Memory and Acetylcholine

What is Acetylcholine?

Acetylcholine is an important neurotransmitter in the nervous system. It is found in both peripheral and central nervous systems as well as in the cardiovascular and neuromuscular systems.

While acetylcholine activates muscles and seems to produce predominantly excitatory responses in the peripheral nervous system, it is mainly a neuromodulator in the central nervous system. As a neuromodulator, acetylcholine helps sustain attention by enhancing sensory perception while we are awake. While we are asleep, it promotes the REM (rapid eye movement) stage of sleep.

The acetylcholine pathways in the brain represent areas where there are high concentrations of the neurotransmitters as well as the cholinergic nerves that help transmits signals mediated by it.

These pathways involved usually terminate at or pass through the cortex and hippocampus, areas of the brain involved in attention, learning, and memory.

There are 2 main types of acetylcholine receptors in the body. These are muscarinic and nicotinic receptors.

Muscarinic receptors are activated by both acetylcholine and muscarine but are blocked by atropine. They can be found in both the central and peripheral nervous systems as well as in the lungs, heart, sweat glands, and gastrointestinal tract.

Nicotinic receptors, on the other hand, are activated by nicotine and acetylcholine. They are mostly found in muscles and on the surface of nerve cells in the central nervous system.

Acetylcholine is synthesized in nerve cells making up the cholinergic pathway especially those found in the basal forebrain. The neurotransmitter is produced from choline and acetyl CoA in a reactive step catalyzed by the enzyme, choline acetyltransferase.

Another enzyme, acetylcholinesterase, found in the synapses between nerve cells is responsible for breaking down acetylcholine into choline and acetate.

Some neurodegenerative diseases including Alzheimer’s disease involve damage to the acetylcholine-producing cells in the basal forebrain. The resulting reduction in acetylcholine production is believed to contribute to memory impairments.

To improve acetylcholine activity in that area of the brain, a group of drugs known as cholinesterase inhibitors is usually prescribed. These drugs act by blocking the actions of the enzyme, acetylcholinesterase, thus allowing acetylcholine to act longer at the synapses between cells.

Cholinesterase inhibitors are commonly used to improve memory in people suffering from mild dementia.

How Acetylcholine Affects Memory

The Paradoxical Effects of Acetylcholine on Cholinergic Neurons

For a long while, scientists have known that the cholinergic pathway is involved in memory and learning. The prime example of this involvement is seen with scopolamine which is known to block the muscarinic subtype of acetylcholine receptors.

Individuals given scopolamine often have short-term memory loss and cannot recall events while they are under the influence of the drug.

Other experiments have demonstrated the flip side of this observation: that acetylcholine and drugs that bind to its receptors to mimic its effect in the cortical neurons can enhance memory.

Once bound to these receptors, acetylcholine and cholinergic agonists that mimic it cause membrane depolarization by reducing the potassium ion potential of membranes. This causes an effect known as “suppression of adaptation” in the neurons and it can improve memory functions.

However, this effect of acetylcholine also suppressed synaptic transmission which should prevent learning new memories.

While it would seem that acetylcholine does have paradoxical effects on memory formation, newer studies showed that the suppression of synaptic transmission only happened in the cortex and especially in the hippocampus.

By suppressing signal transmission in the hippocampus, acetylcholine actually prevents the retrieval of old memories from interfering with the making of new memories.

Therefore, acetylcholine serves a very important function by clearly separating the encoding and retrieval of memories. This allows for no interference between memories, and for the separation of memories into clear segments that can be easily retrieved later.

Acetylcholine and the 3 Stages of Memory Functioning

Further research shows that acetylcholine and the entire cholinergic pathway are more important for making memories than the other 2 stages involved in memory functions.

Basically, there are 3 stages involved in memory functioning: the making of the memory or encoding, the creation of long-term memory from the new memory or consolidation, and the recall of the memory or retrieval.

Acetylcholine has a more profound effect on encoding new memories than on consolidation and retrieval.

To demonstrate this preference for acetylcholine, researchers showed that scopolamine (a drug that reduces the activity of acetylcholine) can prevent the encoding of new memories in animal models but has no such effect on memory retrieval.

When scopolamine was given after new memories were encoded, it actually enhanced the ability to recall the stored memory. This is because by preventing the encoding of new memory, scopolamine reduced any interference that would have occurred as the brain simultaneously encode, store, and retrieves information.

