Increases in cortical acetylcholine release during sustained attention performance in rats

“It is now known, for example, that performance on visual attentional paradigms, including the 5-CSRTT, leads to large and sustained increases in cortical ACh release [30,66,82,98], consistent with a purported involvement of the basal forebrain cortical cholinergic system in visual attentional processes [82,92,113,122].”

“In contrast, distractor stimuli in the sustained attention task should not evoke cholinergic transients (Himmelheber et al, 2000; Gill et al, 2000; WM Howe et al, unpublished results).”

“There is now ample experimental evidence in support of the hypothesis that the integrity of cortical cholinergic inputs is necessary for normal attentional performance, and that such performance robustly activates cortical cholinergic inputs [3,29,32,33,39, 50,73,101,99,132,162,183,180,181].”

“…in cortical ACh release, specifically in association with demands on attentional processes but not with the basic behavioral operations associated with cognitive task performance (Arnold et al., 2002; Dalley et al., 2001; Himmelheber et al., 2000; McGaughy et al., 2002; Passetti et al., 2000).”

“…activating circuitry, depending on the subjects' motivation, that is involved in the mediation of attentional performance (Christakou et al., 2004; Himmelheber et al., 2000a; Miner and Sarter, 1999) and, more importantly, that entails activation of the top-down effects required to protect…”

“…in rats performing various tests of attention has repeatedly demonstrated an increase in acetylcholine (ACh) efflux in the area of the frontoparietal (Himmelheber et al., 1997, 2000, 2001) or medial prefrontal cortex (mPFC) (Passetti et al., 2000; Dalley et al., 2001; McGaughy et al., 2002).”

“Microdialysis studies have indicated that ACh release is increased with cortical activation in association with attentive waking (Himmelheber et al., 2000) and PS compared with slow-wave sleep (SWS) (Marrosu et al.”

“The present results agree with those showing that attentional testing is correlated with elevated cortical ACh efflux, even in the presence of decreased accuracy (Himmelheber et al., 2000).”

“This paradigm demonstrates compatibility with the 5-CSR task insofar as increased acetylcholine levels have been reported in rats performing the task (Himmelheber et al., 2000), although the specific role of acetylcholine in task performance is unclear (Himmelheber et al., 2001; Kozak et al., 2006).”

“…some data have suggested that the level of ACh efflux is associated not so much with the level of attentional performance (Passetti, Dalley, OÕConnell, Everitt, & Robbins, 2000), but with the attentional ''effort'' required to maintain or regain attentional performance (Himmelheber et al., 2000).”

“Experiments in which ACh release has been measured in vivo in freely moving animals have also provided support for an involvement of the nucleus basalis cortical cholinergic pathway in attention (Sarter et al., 1996; Himmelheber et al., 2000; Passetti et al., 2000).”

“…ACh, has been shown to increase in the prefrontal cortex in many situations requiring enhancements in attention, ranging from presentation of novel stimuli to the accomplishment of an attentiondemanding task in the presence of distractions (Himmelheber et al, 2000; Passetti et al, 2000).”

“There are also projections from the basal forebrain to the frontal cortex, which are involved in attentional processes (37).”

“Demanding tasks are more likely to cause plasticity because they lead to increased neuromodulator release compared to tasks that are easy to perform (Arnold et al., 2002; Himmelheber et al., 2000).”

“Similarly, microdialysis studies have supported a role of the ascending cholinergic system in attentional performance, via the demonstration of increased ACh release in the PFC of animals performing an operant, sustained attention task, and suggest that this release is a function of attentional demand (Arnold et al.,…”

“…the pre-task handling and transfer of animals just prior to the onset of the behavioral task, and thus, eliminating the large pre-task increase in cortical ACh e¥ux observed in the studies by Himmelheber et al. (2000, 2001), the current experiment demonstrated a much larger percent increase (V140”

“2001) and is directly correlated with the attentional effort during an operant task designed to assess sustained attention (Himmelheber et al. 2000).”

“Experiments monitoring acetylcholine release through micro-dialysis in freely moving rats have observed relative increases in acetylcholine associated with attention-like behavior (Moore et al., 1992; Inglis et al., 1994; Sarter et al., 1996; Himmelheber et al., 2000).”

