RT Journal Article SR Electronic T1 Systemic Nicotine Increases Gain and Narrows Receptive Fields in A1 via Integrated Cortical and Subcortical Actions JF eneuro JO eNeuro FD Society for Neuroscience SP ENEURO.0192-17.2017 DO 10.1523/ENEURO.0192-17.2017 A1 Caitlin Askew A1 Irakli Intskirveli A1 Raju Metherate YR 2017 UL http://www.eneuro.org/content/early/2017/06/12/ENEURO.0192-17.2017.abstract AB Nicotine enhances sensory and cognitive processing via actions at nicotinic acetylcholine receptors (nAChRs), yet the precise circuit- and systems-level mechanisms remain unclear. In sensory cortex, nicotinic modulation of receptive fields (RFs) provides a model to probe mechanisms by which nAChRs regulate cortical circuits. Here we examine RF modulation in mouse primary auditory cortex (A1) using a novel electrophysiological approach: current-source density (CSD) analysis of responses to tone-in-notched-noise (TINN) acoustic stimuli. TINN stimuli consist of a tone at the characteristic frequency (CF) of the recording site embedded within a white noise stimulus filtered to create a spectral “notch” of variable width centered on CF. Systemic nicotine (2.1 mg/kg) enhanced responses to the CF tone and to narrow-notch stimuli, yet reduced the response to wider-notch stimuli, indicating increased response gain within a narrowed RF. Subsequent manipulations showed that modulation of cortical RFs by systemic nicotine reflected effects at several levels in the auditory pathway: nicotine suppressed responses in the auditory midbrain and thalamus, with suppression varying with spectral distance from CF so that RFs became narrower, and facilitated responses in the thalamocortical pathway, while nicotinic actions within A1 further contributed to both suppression and facilitation. Thus, multiple effects of systemic nicotine integrate along the ascending auditory pathway. These actions at nAChRs in cortical and subcortical circuits, which mimic effects of auditory attention, likely contribute to nicotinic enhancement of sensory and cognitive processing.Significance Statement Nicotinic acetylcholine receptors (nAChR) are critical for cognitive and sensory processing, and their dysfunction contributes to multiple disorders, including schizophrenia and Alzheimer’s disease. Accordingly, nAChR agonists are being explored as potential therapeutics, yet little is known about the circuit-level mechanisms by which nAChRs enhance cognitive and sensory processing. Here we probe modulation of auditory receptive fields by systemically-administered nicotine and discover that the overall effect in primary auditory cortex results from multiple, integrated effects within the auditory pathway. Our results not only address mechanisms of auditory processing, but, given the similar distribution of nAChRs across cortical areas, may promote an understanding of nicotinic modulation of cortical information processing more generally.