Visual attention in monkeys is regulated in part by a set of brain-cell receptors known as muscarinic acetylcholine receptors, researchers in the United Kingdom report. The unexpected result represents a significant advance in the study of attentional processes that is likely to energize the young field, scientists say.

“For the first time we have shown a direct link between a neurotransmitter, the mediating receptor and attention at the cellular and systems level,” says Newcastle University neuroscientist Alex Thiele, whose laboratory led the research team.

“This is a very solid study and an important finding,” says Martin Sarter, whose laboratory at the University of Michigan has done work in this area.

Finding out how neuronal attention works in enough detail to model it and even to restore it in disordered brains with rationally targeted drugs is one of the great goals of neuroscience. But the study of attention is relatively young. Researchers have known, for example, that when brain cells in the visual cortex that code for a given stimulus “attend” to that stimulus, their firing rates increase, effectively causing the “signal” they send to other parts of the brain to rise higher above the “noise” of unrelated neuronal activity. Neuroscientists also have known that when some regions of the cortex are deprived of the neurotransmitter acetylcholine, their ability to attend to stimuli is reduced. But until now no one had established firmly what kind of acetylcholine receptor on brain cells mediates the state of attention.

For their study, reported online July 16 on Nature.com, Thiele’s group implanted an electrode in the primary visual cortex of each of three rhesus macaque monkeys. The researchers then used these electrodes to record the activity of nearby neurons as the monkeys watched images on a computer screen. For each monkey, the group of recorded neurons was sensitive to a particular area of the visual field, and recordings were taken when the monkey attended or didn’t attend to visual stimuli placed within this field.

The researchers started by establishing baseline profiles of the activity of each group of neurons while in the attentional state. They then carefully directed doses of various test chemicals to the same neurons, to see how the chemicals affected the neurons’ ability to attend to stimuli.

As expected from previous research, doses of acetylcholine, one of the most commonly observed neurotransmitters in the nervous system, appeared to enhance the attentional response. But the researchers also were able to discern which receptors on neurons were being targeted by all this acetylcholine. There are two broad classes of acetylcholine receptor, known as muscarinic and nicotinic (after the acetylcholine-like chemicals muscarine and nicotine, which bind to them). Thiele’s team found that the chemical scopolamine, which “antagonizes” or blocks muscarinic receptors, exerted a significant effect on the neurons, reducing their ability to attend to stimuli, while a nicotinic receptor antagonist essentially had no effect.

“Our results show that in a certain part of the brain any attentional deficits can arise due to acetylcholine not activating muscarinic receptors, while the other, nicotinic receptor group is not really involved in attention in this part of the brain,” says Thiele.

Unfinished business

Is a side-effect-free cure for attention-deficit conditions now at hand, because of this study? Unfortunately not. As Thiele notes, it remains to be seen whether the muscarinic system mediates attentional processes in all other brain areas, in humans and in monkeys.

He says he doubts that it does. Sarter, too, notes of the finding that it “flies a bit in the face of a substantial amount of evidence” suggesting that nicotinic receptors, which are also more swiftly responsive than muscarinic receptors, are involved in modulating attention-related processes in the brain. “I am not convinced that their conclusion is the end of that story,” says Sarter.

Drug developers for the best known attention-deficit condition, attention-deficit/hyperactivity disorder, appear to think the same way. Their approaches recently have focused not on muscarinic receptors but on nicotinic and other receptor types. At a scientific conference in May, for example, researchers from Abbott Laboratories announced good results from a medium-sized clinical trial in ADHD patients of a nicotinic receptor activator, or “agonist.”

Thiele says that his lab’s recent findings may be more relevant to another kind of attention deficit seen in Alzheimer’s disease and associated with acetycholine deficiency. A 2003 study led by researchers at Sweden’s Karolinska Institute found a specific depletion of muscarinic receptors in brain areas affected by the disease.

But the current lack of knowledge about attentional processes, and the relatively basic tools neuroscientists can even apply to them nowadays, suggests that many more such studies will be needed before neuroscientists can understand these neuronal systems in enough detail to design more-effective therapies.

“Once all this has been mapped out, then we may have a mechanistic understanding of what goes wrong in Alzheimer’s and other attention deficits, which may eventually lead to better treatment,” says Thiele. “But this is music of the future.”