Unilateral electrical stimulation of rat locus coeruleus elicits bilateral response of norepinephrine neurons and sustained activation of medial prefrontal cortex

The brain stem nucleus locus coeruleus (LC) is thought to modulate cortical excitability by norepinephrine (NE) release in LC forebrain targets. The effects of LC burst discharge, typically evoked by a strong excitatory input, on cortical ongoing activity are poorly understood. To address this question, we combined direct electrical stimulation of LC (LC-DES) with extracellular recording in LC and medial prefrontal cortex (mPFC), an important cortical target of LC. LC-DES consisting of single pulses (0.1-0.5 ms, 0.01-0.05 mA) or pulse trains (20-50 Hz, 50-200 ms) evoked short-latency excitatory and inhibitory LC responses bilaterally as well as a delayed rebound excitation occurring similar to 100 ms after stimulation offset. The pulse trains, but not single pulses, reliably elicited mPFC activity change, which was proportional to the stimulation strength. The firing rate of similar to 50% of mPFC units was significantly modulated by the strongest LC-DES. Responses of mPFC putative pyramidal neurons included fast (similar to 100 ms), transient (similar to 100-200 ms) inhibition (10% of units) or excitation (13%) and delayed (similar to 500 ms), sustained (similar to 1 s) excitation (26%). The sustained spiking resembled NE-dependent mPFC activity during the delay period of working memory tasks. Concurrently, the lowfrequency (0.1-8 Hz) power of the local field potential (LFP) decreased and high-frequency (>20 Hz) power increased. Overall, the DES-induced LC firing pattern resembled the naturalistic biphasic response of LC-NE neurons to alerting stimuli and was associated with a shift in cortical state that may optimize processing of behaviorally relevant events.