“This claim is supported by recent in vivo microdialysis studies showing large and sustained elevations in cortical acetylcholine (ACh) release during established attentional performance (Himmelheber et al., 2000; Dalley et al., 2001; McGaughy et al., 2002) and evidence for a significant positive relationship between A…”

“Studies in which cortical ACh efflux was measured while animals perform tasks taxing attentional capacities demonstrated attentional demand-associated increases in cortical ACh efflux [5,41,80].”

“The LC-NE system is associated with ‘‘alertness’’ for incoming external stimuli (exogenous attention [30,31]), with sustained endogenous attention generally considered the responsibility of cholinergic pathways [30,32,33].”

“, 2002), and as the task increases in difficulty, the release of ACh increases (Himmelheber et al., 2000).”

“…(Briand et al., 2008; McGaughy & Sarter 1995, 1998, 1999; McGaughy et al., 1996; 1997,1999, 2000; Turchi et al.,1995, 1996; Turchi & Sarter 2001a,b; Himmelheber et al. 2000a,b, 2001; Holley et al., 1995; Miner et al., 1997, 1999; Gill et al., 2000; Burk et al., 2001, 2002; Nelson et al., 2002;…”

“Microdialysis methods reveal that performance in certain cognitive tasks is sufficient to stimulate cortical ACh release (Himmelheber et al., 2000; Passetti et al., 2000; Dalley et al., 2001; Arnold et al., 2002).”

“[120] Himmelheber AM, Sarter M, Bruno JP.”

“…the cognitive functions of the basal forebrain system depends on evidence regarding its main noncholinergic components, and the generation of such evidence is contingent on the development of methods to manipulate and monitor selectively the activity of the GABAergic corticopetal projections.”

“The literature is rich with evidence of the involvement of the cholinergic system in attention mechanisms (Everitt and Robbins, 1997; Hasselmo and McGaughy, 2004; Himmelheber et al, 2000; Robbins, 1997; Sarter and Bruno, 2000; Sarter et al, 2003, 2005b; Yu and Dayan, 2002).”

“Indeed, the neocortical ACH concentration specifically increases during wakefulness and periods of sustained attention (1, 2).”

“ACh has been related to attentional processes (Himmelheber et al., 2000) and plays an important role in cognitive processing.”

“…cognitive control functions used to modulate behavior in the face of challenge or changing reward contingencies (Posner & Snyder, 1975; Schiffrin & Schneider, 1977; see Gill et al., 2000; Himmelheber et al., 2000; McGaughy, Kaiser, & Sarter, 1996 for previous rat studies using this manipulation).”

“This finding is also in line with other studies demonstrating that cognitive and motoric correlates of ACh release in the cortex can be dissociated (Himmelheber et al., 2000).”

“Increased cholinergic transmission in the cortex is thought to play a central role in FG-7142induced increases in vigilance (Himmelheber et al. 2000).”

“This view has been supported by recent in vivo microdialysis studies demonstrating that in sustained attention tasks acetylcholine efflux in the prefrontal cortex is increased, and specifically that these increases may be related either to task difficulty (use of distractor stimulus: Himmelheber et al 2000 ), or to ex…”

“As described above, in-vivo microdialysis studies in SAT-performing rats demonstrate that ACh release increases in right prefrontal cortex during attentional performance, above and beyond the release levels seen in tasks with matched motor or reward components, but low demands on attention (Arnold et al., 2002; Dalley…”

“Estimates about the relative proportion of GABAergic corticopetal to cholinergic corticopetal neurons range from 20 to 50% (Gritti et al., 1997; Rye et al., 1984), supporting the possibility that both populations arise mainly from the medial GP and the SI.”

“…prefrontal cortex (PFC), is consistently implicated in mediating many forms of behavioral control (Mesulam, 1999; Dalley et al., 2004), and cholinergic efflux in this area is critical to these functions (Himmelheber et al., 2000; Dalley et al., 2001; McGaughy et al., 2002a; Kozak et al., 2006).”

“These findings are aligned with previous work, given that cue detection has been shown to involve transient rises in ACh release (Himmelheber et al., 2000; Parikh et al., 2007).”

“The importance of prefrontal cholinergic modulation was further suggested by microdialysis studies showing robust acetylcholine efflux within the prefrontal cortex during the performance of attention tasks [30–32], which reflects both attentional effort [33, 34] and behavioral context [35].”

“Some studies showed that although ACh is released in several situations ranging from low- to high-demand, BF cholinergic transmission is more essential under conditions in which there are increased task or attentional demands (Himmelheber et al., 2000; Ragozzino, 2000; Turchi & Sarter, 2000; Himmelheber et al., 2001).”

