Deterministic functions of cortical acetylcholine

Abstract

Traditional descriptions of the basal forebrain cholinergic projection system to the cortex have focused on neuromodulatory influences, that is, mechanisms that modulate cortical information processing but are not necessary for mediating discrete behavioral responses and cognitive operations. This review summarises and conceptualises the evidence in support of more deterministic contributions of cholinergic projections to cortical information processing. Through presynaptic receptors expressed on cholinergic terminals, thalamocortical and corticocortical projections can evoke brief cholinergic release events. These acetylcholine (ACh) release events occur on a fast, sub-second to seconds-long time scale ('transients'). In rats performing a task requiring the detection of cues as well as the report of non-cue events cholinergic transients mediate the detection of cues specifically in trials that involve a shift from a state of monitoring for cues to cue-directed responding. Accordingly, ill-timed cholinergic transients, generated using optogenetic methods, force false detections in trials without cues. We propose that the evidence is consistent with the hypothesis that cholinergic transients reduce detection uncertainty in such trials. Furthermore, the evidence on the functions of the neuromodulatory component of cholinergic neurotransmission suggests that higher levels of neuromodulation favor staying-on-task over alternative action. In other terms, higher cholinergic neuromodulation reduces opportunity costs. Evidence indicating a similar integration of other ascending projection systems, including noradrenergic and serotonergic systems, into cortical circuitry remains sparse, largely because of the limited information about local presynaptic regulation and the limitations of current techniques in measuring fast and transient neurotransmitter release events in these systems.

Keywords: acetylcholine; attention; cortex; neuromodulation; noradrenaline; serotonin.

Fig. 1

Illustration of (A) the integration of cortical cholinergic inputs into cortical circuitry and (B) cue-evoked glutamatergic and cholinergic transients. The illustrations are based on evidence from our electrochemical studies (Parikh et al., 2007, 2010; Parikh & Sarter, 2008; Howe et al., 2013). In attentional contexts, all cues that are detected (see text for definition of ‘detection’) elicit a glutamatergic (Glu) transient from mediodorsal thalamic afferents (MD in A). Such glutamatergic transients are necessary, but not sufficient, to generate cholinergic transients (ACh), perhaps via ionotropic glutamate receptors that may be expressed at cholinergic terminals (see text). Glutamate may elicit cholinergic transients regardless of cholinergic depolarisation (Kunz et al., 2013), thereby integrating cholinergic inputs into cortical circuitry and employing these terminals for cortical information processing. (B) Glutamatergic and cholinergic transients (spline-interpolated traces) recorded in the medial prefrontal thalamic input layers during incongruent hits. As detailed in the text, all cues yielding hits, regardless of trial sequence, evoke glutamatergic transients. These transients peak at around the time the levers are extended and prior to the response. The absence of a cue-evoked glutamatergic transient invariably predicts a miss. Cholinergic transients are observed only during cued trials yielding hits that are preceded by trials ending with correct rejections or misses (‘incongruent hits’), but not in trials preceded by a hit (‘consecutive hits’). Thus, it is hypothesised that cholinergic transients mediate cue detection during trials involving a shift from perceptual attention to cue-oriented behavior (Howe et al., 2013). As indicated by gamma oscillations seen during such trials, the interactions between glutamatergic and cholinergic transients during incongruent hits synchronises cortical output assemblies to forward the processing of the cue to further telencephalic regions, thereby mediating an attentional mode shift and the detection of the cue in trials requiring such a shift. In addition to this deterministic function of ACh, basal forebrain cholinergic projections also modulate the glutamatergic–cholinergic transient interactions via stimulating alpha4beta2* nAChRs; it is hypothesised that these cholinergic neurons form a separate population of basal forebrain cholinergic neurons (A). Cholinergic neuromodulatory upregulation of glutamatergic–cholinergic interactions is a functions of attentional effort (e.g., St Peters et al., 2011; see also main text). Thus, such upregulation restores or increases detection rates.