Leveraging the cortical cholinergic system to enhance attention

Abstract

Attentional impairments are found in a range of neurodegenerative and neuropsychiatric disorders. However, the development of procognitive enhancers to alleviate these impairments has been hindered by a lack of comprehensive hypotheses regarding the circuitry mediating the targeted attentional functions. Here we discuss the role of the cortical cholinergic system in mediating cue detection and attentional control and propose two target mechanisms for cognition enhancers: stimulation of prefrontal α4β2* nicotinic acetylcholine receptors (nAChR) for the enhancement of cue detection and augmentation of tonic acetylcholine levels for the enhancement of attentional control. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Figure 1

Distractor-induced impairment in attentional performance and prefrontal acetylcholine (ACh) release in the presence and absence of a distractor. (a) The sustained attention task (SAT) consists of randomly ordered signal (light signals 500, 50, or 25 ms long) and non-signal events, spaced by 9±3 s. Two seconds after an event, levers are made available and animals need to respond within 4 s. Following a lever press or after 4 s, levers are withdrawn. (b) Hits and correct rejections, but not misses and false alarms, are rewarded (note that arrows indicating the 4 response types in a are color-coded and match arrows in b). Sessions lasted 40 min and were blocked post hoc into five 8-min blocks of trials (t1–t5). (c) For testing on the distractor condition sustained attention task (dSAT), the distractor (chamber lights flashing on/off at 0.5 Hz) occurred during blocks 2 and 3. The vertical red and black bars illustrate a random sequence of signal and non-signal trials (signal duration indicated by the length of the red bars. (d) In the absence of a distractor (SAT; n=6), performance varied with signal duration and remained stable over the 5 task blocks (t1–t5). This plot and the plot in e show SAT and dSAT scores, respectively, which are an overall measure of performance calculated as follows: SAT/dSAT = (hit − false alarm) / [2(hit + false alarm) (hit + false alarm)²]. (e) Presentation of the distractor (dSAT; n=9) during task blocks 2 and 3 transiently impaired performance. During the post-distractor blocks, animals’ performance recovered. (f) SAT performance evoked a steep initial increase in ACh release in the medial prefrontal cortex as measured via in-vivo microdialysis. Release levels remained stable throughout the remainder of the performance session. Presentation of the distractor further increased ACh release (b1–b3 depict baseline collections prior to task onset, t1–t5 depict the 5 task blocks and at1–at4 indicate data from four collections following completion of the task (8 min/collection). (g) The severity of the distractor-induced impairment of performance was significantly correlated with distractor-induced increases in cholinergic activity. The abscissa of this graph depicts the differences between t1 and t2/t3 dSAT scores, with larger numbers indicating more severe impairments. Thus, higher increases in ACh release were correlated with less severe distractor effects on performance. (Post hoc multiple comparisons, using t-test or the Least Significance Difference (LSD), are indicated by symbols: *p<0.05). Adapted and modified from Figure 1 in St. Peters, M., Demeter, E., Lustig, C., Bruno, J.P., Sarter, M., 2011. Enhanced control of attention by stimulating mesolimbic-corticopetal cholinergic circuitry. J. Neurosci. 31, 9760–9771, with permission from the Society for Neuroscience.