How Our Brain Uses Acetylcholine to Think Smart


So, we have all heard of neurotransmitters, yes? In case we need a quick refresher, let’s go over how they are produced! Neurotransmitters are chemical substances found to be released by the tips of nerve fibers, or terminal branches of axons, which stem off of the axon originating from the cell body (where the nucleus of the cell is housed). So, we have the cell body which houses the nucleus, an axon shooting off of this body, with several branches (terminal branches of the axon) forking off the end of the axon opposite to the cell body. These several forks, or terminal branches, form junctions with other cells to communicate and pass along signals. 

Upon the arrival of several nerve impulses shooting down said axon from the cell body, there may or may not be a release of neurotransmitters. In order for these nerve impulses to be causative of any response at the terminal branches of the axon, there must be an action potential; this is where something known as the all-or-none law comes into play. This law essentially states that nerve cells do not have small or large action potentials- they are all the same size- and can only be achieved if the nerve impulse / stimulus exceeds the threshold potential. There is either an action potential, or there is not- no middle ground! If this threshold potential is exceeded, then the terminal branches of the axon can give a response- in our case, this is the release of neurotransmitters into the synaptic cleft (the space between two neighboring synapses)! Now the exact number of neurotransmitters that exist is unknown, but it is suggested that there are over 100. For our purposes, though, we will be focusing on just one in this article: Acetylcholine.


Acetylcholine, often referred to as ACh in the scientific literature, was the very first neurotransmitter discovered! Sir Henry Hallett Dale in 1914 discovered that acetylcholine played a role as a chemical mediator, indicating that it is absolutely essential for electrical impulses to be transmitted to a muscle from a nerve throughout the entire body.  A little later, Otto Loewi confirmed in his studies the existence of acetylcholine, and both Loewi and Dale were presented with the Nobel Prize in Physiology and Medicine for its discovery and identification. It is constituted by a chemical compound of acetic acid and choline, the latter of which many of you have become familiarized with during your nootropic journey. An enzyme known as acetylcholinesterase hydrolyzes (breaks down with water) acetylcholine to ensure a rapid decrease of its presence once it has been released from the presynaptic terminal branches of axons of cholinergic neurons. This is the brain’s way of ensuring a proper balance of acetylcholine and other neurochemicals. Acetylcholinesterase is highly concentrated in the synaptic cleft, which is the space between two terminal branches of the axon of neighboring cholinergic neurons. Acetylcholinesterase inhibitors are found in organically occurring substances across the planet, such as the Chinese club moss huperzine A, or huperzia Serrata– a very well-known nootropic supplement touted for its memory enhancement capabilities (we will talk about why this is very soon). Acetylcholine is widely present throughout the body, located in central nervous system synapses, neuromuscular junctions, autonomic ganglia and autonomic innervated organs of the peripheral nervous system.

Role in the Brain

Acetylcholine works in the central nervous system (CNS) through mediating brain systems responsible for attention, motivation (working through the limbic system which plays a crucial role in the brain’s reward system), learning, memory, neuroplasticity and arousal. In the peripheral nervous system, acetylcholine is responsible for muscle action, or executing physical behavior, by transmitting impulses between motor neurons and skeletal muscles. As you can see, acetylcholine is pretty crucial for functioning on a general level- I mean, movement would be severely impeded if something were to interact in a negative fashion with acetylcholine! Decreased levels of acetylcholine in the body has been indicated to be potentially causative of Alzheimer’s disease and Myasthenia Gravis. With respect to Alzheimer’s disease, this is a result of a significant reduction of acetylcholine concentration in the caudate nucleus and the cerebral cortex. In the instance of Myasthenia Gravis, an individual’s own antibodies have destroyed acetylcholine receptors thus causing trouble at the neuromuscular junction- no receptors means the acetylcholine has nowhere to bind and take effect!

How it works

In so far as cognitive performance is concerned, acetylcholine receptors are found heavily concentrated in both the basal forebrain and the hippocampus, and these two regions of the brain play a significant role in the influence of learning and memory. Acetylcholine enhances both memory encoding and memory retrieval, while prompting synaptogenesis- otherwise known as the formation of novel synapses between neurons in the nervous system- and these new connections would make for greater mental agility. If you wanted to boost your brain power a bit further, the axons we talked about earlier are coated in myelin sheaths which help to conduct nerve impulses at a more efficient rate, and fish oil consumption has been found to increase remyelination of this axons! One c
an manipulate acetylcholine to boost cognitive performance in a variety of ways, and many people already do this whether they are aware or not! A lot of “biohackers” may ingest cholinergics, or substances that work to increase the concentration of acetylcholine in the brain. There are different versions of choline (one of the two constituents of acetylcholine, as we mentioned earlier), which is a precursor of acetylcholine, such as Alpha-GPC and CDP Choline. One could ingest a cholinergic to potentially elevate their levels of active acetylcholine. Elevating the levels of acetylcholine in the pre and post-synaptic membranes of the brain would lead to the brain adapting, and creating more post-synaptic receptors to accommodate this new influx of the neurotransmitter. With new receptors comes more binding sites for which all of this acetylcholine can now attach to in the post-synaptic membrane and take effect; these effects could be an increase in memory retention, motivation, and recall- or otherwise. So, we can increase the levels of acetylcholine in our brains through ingesting its precursor, choline, or we can do so by preventing the acetylcholine we already have (that is produced endogenously, as opposed to exogenously) from being broken back down to choline and acetic acid (its two constituents) by inhibiting the enzyme that causes this degradation- acetylcholinesterase.  


Why might inhibiting the aforementioned enzyme acetylcholinesterase be a good thing in terms of cognitive performance? Well, let’s first break down that word. So, acetylcholinesterase could be divided into acetylcholine and erase, if you will, suggesting that it erases or removes acetylcholine from the cell cycle. When an individual consumes, to use our example from earlier, a dose of the Chinese club moss huperzine-A then a bulk of the concentration of acetylcholinesterase waiting at the synaptic cleft to break down acetylcholine is ultimately rendered useless. This means that the acetylcholine can simply be continuously recycled into the cell cycle, the brain builds more and more receptor sites, and generally individuals may notice significant cognitive enhancements. It has been suggested that acetylcholine can even enhance the strength of neuronal connectivity (making stored information and pathways slower to degrade) and maintaining rapid eye movement (REM) sleep (which is crucial for memory consolidation and encoding)! It must be noted, however that it is important to cycle cholinergics and acetylcholinesterase uptake inhibitors (like huperzine-A). This is said, because if one were to continuously prevent their acetylcholine from being hydrolyzed and removed from the cell cycle, the brain would accommodate all of this extra acetylcholine, to an extent. At a certain point, it is suggested, the brain could downregulate its endogenous production (produced within the brain) of acetylcholine, given that our brains are always working via innate, compensatory, homeostatic mechanisms to bring our neurochemistry to a balance. If you were to take an acetylcholinesterase uptake inhibitor for three months, and then cease taking it, you may find yourself at a severe deficit of acetylcholine once the acetylcholinesterase begins removing your active acetylcholine from the cell cycle at a time when your brain is under the impression that you have plenty of acetylcholine and it does not need to produce that much. Of course, this will correct over time, as your brain is always working towards homeostasis, but cycling is always a safe bet when it comes to any psychoactive substance to reduce the risk of tolerance and downregulation of any sort! All that said, acetylcholine is a major player in overall functioning, inducing muscle contractions necessary for physical movement, attentional factors, REM sleep, general cognitive functioning and so much more! Its importance truly cannot be understated.


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