title: Unilateral electrical stimulation of rat locus coeruleus elicits bilateral response of norepinephrine neurons and sustained activation of medial prefrontal cortex.
abstract: 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 ∼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 ∼50% of mPFC units was significantly modulated by the strongest LC-DES. Responses of mPFC putative pyramidal neurons included fast (∼100 ms), 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 during the delay period of working memory tasks. Concurrently, the low-frequency (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.
authors.affiliation: Max Planck Institute for Biological Cybernetics, Tübingen, Germany; and.
authors.forename: Aude
authors.initials: A
authors.lastname: Marzo
authors.affiliation: Max Planck Institute for Biological Cybernetics, Tübingen, Germany; and.
authors.forename: Nelson K
authors.initials: NK
authors.lastname: Totah
authors.affiliation: Max Planck Institute for Biological Cybernetics, Tübingen, Germany; and.
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Neves
authors.affiliation: Max Planck Institute for Biological Cybernetics, Tübingen, Germany; and Centre for Imaging Sciences, Biomedical Imaging Institute, University of Manchester, Manchester, United Kingdom.
authors.forename: Nikos K
authors.initials: NK
authors.lastname: Logothetis
authors.affiliation: Max Planck Institute for Biological Cybernetics, Tübingen, Germany; and oxana.eschenko@tuebingen.mpg.de.
authors.forename: Oxana
authors.initials: O
authors.lastname: Eschenko
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D004558:Electric Stimulation / Q000379:methods; D007839:Functional Laterality / Q000502:physiology*; D008125:Locus Coeruleus / Q000502:physiology*; D008297:Male; D008839:Microelectrodes; D009474:Neurons / Q000502:physiology*; D009638:Norepinephrine / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000502:physiology*; D017966:Pyramidal Cells / Q000502:physiology; D017207:Rats, Sprague-Dawley
chemical_list: D009638:Norepinephrine
keywords: arousal; cortical excitability; direct electrical stimulation; locus coeruleus; neuromodulation