Unilateral electrical stimulation of the rat Locus Coeruleus elicits bilateral 1 response of norepinephrine neurons and sustained activation of the medial 2 Prefrontal Cortex 3 Running Title : Effects of LC stimulation on activity in LC and mPFC 4 5

27 The brain stem nucleus Locus Coeruleus (LC) is thought to modulate cortical excitability 28 by norepinephrine (NE) release in LC forebrain targets. The effects of LC burst 29 discharge, typically evoked by a strong excitatory input, on cortical ongoing activity are 30 poorly understood. To address this question, we combined direct electrical stimulation of 31 LC (LC-DES) with extracellular recording in LC and medial prefrontal cortex (mPFC), an 32 important cortical target of LC. LC-DES consisting of both, single pulses (0.1 0.5 ms, 33 0.01 0.05 mA) or pulse trains (20 50 Hz, 50 200 ms), evoked short-latency excitatory 34 and inhibitory LC responses bilaterally, as well as a delayed rebound excitation 35 occurring ~100 ms after stimulation offset. The pulse trains, but not single pulses, 36 reliably elicited mPFC activity change, which was proportional to the stimulation 37 strength. The firing rate of ~50% of mPFC units was significantly modulated by the 38 strongest LC-DES. Responses of mPFC putative pyramidal neurons included fast (~100 39 ms), transient (~100 – 200 ms) inhibition (10% of units) or excitation (13%), and delayed 40 (~500 ms), sustained (~1 s) excitation (26%). The sustained spiking resembled NE41 dependent mPFC activity during the delay period of working memory tasks. 42 Concurrently, the low-frequency (0.1-8 Hz) power of the local field potential (LFP) 43 decreased and high-frequency (> 20 Hz) power increased. Overall, the DES-induced LC 44 firing pattern resembled the naturalistic biphasic response of LC-NE neurons to alerting 45 stimuli and was associated with a shift in cortical state that may optimize processing of 46 behaviorally-relevant events. 47