Acetylcholine and SK Channels

In a study published in the journal, Neuron, researchers from the University of Bristol were able to find another missing link that provides a deeper insight into our acetylcholine improves memory and slows down cognitive decline.

One of the ways acetylcholine contributes to learning and memory is through increasing the activity of NMDA (N-methyl-D-aspartate) receptors in the brain.

Acetylcholine does this by blocking proteins of the SK channels which normally inhibit NMDA receptors.

There are 4 SK channels (small conductance calcium-activated potassium channels) and they are known to regulate the hyperpolarization of neurons in the brain. Because they also influence synaptic plasticity, SK channels affect memory and learning.

SK channels block the normal functioning of NMDA receptors and, therefore, interfere with the ability of neurons to modulate signal transmission. This action limits the encoding of memories in the brain.

The Bristol study found out that acetylcholine can lift this blockade caused by SK channels.

By developing drugs that target and block the SK channels, it is possible to improve memory and learning without directly increasing acetylcholine production in the brain.

Drugs that target the cholinergic pathway may increase acetylcholine synthesis, activate acetylcholine receptors, and/or block SK channels.

Studies on Acetylcholine and Memory

The summaries below represent the breadth of studies done on the influence of acetylcholine on memory.

Acetylcholine and Memory Restoration after Brain Damage

In a 1995 study published in the journal, Nature, researchers were able to demonstrate the central importance of acetylcholine to learning and memory.

In this study, the researchers damaged a specific part of the neocortex in adult rats. This part of the brain houses the cholinergic pathway responsible for memory and learning. After inducing this selective and permanent impairment of memory, the researchers then implanted grafts of brain parts that produce acetylcholine into the damaged sections of the rats’ neocortex.

Those rats in which the graft took resumed production of acetylcholine in their neocortexes and these were also the rats who experienced an improvement in spatial memory tested with navigational tasks.

This study not only demonstrates that acetylcholine is essential for memory and learning but also that increasing its levels in the neocortex can restore memory and reducing learning deficits even in subjects who suffered brain damage from neurodegenerative diseases.

Acetylcholine, Sleep-Wake Cycle, and Memory Formation

In a 1999 study published in the journal, Trends in Cognitive Sciences, the researcher was able to explain how changes in acetylcholine levels and cholinergic tone during waking and sleep provide the right balance for consolidating long-term memories.

The paper identified that the high levels of acetylcholine during the waking hours are the perfect condition for encoding new memories in the hippocampus because acetylcholine also suppresses the excitatory signal transmission that may interfere with memory formation.

However, the low levels of acetylcholine seen during slow-wave sleep are necessary for lifting this suppression of signal transmission to facilitate the consolidation of memories encoded during the waking hours.

This two-stage function of acetylcholine is further confirmed by the next study in this summary.

In a 2003 study published in the Proceedings of the National Academy of Sciences, the prediction that low acetylcholine levels were necessary for the consolidation of certain types of long-term memories during slow-wave sleep was tested and confirmed.

The researchers increased cholinergic activity during slow-wave sleep in some human subjects by giving them infusions of 0.75 mg of physostigmine (a cholinesterase inhibitor that increases the activity of acetylcholine in the brain).

This drug completely blocked the storage of declarative memories which usually occurs during slow-wave sleep. However, during waking the memory consolidation continued normally.

Declarative memories are long-term memories related to facts and knowledge that can be consciously recalled. These are unlike non-declarative memories which are skills that are unconsciously recalled and utilized.

How to Increase Acetylcholine Levels in the Brain

There are no dietary sources of acetylcholine and also no acetylcholine supplements. Therefore, the best way to increase acetylcholine production in the brain is to increase the amount of choline in the body since choline is the direct precursor of acetylcholine.

Supplements are an even better way to increase choline (and acetylcholine) levels because they do not compete with other nutrients for absorption like choline obtained from diets.

Common choline supplements include those that pack choline, phosphatidylcholine, or any other choline salt. Usually, 500 – 2000 mg taken in 3 divided doses daily is the recommended dosage of choline supplements.

Other supplements can also increase acetylcholine levels in ways other than increasing choline levels.

These can support acetylcholine in the body (manganese 1 - 5 mg daily, for example) or increase the activity of acetylcholine (Huperzine A, an herb that contains cholinesterase inhibitor).