High temporal resolution microdialysis reveals cholinergic spikes preceding upshifts in attentional performance.

Prefrontal cholinergic neurotransmission mediates the cognitive control of attention and the detection of cues. Two modes of cholinergic neurotransmission can be separated. Relatively slow or tonic (tens of seconds or minutes) modulate cortical circuitry as a function of the demands on attention (St. Peters et al, 2011). Fast, second-based release events (or transients) are generated via local cortical circuitry and are necessary for the detection of cues (Hasselmo & Sarter 2011). Transients are recorded using amperometry and enzyme-coated microelectrodes. Tonic levels of cholinergic neurotransmission are monitored by microdialysis; importantly this is not a confound of the necessity of long collection intervals but our evidence indicates that tonic levels are not merely representing integrated transients. To further test this hypothesis and to explore the timescale of variations in tonic cholinergic activity in a given behavioral context and to refine the relationships between behavioral/cognitive processes and such variations, we employed a novel HPLC-tandem mass spectrometry (MS) method (Song et al, 2012) to detect acetylcholine (ACh) and several monoamines and amino acids from 3-min collections (1 µL/min; no AChesterase inhibitor added). The focus on 3-min collections was based on our observation that rats performing the sustained attention task (SAT) frequently shift between good and poor levels of performance (defined as SAT scores >0.34 and at chance, or <0.17, respectively). Averaged across SAT sessions, ACh release levels corresponded with those previously obtained from 8-min collections and conventional HPLC-EC methods. However, performance-associated ACh levels fluctuated drastically across 3-min collections, ranging from pre-task baseline levels to 500% above baseline. Cholinergic spikes were observed just prior to shifts from random levels of performance to good levels of performance. Specifically, over 14 animals, 75% of such up-shifts were preceded by increases in cholinergic neurotransmission that were at least 3 SD above baseline levels. These findings indicate the usefulness of high temporal resolution microdialysis. The results are consistent with the hypothesis that tonic cholinergic activity modulates cortical target circuitry as a function of the subjects’ motivation to enhance attentional performance and to orchestrate, the mechanisms designed to enhance signal processing, noise filtering and task compliance (Sarter & Paolone 2011). Tonic cholinergic activity in SAT performing animals is a major target of treatments designed to benefit cognitive performance in ADHD, schizophrenia, PD and other disorders.