. However, the underlying cellular mechanisms remain largely unknown. Previously, we reported that LC-NE neurons exhibit slow inward currents (SICs), which can effectively drive phasic activation ex vivo. In many brain regions, SICs have been shown to be mediated by glutamate released from astrocytes, which synchronizes the activity of nearby neurons. Consistent with this, we found that briefly activating (for 30 seconds) astrocytes in the LC via optogenetics or by puffing extracellular glutamate (or NMDA) results in a long-lasting increase in astrocytic activity (up to 20 minutes), as monitored by the GCaMP6f signal. There is also an increase in SIC frequency recorded in LC–NE neurons. We found that inducing this form of functional plasticity between astrocytes and NE neurons depends on activating NMDA receptors on astrocytes. Furthermore, we estimate that the threshold for induction with glutamate puffing is 0.5 mM. In conclusion, our findings suggest that astrocytes contribute to the operation of the neuronal network that generates LC phasic activation through NMDA receptor-dependent modulation. Given the significant role of phasic LC activation, these results may provide new insight into how the LC regulates behavior from the perspective of plasticity in astrocyte-NE neuron communication.