Nicotinic neuromodulation in auditory cortex requires MAPK activation in 2 thalamocortical and intracortical circuits

20 Activation of nicotinic acetylcholine receptors (nAChRs) by systemic nicotine enhances sensory21 cognitive function and sensory-evoked cortical responses. Although nAChRs mediate fast 22 neurotransmission at many synapses in the nervous system, nicotinic regulation of cortical 23 processing is neuromodulatory. To explore potential mechanisms of nicotinic neuromodulation, 24 we examined whether intracellular signal transduction involving mitogen-activated protein 25 kinase (MAPK) contributes to regulation of tone-evoked responses in primary auditory cortex 26 (A1) in the mouse. Systemic nicotine enhanced characteristic frequency (CF) tone-evoked 27 current-source density (CSD) profiles in A1, including the shortest-latency (presumed 28 thalamocortical) current sink in layer 4 and longer-latency (presumed intracortical) sinks in 29 layers 2-4, by increasing response amplitudes and decreasing response latencies. Microinjection 30 of the MAPK kinase (MEK) inhibitor U0126 into the thalamus, targeting the auditory 31 thalamocortical pathway, blocked the effect of nicotine on the initial (thalamocortical) CSD 32 component, but did not block enhancement of longer-latency (intracortical) responses. 33 Conversely, microinjection of U0126 into supragranular layers of A1 blocked nicotine’s effect 34 on intracortical, but not thalamocortical, CSD components. Simultaneously with enhancement of 35 CF-evoked responses, responses to spectrally-distant (nonCF) stimuli were reduced, implying 36 nicotinic “sharpening” of frequency receptive fields, an effect also blocked by MEK inhibition. 37 Consistent with these physiological results, acoustic stimulation with nicotine produced 38 immunolabel for activated MAPK in A1, primarily in layer 2/3 cell bodies. Immunolabel was 39 blocked by intracortical microinjection of the nAChR antagonist dihydro-β-erythroidine, but not 40 methyllycaconitine, implicating α4β2*, but not α7, nAChRs. Thus, activation of MAPK in 41