Nicotinic modulation of cortical circuits

Abstract

The ascending cholinergic neuromodulatory system sends projections throughout cortex and has been shown to play an important role in a number of cognitive functions including arousal, working memory, and attention. However, despite a wealth of behavioral and anatomical data, understanding how cholinergic synapses modulate cortical function has been limited by the inability to selectively activate cholinergic axons. Now, with the development of optogenetic tools and cell-type specific Cre-driver mouse lines, it has become possible to stimulate cholinergic axons from the basal forebrain (BF) and probe cholinergic synapses in the cortex for the first time. Here we review recent work studying the cell-type specificity of nicotinic signaling in the cortex, synaptic mechanisms mediating cholinergic transmission, and the potential functional role of nicotinic modulation.

Keywords: cholinergic; interneuron; nicotinic receptors; optogenetics; volume transmission.

Figure 1

Nicotinic signaling in the cortex. Colored cells represent cell-types known to exhibit nAChR-dependent responses to activation of cholinergic axons; black cells represent cell-types that exhibit nicotinic responses to exogenous application of cholinergic agonists; gray cells represent cell-types that do not express nicotinic receptors. The question mark for L5 pyramidal cells reflects the fact that studies disagree as to whether this cell-type expresses functional nicotinic receptors. Two types of nicotinic signaling are depicted: putative volume transmission targeting non-α7 nAChRs (gradient) and putative classical synapses targeting α7 nAChRs (green symbol with orange border).

Figure 2

Synaptic mechanisms underlying cholinergic transmission. (A) Example dual-component response recorded under voltage clamp. Note the fast α7 mediated response followed by the slower non-α7 response. Inset, fast component is displayed on an expanded timescale. (B) Response amplitude for the slow component is plotted against the response amplitude of the fast component for two cells. Note that the fast component exhibits much more variability in amplitude relative to the slow component. (C) Variability of the two response components quantified as the coefficient of variation (CV). (D) Example single trial responses to photostimulation demonstrate a reliable slow component across trials in which the fast component varied widely. Orange traces represent trials in which a fast component was not detectable. (E) Dual-component nicotinic responses before and after application of the AChE inhibitor ambenonium. Inset, expanded timescale reveals no effect of the AChE blocker on the fast component. Blue circles and ticks represent photostimulation.