Inhibition of norepinephrine signaling during a sensitive period disrupts locus coeruleus circuitry and emotional behaviors in adulthood

Deficits in arousal and stress responsiveness span numerous psychiatric developmental disorders including depression and anxiety. Arousal is supported by norepinephrine (NE) released from locus coeruleus (LC) neurons onto cortical and limbic areas. During development, the NE system matures in concert with increased exploration of the animals environment. While several psychiatric medications target the LC-NE system, the possibility that its modulation during discreet developmental periods can have long-lasting consequences for mental health has not been explored. We used a pharmacogenetic strategy in mice to reversibly inhibit NE signaling during brief developmental periods to determine the long-lasting impact on adult circuits mediating emotional behavior. We also examine whether disruption of NE signaling during development results in permanent changes within the adult LC-NE system. Finally, we test whether developmental exposure to the -2 receptor agonist guanfacine recapitulates the effect seen with our pharmacogenetic strategy. Our results reveal a sensitive period (postnatal days 10-21) during which alterations in NE signaling result in long-term changes in adult emotional behavior. Changes in NE signaling during this sensitive period results in changes in stress-related LC neuron activity, alterations in -2 autoreceptor function, and circuit-specific molecular changes in LC-NE target regions in adulthood. Treating animals with guanfacine during the sensitive period produced similar results. Our findings indicate an early critical role for NE in sculpting brain circuits that support adult emotional function.