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

The brain stemnucleus locus coeruleus (LC) is thought to modulate cortical excit-ability by norepinephrine (NE) release in LC forebrain targets. Theeffects of LC burst discharge, typically evoked by a strong excitatoryinput, on cortical ongoing activity are poorly understood. To addressthis 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 ofsingle 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 re-sponses bilaterally as well as a delayed rebound excitation occurring100 ms after stimulation offset. The pulse trains, but not singlepulses, reliably elicited mPFC activity change, which was propor-tional to the stimulation strength. The firing rate of50% of mPFCunits was significantly modulated by the strongest LC-DES. Re-sponses of mPFC putative pyramidal neurons included fast (100ms), transient (100–200 ms) inhibition (10% of units) or excitation(13%) and delayed (500 ms), sustained (1 s) excitation (26%).The sustained spiking resembled NE-dependent mPFC activity duringthe delay period of working memory tasks. Concurrently, the low-frequency (0.1–8 Hz) power of the local field potential (LFP) de-creased and high-frequency (20 Hz) power increased. Overall, theDES-induced LC firing pattern resembled the naturalistic biphasicresponse of LC-NE neurons to alerting stimuli and was associatedwith a shift in cortical state that may optimize processing of behav-iorally relevant events.