Time to Pay Attention: Attentional Performance Time-Stamped Prefrontal Cholinergic Activation, Diurnality, and Performance

Abstract

Although the impairments in cognitive performance that result from shifting or disrupting daily rhythms have been demonstrated, the neuronal mechanisms that optimize fixed time daily performance are poorly understood. We previously demonstrated that daily practice of a sustained attention task (SAT) evokes a diurnal activity pattern in rats. Here we report that SAT practice at a fixed time produced practice time-stamped increases in prefrontal cholinergic neurotransmission that persisted after SAT practice was terminated and in a different environment. SAT time-stamped cholinergic activation occurred irrespective of whether the SAT was practiced during the light or dark phase or in constant light conditions. In contrast, prior daily practice of an operant schedule of reinforcement, albeit generating more rewards and lever presses per session than the SAT, neither activated the cholinergic system nor affected the animals' nocturnal activity pattern. Likewise, food-restricted animals exhibited strong food anticipatory activity (FAA) and attenuated activity during the dark period but FAA was not associated with increases in prefrontal cholinergic activity. Removal of cholinergic neurons impaired SAT performance and facilitated the reemergence of nocturnality. Shifting SAT practice away from a fixed time resulted in significantly lower performance. In conclusion, these experiments demonstrated that fixed time, daily practice of a task assessing attention generates a precisely practice time-stamped activation of the cortical cholinergic input system. Time-stamped cholinergic activation benefits fixed time performance and, if practiced during the light phase, contributes to a diurnal activity pattern.

Monitoring cholinergic activity during attentional performance in mice heterozygous for the choline transporter: A model of cholinergic capacity limits

“…Furthermore, SAT-associated increases in cholinergic activity entrain circadian rhythms and are influenced by neuronal clocks, inducing diurnality in rodents and optimizing fixed-time performance, respectively (Paolone et al, 2012; Gritton et al, 2013). Because of the limited capacity for electrically (Parikh et al, 2013a) and pharmacologically-evoked ACh release in CHT+/− mice (above), the performance of CHT+/− mice as well as SAT-associated increases in ACh release were expected to be lower in CHT+/− mice when compared with WT animals.…”

“…However, pre-task ACh levels were significantly higher than basal levels in non-performing mice and prior to the atropine challenge (above; F(1,17)=8.20, p<0.05; basal non-performing: 3.52±0.86 fmol/15 μL; performing: 6.59±0.65 fmol/15 μL; genotype and interaction: both n.s. ), reflecting cholinergic activation in both strains as a function of fixed daily practice time (Paolone et al, 2012). In WT mice, SAT performance-associated increase in ACh release was comparable to that seen previously in rats (e.g., St Peters et al, 2011b).…”

“…Animals were housed individually in a temperature (23°C) and humidity-controlled (45%) environment, and kept on a 12:12 light/dark cycle (lights on at 7:30 a.m.). Training and testing on the SAT took place during the light phase; this method is justified given that in rodents, daily attention practice evokes a diurnal activity pattern (Gritton et al, 2009, 2012, 2013; Paolone et al, 2012). Mice were 12 weeks of age and weighed 20-30 g at the beginning experiments.…”

“…Furthermore, we showed that the outward trafficking of CHTs produced by an operant, sustained attention task (SAT), and in the presence of a distractor , was attenuated in these mutants (Parikh et al, 2013a). The present experiments addressed the essential question of whether CHT heterozygosity also limits cholinergic output in vivo while performing an attention task known to require and increase cortical cholinergic activity (e.g., Kozak et al, 2007; St Peters et al, 2011b; Paolone et al, 2012, 2013). …”

Thalamic cholinergic innervation makes a specific bottom-up contribution to signal detection: Evidence from Parkinson’s disease patients with defined cholinergic losses

“…Instead, cortical, and especially fronto-parietal, cholinergic activity are hypothesized to support “attentional effort” – the motivated activation of top-down attention to stabilize task representations, especially when performance is challenged (Lustig & Sarter, 2016; Raizada & Poldrack, 2008; Sarter et al, 2006). Fronto-parietal cholinergic activity increases reliably from baseline to the SAT, and further in response to the dSAT condition or other challenges (see Kozak et al, 2006); even placing trained animals in the operant chamber or simply testing them at the same time every day can lead to increases in frontoparietal cholinergic activity suggesting a readiness to engage in the task (Paolone et al, 2012). However, evidence from both the rodent and human studies suggests that, given the bottom-up nature of the target signal in the dSAT, this increased engagement is more strongly associated with attempts to recover performance after it has been impaired by the challenge than the ability to maintain it (e.g., Demeter et al, 2011; Berry et al, 2015, in revision; Howe et al, 2010; Kozak et al, 2006; 2007; Parikh et al, 2013).…”