ReviewAcetylcholine and attention
Research highlights
▶ Acetylcholine (ACh) has been implicated in attention, learning and short-term memory. ▶ We summarize animal and human studies on the role of ACh in attention and cognition. ▶ ACh in (pre)frontal, parietal and somatosensory areas is important for attention. ▶ ACh in the septohippocampal system is involved in memory functions. ▶ The role of ACh in cognition varies between brain regions and ACh receptor subtypes.
Introduction
Since the first publications of Bartus et al. [1], [2] acetylcholine (ACh) has been claimed playing a critical role in cognitive functions, especially learning and memory. Research with Alzheimer disease patients and experimental manipulations in animals (cholinergic lesions and drug studies) provided further support for the notion that ACh is involved in learning and memory. A vast amount of experimental studies showed learning and memory impairments in a wide variety of tasks after compromising the cholinergic system using muscarinic or nicotinic antagonists and after lesioning cholinergic cells concluding that ACh was involved in memory functions. Of note, the effects were most prominent in short-term memory and working memory tasks [3]. These data provided further support for the cholinergic hypothesis of memory dysfunction and fueled the development of cholinergic drugs for treating memory disorders. At present, cholinesterase inhibitors (and the NMDA antagonist memantine) are the only approved drugs for treating cognitive impairments in Alzheimer's disease. However, it must be noted that the effects of cholinesterase inhibitors are limited and associated with various side effects [4], [5]. Despite this limited success of cholinesterase inhibitors in treating cognitive function in dementia, recent drug development programs still concentrate on cholinergic targets, like the nicotinic receptor [6], [7], [8] and the muscarinic type 1 receptor [9], [10]. Thus, ACh is still considered as an important neurotransmitter involved in cognitive functions.
During the last decade the role of ACh in cognitive functions has been refined [11], [12], [13], [14], [15]. In contrast to a general role in learning and memory recent studies provide also support for a role of cortical ACh in attention (more specifically: attentional effort and orienting) and detection of behavioral significant stimuli [16], [17], [18]. These more recent insights have become available by means of novel behavioral tests, development of toxins for selective cholinergic lesions, tools for measuring phasic ACh release and for pharmacologically altering central cholinergic neurotransmission.
To give a first example, a highly specific toxin was developed (i.e., 192-IgG-saporin) that was very selective for cholinergic cells [19]. The principle of this toxin was based on the unique property of cholinergic neurons which contain the p75 low affinity nerve growth factor receptor. By using the conjugate of the non-selective toxin saporin with a carrier that binds to the nerve growth factor receptor, a selective lesion of the cholinergic system could be achieved. This enabled investigating the function of lowered ACh levels in the brain and even in selective brain areas.
Further, selective drugs for receptor subtypes (i.e. muscarinic and nicotinic) became available allowing a differentiation of the cholinergic system on a receptor level. In addition, an increasing number of studies examined the effects of intracerebral injections of these selective cholinergic drugs. These studies provided a more detailed picture of the role of cholinergic receptors in specific brain areas. Moreover, novel microdialysis techniques allow for the investigation of changes in ACh efflux on a much smaller timescale. Finally, more sophisticated behavioral tests became available for testing the specificity of the cholinergic manipulation on various cognitive domains, attentional functions in particular. Taken together, all these developments contributed to a better understanding of the role of the cholinergic system in cognitive functions.
The current review provides a summary of animal and human experiments which have assessed the role of ACh in particular brain regions in attentional processes. First, an overview will be given of the studies in which the effects of selective cholinergic lesions were examined. Next, a summary will be made of studies investigating neurophysiological changes (e.g., in ACh release) in several behavioral paradigms. Further, we will discuss studies in which drugs were locally applied in animals. Finally, an attempt will be made to relate the findings in animals to those reported in human imaging studies examining the role of cholinergic signaling in particular brain regions in attentional functions. We will show that the role of the cholinergic system in relation to cognitive functions cannot be regarded as a whole. Rather, the role of cholinergic neurotransmission in cognitive function is dependent on the particular brain region which is targeted. On the basis of these findings the role of ACh in attention will be discussed.
Section snippets
Cholinergic lesion studies in rats
The early studies investigating the cholinergic system used non-selective tools (e.g., ibotenic acid quinolinic acid, AMPA) to lesion cholinergic neurons in the basal forebrain in rodents. This was a non-optimal choice because of the diffuse spread of cholinergic cells in rodents in the nucleus basalis. Thus, these excitotoxic lesions also affected all neurons containing glutamatergic receptors, making it very difficult to interpret the effects in terms of a specific cholinergic deficit. The
Neurophysiological studies in rats
Experiments in which tonic ACh release has been measured in vivo in moving animals have indicated that the link between cholinergic signaling and attentional performance is more complex than suggested by lesion studies. For instance, increases in ACh efflux have been observed after transfer to an operant chamber associated with performance of a sustained attention task [41], exposure to darkness [42], anticipation and consumption of a palatable meal [43], elevated motor activity [44], [45],
Pharmacological studies in rats
Experiments which have used central infusion of cholinergic compounds into discrete brain regions in order to assess the effect of these treatments on attentional paradigms are unfortunately relatively sparse. An additional approach has been to use central injection of muscarinic or nicotinic antagonists as a means of deducing the role of a particular brain region in behavioral paradigms measuring non-attentional functions such as short-term memory or stimulus discrimination. Thus, strong
Neuroimaging studies in humans
As presented in the previous sections, cholinergic signaling in prefrontal and parietal areas appears to be most strongly implicated in attentional processes, at least in animals. Here we review human data and evaluate to what extent animal data can be translated to those found in human studies. Relatively many studies have been performed which looked into the role of ACh in human cognition. In studies with human participants, differentiations are normally made between various types of
Conclusions
The current review article summarizes studies in animals and humans which have investigated the role of ACh in cognition. An attempt has been made to differentiate between brain regions involved in attentional processes versus those important for other cognitive functions. To this purpose, various experimental methods and interventions were used. Animal behavioral studies have injected the selective immunotoxin IgG-saporin to induce specific cholinergic lesions, employed neurophysiological
Conflict of interest
The authors declare that, except for income received from their primary employer, no financial support or compensation has been received from any individual or corporate entity over the past three years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.
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