“It has been proposed that cortical cholinergic modulation underlies attention (Arnold et al. 2002; Deco and Thiele 2011; Hasselmo and McGaughy 2004; Herrero et al. 2008; Himmelheber et al. 2000; McGaughy and Sarter 1998; Sarter et al. 2005).”

“REVIEW ARTICLE published: 25 September 2014 doi: 10.3389/fnsyn.2014.00021 Paying attention to smell: cholinergic signaling in the olfactory bulb”

“Cholinergic activity is also high in the attentive state (Himmelheber et al., 2000).”

“role of cholinergic system in the mPFC focused mainly on behavioral arousal and attentional performance (Day et al. 1991; Himmelheber et al. 2000; Passetti et al. 2000; McGaughy et al. 2002; Parikh et al. 2007).”

“Distracting stimuli can be effective in impairing sustained attention (Johnson and Burk, 2006; McGaughy and Sarter, 1995a; Newman and McGaughy, 2008), although the timing of the presentation of the distractors is critical, and animals adapt to their occurrence (Himmelheber et al., 2000).”

“Based on an extensive literature that supports the role of cortical cholinergic inputs in attentional functions (for review see [9,55, 57]), including studies demonstrating strong correlations between the loss of cortical cholinergic inputs and impairments in sustained attention performance [35], or sustained attentio…”

“This is also consistent with a key role for ACh in supporting attentive listening by suppressing distractors—a main feature of the present task (Berry et al., 2014; Demeter & Sarter, 2013; Himmelheber et al., 2000; Kim et al., 2017; Sarter et al., 2006).”

“Similar to the results from previous experiments (Arnold et al, 2002; Himmelheber et al, 2000; Kozak et al, 2006), performance of the attention task increased ACh release in the mPFC over baseline.”

“AAA is involved in sustaining attention (52) and memory (53), which is occupied by magnocellular cholinergic neurons that secrete acetylcholine (54).”

“These previous studies may provide some clues to a puzzling question: Why – despite extensive previous evidence indicating the critical role of right PFC cholinergic innervation in maintaining performance during challenges to attention (e.g. Gill et al., 2000; Himmelheber et al., 2000; St Peters et al., 2011) – do nei…”

“ACh has been named as essential to promote REM sleep (Platt and Riedel, 2011) and sustained attention (Himmelheber et al., 2000), while ACh disruption (increased signalling) is thought to be a primary cause of anxiety and depression (Higley and Picciotto, 2014), as well as the memory, learning and…”

“The cholinergic innervations of the cortex play fundamental roles in cognitive functions associated with attention, learning, memory (Himmelheber et al. 2000), experiencedependent plasticity, and sensory processing (Alenda and Nuñez 2007; Lendvai et al. 2000).”

“ACh has been related to attentional processes (Himmelheber et al., 2000) and plays an important role in cognitive processing.”

“These findings are consistent with previous microdialysis work demonstrating positive associations between task-related attentional effort and ACh efflux in frontoparietal cortices in rats (Himmelheber et al., 2000, 2001).”

“Finally, the magnitude of cortical ACh release is related to the extent of the attentional demands in this vigilance task (Himmelheber et al. 2000).”

“…release is increased with cortical activation during attentive wakefulness and REM sleep (Celesia & Jasper, 1966; Marrosu et al., 1995; Himmelheber et al., 2000), and can stimulate fast cortical activity by depolarizing rhythmic-bursting pyramidal neurons via muscarinic receptors…”

“…cortical cholinergic modulation underlies attention (Arnold et al., 2002; Deco and Thiele, 2011; Hasselmo and McGaughy, 2004; Herrero et al., 2008; Himmelheber et al., 2000; McGaughy and Sarter, 1998; Sarter et al., 2005), and it has also been argued that changes in GABAergic inhibition could…”

“…observed in attention task-performing animals are not reproduced in animals performing tasks controlling for operant responding, reward rate, motor activity, or non-contingent stimulus presentation (Himmelheber et al. 1997, 2000; Passetti et al. 2000; Dalley et al. 2001, 2005; Arnold et al. 2002).”

“…2004), and DA receptor activity regulates cortical ACh efflux (Moore et al. 1999; Zmarowski et al. 2005), which is essential in the mediation of attentional processes , as demonstrated with the signal detection task which taps sustained attention (McGaughy et al. 1996; Himmelheber et al. 2000).”