Researchers Discover Key Role for Cholinergic Neurons

In a recent study entitled “Central Cholinergic Neurons Are Rapidly Recruited by Reinforcement Feedback” and published in Cell, Cold Spring Harbor Laboratory researchers found that cholinergic neurons play a key role in the response to unexpected triggers.

Cholinergic neurons are nerve cells which mainly use the neurotransmitter acetylcholine to transmit messages throughout the brain. They have been suggested to play a role in attention, arousal and learning mechanisms. Increasing interest in these neurons in recent years is justified by their link to age-related cognitive decline and neurodegeneration, as it occurs in Alzheimer’s disease, the most common form of dementia in the elderly characterized by cognitive and behavioral problems that gradually lead to behavior and personality changes, a decline in cognitive abilities and ultimately to severe loss of mental function. It has been reported that the dysfunction and loss of cholinergic neurons in the basal forebrain is among the earliest pathological events associated with Alzheimer’s disease.

The precise role of cholinergic neurons in behavior is, however, poorly elucidated, in part due to the technical difficulties to record them in vivo. “These are very, very, difficult-to-find neurons, and they form an incredibly important system in the brain,” explained the study’s senior author Dr. Adam Kepecs in a news release. “Until recently we didn’t have the techniques to approach this system with the precision required.”

Now, researchers were able to study the activity of cholinergic neurons for the first time through an optogenetic neuron identification technique where mouse neurons are genetically engineered to respond to light.

The team assessed the activity of cholinergic neurons in mice while the animals performed a sound detection task that required their constant attention. If the answer to the task was correct, mice were rewarded with a drop of water, whereas if the answer was incorrect they were “punished” with a mild puff of air to their face. Interestingly, researchers found that cholinergic neurons respond rapidly to reward and punishment with a remarkable precision, taking only a few thousandths-of-a-second.

The team created a computational model based on their experiments which showed that the modulation of the signal strength was correlated to the degree of surprise expressed by mice towards the reward or punishment. In other words, if mice knew that their response was correct, then the reward generated a weak signal because the animal was not surprised by the result; however, it the animal was unsure, the reward would be associated with a higher level of surprise, generating a stronger cholinergic signal.

“This suggests to us that it’s not really about punishment, per se, but it’s simply that punishment usually is more surprising,” explained Dr. Kepecs. “The fact that something is unexpected, and knowing the degree to which it is, is an obvious advantage to the individual”; an observation that may explain why these fast real-time alerts have evolved.

The research team concluded that cholinergic neurons in the basal forebrain can send a rapid message throughout the brain cortex informing of any surprising rewards or punishments. The authors believe that cholinergic signaling could be useful to enhance neuron plasticity, increasing the flexibility in neuronal connections involved in learning processes. The finding that cholinergic neurons play such a key role, together with the fact that they seem to be dysfunctional or lost in Alzheimer’s, may explain some of the cognitive and behavioral issues observed in patients with the disease.