Enhanced Sensory-Cognitive Processing by Activation of Nicotinic Acetylcholine Receptors

Abstract

Activation of nicotinic acetylcholine receptors (nAChRs) enhances sensory-cognitive function in human subjects and animal models, yet the neural mechanisms are not fully understood. This review summarizes recent studies on nicotinic regulation of neural processing in the cerebral cortex that point to potential mechanisms underlying enhanced cognitive function. Studies from our laboratory focus on nicotinic regulation of auditory cortex and implications for auditory-cognitive processing, but relevant emerging insights from multiple brain regions are discussed. Although the major contributions of the predominant nAChRs containing α7 (homomeric receptors) or α4 and β2 (heteromeric) subunits are well recognized, recent results point to additional, potentially critical contributions from α2 subunits that are relatively sparse in cortex. Ongoing studies aim to elucidate the specific contributions to cognitive and cortical function of diverse nAChRs.

Implications: This review highlights the therapeutic potential of activating nAChRs in the cerebral cortex to enhance cognitive function. Future work also must determine the contributions of relatively rare but important nAChR subtypes, potentially to develop more selective treatments for cognitive deficits.

Figure 1.

Overview schematic of nicotinic acetylcholine receptor (nAChR)-mediated regulation of diverse types of neurons and afferent inputs in prefrontal cortex. LI–LVI, cortical layers 1 through 6. From Poorthuis et al..

Figure 2.

Systemic nicotine enhances gain and narrows receptive fields in mouse A1. Left: Example traces are current sinks in layer 4 of anesthetized mice, recorded using a 16-channel linear probe and evoked by acoustic “notched-noise” stimuli centered at the characteristic frequency (CF) (ie, white noise filtered to remove a spectral “notch” centered at CF for the recording site). Current sinks reflect stimulus-evoked synaptic activity at the recording site. Example shows that a narrow-notch stimulus that activates most of the receptive field produces a robust current sink (top black trace) that is enhanced by systemic nicotine (2 mg/kg), indicating increased gain. A wide-notch stimulus that activates only the edges of the receptive field produces a weaker response that is abolished by nicotine (bottom), indicating narrowing of the receptive field by nicotine. Right: group data from current-source density recordings in 23 mice plotting the initial slope of layer 4 current sink versus notch width of stimulus (normalized to a reference width that elicits the half-max response in each animal). Systemic nicotine enhances gain (curve shifts to higher values) and narrows receptive fields (curve shifts to narrower notch widths). Modified from Askew et al..

Figure 3.

Activation of α2 nicotinic acetylcholine receptor (nAChR)-expressing inhibitory interneurons enhances long-term potentiation (LTP) in hippocampal slices. (a) Potentiation of Schaffer collateral synapses in Chrna2-cre and Chrna2-cre;Viaat^loxP/loxP mice with Cre recombinase-induced expression of channelrhodopsin in control conditions (no light) and with a light pulse applied 5 minutes before and during Schaffer collateral weak theta-burst stimulation (wTBS; subthreshold for LTP). Bar graphs show the mean normalized slope 30 minutes after wTBS. (b) Data are presented in (a), but with 1 μM bath-applied nicotine instead of light stimulation. Chrna2-cre, mouse line expressing Cre recombinase under the control of the Chrna2 promoter. Chrna2-cre;Viaat^loxP/loxP, mouse line with inhibition from α2 nAChR-expressing cells abolished by crossing Chrna2-cre mice with mice carrying a loxP-flanked Viaat allele. From Leão et al..