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Introduction: In primary auditory cortex (A1), nicotinic acetylcholine receptors (nAChRs) containing α2 subunits are expressed in layer 5 Martinotti cells (MCs)—inhibitory interneurons that send a main axon to superficial layers to inhibit distal apical dendrites of pyramidal cells (PCs). MCs also contact interneurons in supragranular layers that, in turn, inhibit PCs. Thus, MCs may regulate PCs via inhibition and disinhibition, respectively, of distal and proximal apical dendrites. Auditory inputs to PCs include thalamocortical inputs to middle layers relaying information about characteristic frequency (CF) and near-CF stimuli, and intracortical long-distance ("horizontal") projections to multiple layers carrying information about spectrally distant ("nonCF") stimuli. CF and nonCF inputs integrate to create broad frequency receptive fields (RFs). Systemic administration of nicotine activates nAChRs to "sharpen" RFs—to increase gain within a narrowed RF—resulting in enhanced responses to CF stimuli and reduced responses to nonCF stimuli. While nicotinic mechanisms to increase gain have been identified, the mechanism underlying RF narrowing is unknown. Methods: Here, we examine the role of α2 nAChRs in mice with α2 nAChR-expressing neurons labeled fluorescently, and in mice with α2 nAChRs genetically deleted. Results: The distribution of fluorescent neurons in auditory cortex was consistent with previous studies demonstrating α2 nAChRs in layer 5 MCs, including nonpyramidal somata in layer 5 and dense processes in layer 1. We also observed label in subcortical auditory regions, including processes, but no somata, in the medial geniculate body, and both fibers and somata in the inferior colliculus. Using electrophysiological (current-source density) recordings in α2 nAChR knock-out mice, we found that systemic nicotine failed to enhance CF-evoked inputs to layer 4, suggesting a role for subcortical α2 nAChRs, and failed to reduce nonCF-evoked responses, suggesting that α2 nAChRs regulate horizontal projections to produce RF narrowing. Discussion: The results support the hypothesis that α2 nAChRs function to simultaneously enhance RF gain and narrow RF breadth in A1. Notably, a similar neural circuit may recur throughout cortex and hippocampus, suggesting widespread conserved functions regulated by α2 nAChRs. [ABSTRACT FROM AUTHOR]

Nicotinic acetylcholine α4β2∗ receptors (nAChRs) are implicated in various neurodegenerative diseases and smoking addiction. Imaging of brain high-affinity α4β2∗ nAChRs at the cellular and subcellular levels would greatly enhance our understanding of their functional role. Since better resolution could be achieved with fluorescent probes, using our previously developed positron emission tomography (PET) imaging agent [18F]nifrolidine, we report here design, synthesis and evaluation of two fluorescent probes, nifrodansyl and nifrofam for imaging α4β2∗ nAChRs. The nifrodansyl and nifrofam exhibited nanomolar affinities for the α4β2∗ nAChRs in [3H]cytisine-radiolabeled rat brain slices. Nifrofam labeling was observed in α4β2∗ nAChR-expressing HEK cells and was upregulated by nicotine exposure. Nifrofam co-labeled cell-surface α4β2∗ nAChRs, labeled with antibodies specific for a β2 subunit extracellular epitope indicating that nifrofam labels α4β2∗ nAChR high-affinity binding sites. Mouse brain slices exhibited discrete binding of nifrofam in the auditory cortex showing promise for examining cellular distribution of α4β2∗ nAChRs in brain regions.

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Nicotinic acetylcholine α4β2 ∗ receptors (nAChRs) are implicated in various neurodegenerative diseases and smoking addiction. Imaging of brain high-affinity α4β2 ∗ nAChRs at the cellular and subcellular levels would greatly enhance our understanding of their functional role. Since better resolution could be achieved with fluorescent probes, using our previously developed positron emission tomography (PET) imaging agent [ 18 F]nifrolidine, we report here design, synthesis and evaluation of two fluorescent probes, nifrodansyl and nifrofam for imaging α4β2 ∗ nAChRs. The nifrodansyl and nifrofam exhibited nanomolar affinities for the α4β2 ∗ nAChRs in [ 3 H]cytisine-radiolabeled rat brain slices. Nifrofam labeling was observed in α4β2 ∗ nAChR-expressing HEK cells and was upregulated by nicotine exposure. Nifrofam co-labeled cell-surface α4β2 ∗ nAChRs, labeled with antibodies specific for a β2 subunit extracellular epitope indicating that nifrofam labels α4β2 ∗ nAChR high-affinity binding sites. Mouse brain slices exhibited discrete binding of nifrofam in the auditory cortex showing promise for examining cellular distribution of α4β2 ∗ nAChRs in brain regions., (Copyright © 2017 Elsevier Ltd. All rights reserved.)