Convergence of nicotine-induced and auditory-evoked neural activity activates ERK in auditory cortex.

Enhancement of sound-evoked responses in auditory cortex (ACx) following administration of systemic nicotine is known to depend on activation of extracellular-signaling regulated kinase (ERK), but the nature of this enhancement is not clear. Here, we show that systemic nicotine increases the density of cells immunolabeled for phosphorylated (activated) ERK (P-ERK) in mouse primary ACx (A1). Cortical injection of dihydro-ß-erythroidine reduced nicotine-induced P-ERK immunolabel, suggesting a role for nicotinic acetylcholine receptors located in A1 and containing α4 and ß2 subunits. P-ERK expressing cells were distributed mainly in layers 2/3 and more sparsely in lower layers, with many cells exhibiting immunolabel within pyramidal-shaped somata and proximal apical dendrites. About one-third of P-ERK positive cells also expressed calbindin. In the thalamus, P-ERK immunopositive cells were found in the nonlemniscal medial geniculate (MG) and adjacent nuclei, but were absent in the lemniscal MG. Pairing broad spectrum acoustic stimulation (white noise) with systemic nicotine increased P-ERK immunopositive cell density in ACx as well as the total amount of P-ERK protein, particularly the phosphorylated form of ERK2. However, narrow spectrum (tone) stimulation paired with nicotine increased P-ERK immunolabel preferentially at a site within A1 where the paired frequency was characteristic frequency (CF), relative to a second site with a spectrally distant CF (two octaves above or below the paired frequency). Together, these results suggest that ERK is activated optimally where nicotinic signaling and sound-evoked neural activity converge.

Nicotinic control of axon excitability regulates thalamocortical transmission.

The thalamocortical pathway, a bundle of myelinated axons that arises from thalamic relay neurons, carries sensory information to the neocortex. Because axon excitation is an obligatory step in the relay of information from the thalamus to the cortex, it represents a potential point of control. We now show that, in adult mice, the activation of nicotinic acetylcholine receptors (nAChRs) in the initial portion of the auditory thalamocortical pathway modulates thalamocortical transmission of information by regulating axon excitability. Exogenous nicotine enhanced the probability and synchrony of evoked action potential discharges along thalamocortical axons in vitro, but had little effect on synaptic release mechanisms. In vivo, the blockade of nAChRs in the thalamocortical pathway reduced sound-evoked cortical responses, especially those evoked by sounds near the acoustic threshold. These data indicate that endogenous acetylcholine activates nAChRs in the thalamocortical pathway to lower the threshold for thalamocortical transmission and to increase the magnitude of sensory-evoked cortical responses. Our results show that a neurotransmitter can modulate sensory processing by regulating conduction along myelinated thalamocortical axons.