Systemic Nicotine Increases Gain and Narrows Receptive Fields in A1 via Integrated Cortical and Subcortical Actions

Abstract

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 increasing 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.

Keywords: A1; acetylcholine; auditory cortex; mouse; nicotine; receptive field.

Figure 1.

TINN stimulus used to estimate RF widths and suppression of tone-evoked responses. A, Example TINN stimulus illustrates time course (left) and spectrum (right) of CF tone (green) and NN (blue). Spectral notch was varied in ∼0.25 octave steps (0.1-2.5 octaves) and centered (using octave scale) at CF. B, Example TINN stimuli and evoked current sinks in L4 of A1; narrow-notch TINN evoked strong response to NN and no response to tone (top row), intermediate-notch TINN evoked weak response to NN and weak response to tone (middle row), wide-notch TINN evoked no response to NN and strong response to tone (bottom row). Shading indicates 10-ms analysis window for NN and tone responses. C, Example analysis of TINN-evoked responses shows current-sink slope versus notch width for NN-evoked responses (top; arrows indicate data points from traces in B) and tone-evoked responses (bottom), with data fitted by sigmoidal curves. Sigmoidal functions provide estimates of RF shape (top) and suppression of tone-evoked response by preceding RF stimulation (bottom). In this and the following figures, current sink slope is in units of mV mm⁻² ms⁻¹.

Figure 2.

Systemic nicotine enhanced responses to narrow-notch stimuli and tone stimuli, and reduced responses to intermediate-notch stimuli in A1. A, Example of nicotine effect on TINN-evoked current sinks in L4 (left) and derived functions (right). B, Group data (n = 23) demonstrating nicotinic enhancement of responses to narrow-notch stimuli and reduction of responses to intermediate-notch stimuli (left). Data are normalized to prenicotine plateau of sigmoid function. Group data are also plotted as postnicotine/prenicotine response ratios versus notch width (right), indicating differential nicotinic effects at narrow versus intermediate notch sizes. C, Group data (n = 18) demonstrating nicotinic enhancement of responses to CF tone contained within TINN stimulus (sigmoidal curves) and to CF tone presented alone (separated data points on right).

Figure 3.

A closer look at responses to intermediate-notch TINN stimuli. A, Superimposed group data for prenicotine responses emphasize substantial suppression of tone-evoked responses, even by relatively weak NN-evoked responses (boxed data points). B, Effects of nicotine on normalized response values (postnicotine minus prenicotine slope) showing reduction of NN-evoked responses at intermediate notch widths and enhancement of tone-evoked responses over a wider range of notch sizes. C, Nicotine-induced shift in width of sigmoid functions (in octaves, measured at 50% max), i.e., RF and tone-suppression functions, reveal larger shift in tone-suppression function.

Figure 4.

Systemic nicotine produced similar effects on TINN-evoked MUA. A, Example of nicotine effect on TINN-evoked MUA in L4 of A1. B, Group data (n = 21) demonstrating nicotinic enhancement of MUA evoked by narrow-notch stimuli and reduction of MUA responses to intermediate-notch stimuli. C, Group data (n = 18) of tone-evoked MUA responses (wide-notch TINN stimuli), illustrating nicotinic enhancement.

Figure 5.

Systemic nicotine effects occurred despite the presence of intracortical muscimol. A, Example of nicotine effect on TINN-evoked L4 current sink in the presence of muscimol (100 µM) to silence intracortical activity and isolate presumed thalamocortical input. B, Group data (n = 8) demonstrating that nicotinic effects on NN-evoked responses occurred in the presence of muscimol. C, Nicotinic enhancement of tone-evoked responses also occurred after muscimol (n = 8).

Figure 6.

In ICc, systemic nicotine reduced responses to intermediate-notch NN stimuli but did not enhance any TINN-evoked response. A, Example of nicotine effect on TINN-evoked LFPs in ICc. Units of LFP slope are µV/ms. B, Group data (n = 8) demonstrating nicotinic reduction of responses to NN stimuli (left). Group data are also plotted as postnicotine/prenicotine response ratios (right), illustrating that the reduction occurs primarily at wider notches. C, Group data (n = 8) showing no effect on tone-evoked responses.

Figure 7.

In MGv, systemic nicotine reduced responses to intermediate-notch NN stimuli but did not enhance any TINN-evoked response. A, Example of nicotine effect on TINN-evoked LFPs in MGv (left, middle), coronal brain slice showing recording probe track (inset), and sigmoidal NN functions (right; units of LFP slope are µV/ms.). B, Group data (n = 7) demonstrating nicotinic reduction of responses to NN stimuli (left). Group data are also plotted as postnicotine/prenicotine response ratios (right), illustrating that the reduction occurs primarily at wider notches. C, Group data (n = 7) showing that nicotine has no effect on tone-evoked responses.

Figure 8.

Simultaneous recordings in A1 and ICc or MGv confirm differential effects of systemic nicotine. A, Examples of nicotine effects on TINN-evoked LFPs in A1 and MGv (top), and in A1 and ICc (bottom), confirming that nicotinic enhancement of TINN-evoked responses occurred only in A1, whereas nicotinic reduction of responses occurred in all three regions. B, Onset latencies in A1, MGv, and ICc (0.1 octave NN stimulus). Systemic nicotine reduced onset latency only in A1.

Figure 9.

Comparison of RFs and response suppression in A1, MGv, and ICc. A, NN-evoked (left) and tone-evoked (right) LFP response functions in A1, MGv, and ICc. Response magnitude normalized to plateau value for each animal; notch width is absolute value (unlike previous figures). B, Comparison of RF width and suppression of tone-evoked response, based on notch width producing 50% max response in A; individual data points are shown with group means. ICc exhibited narrower RFs and suppression of tone-evoked responses at narrower notch widths.

Figure 10.

Nicotine microinjection in STR enhanced TINN-evoked responses in A1. A, Example of NN-evoked current sink enhanced by nicotine microinjection in STR, and subsequently by systemic nicotine (left); graph (right) shows response magnitudes before and after STR microinjection, and inset shows post hoc visualization of fluorescent injection site in STR (horizontal plane; LG, lateral geniculate; RT, reticular nucleus; ACx, auditory cortex). B, Group data (n = 10) showing enhancing effect of nicotine STR microinjections on NN-evoked responses (left). In a subset of six animals that appeared more sensitive to systemic nicotine, STR microinjections were effective, whereas in four animals that were insensitive to systemic nicotine STR microinjections also had no effect (right).

Figure 11.

Cortical microinjection of positive allosteric modulator, NS9283, enhanced TINN-evoked responses in A1. A, Example of NN-evoked current sink in A1 enhanced by intracortical microinjection of NS9283, and subsequently by systemic nicotine (left); graph (right) shows response magnitudes before and after NS9283 microinjection. B, Group data (n = 10) of NS9283 effects on NN-evoked responses (left), implicating enhancement by endogenous ACh. Graph on right correlates effect of NS9283 microinjection (post-NS/pre-NS ratio) with that of systemic nicotine (post-nic/pre-NS ratio), all notch widths included. Correlation reflects similar effects of both drugs, including enhancement at narrow notch widths and suppression at intermediate notch widths.

Figure 12.

Summary schematic depicting effects of systemic nicotine on RFs in the auditory lemniscal pathway. Nicotine narrows RFs in ICc and MGv, increases gain in the thalamocortical (TC) pathway, and both narrows RFs and increases gain in A1. Nicotine effects integrate to produce the RF changes observed in A1.