From promiscuity to specialization: The origin of cholinergic and monoaminergic signaling is pre-bilaterian

For over a century, biologists have understood that animals communicate through a complex chemical language. Nerve cells release tiny molecules called neurotransmitters to tell other cells what to do, whether to contract a muscle, fire a signal to the brain, or change behavior. Among the most important of these messengers are a group known as biogenic amines, which include familiar substances like dopamine and serotonin, as well as acetylcholine. For decades, the prevailing view was that this sophisticated chemical system was a relatively recent invention, appearing only when complex, bilateral animals—creatures with a left and right side, like humans, insects, and worms—evolved. The thinking was that simpler animals, such as sponges and jellyfish, lacked the specific molecular machinery required to produce, transport, and receive these signals, relying instead on more primitive forms of communication.

A new study challenges this long-held timeline, suggesting that the roots of our own nervous system run much deeper into the history of life. By examining the simplest animals on Earth, the researchers found that the chemical tools for this signaling system existed long before the first bilateral animal ever swam. They discovered that these ancient creatures possess the same basic ingredients to make and use these neurotransmitters, but they use them in a much more general, flexible way. The complex, specialized system seen in humans and other advanced animals appears to be a later refinement of an ancient, versatile toolkit that was already present in the common ancestor of all animals.

The researchers set out to test whether these chemical signals were truly absent in early animals or if they had simply been overlooked. They gathered samples from four distinct species representing different branches of the animal family tree: a freshwater sponge, a small freshwater polyp known as Hydra, a sea anemone, and a marine worm. Using highly sensitive chemical analysis, they looked for the presence of various biogenic amines. The results were clear: the sponge, the polyp, and the sea anemone all contained measurable amounts of acetylcholine, dopamine, histamine, adrenaline, and several other related compounds. The sponge even contained adrenaline, a substance often associated with the "fight or flight" response in vertebrates. This finding alone proved that these molecules were not exclusive to complex animals; they were present in creatures that lack a centralized brain or a nervous system as we know it.

The next step was to understand how these animals made these chemicals. In complex animals, the production of specific neurotransmitters is handled by highly specialized enzymes, each designed to create only one specific molecule. The researchers found that the ancient animals did not have these specialized enzymes. Instead, they possessed older, more flexible versions. These ancestral enzymes were "promiscuous," meaning a single enzyme could produce a wide variety of different chemical messengers from the same starting materials. For example, the enzyme responsible for making acetylcholine in humans is a dedicated specialist. In the sponge and the polyp, the equivalent enzyme is a generalist that primarily handles a different metabolic task but can also produce acetylcholine as a side effect. This suggests that the ability to make these signals did not require a dedicated invention; it arose naturally from the metabolic processes that were already active in early cells.

The study also looked at how these chemicals are moved and received. In complex animals, specific transporters load neurotransmitters into tiny storage bubbles, and specific receptors on the surface of cells catch them. The researchers found that the ancient animals possessed the broad-spectrum versions of these transporters and receptors. They had transporters capable of moving many different types of molecules, and receptors that could bind to several different signals. However, they did find a crucial piece of evidence for a specialized system in the polyp and the sea anemone. These animals have receptors that bind specifically to acetylcholine, and they have muscle-like cells that respond to this signal. In the polyp, these receptors are found on nerve cells, but they are also found on the cells that make up the body wall, suggesting that acetylcholine is used to coordinate movement in these simple animals just as it is in our own muscles.

This discovery reshapes our understanding of how nervous systems evolved. It suggests that the chemical language of the nervous system did not appear suddenly with the first complex animal. Instead, the building blocks were already there, scattered across the cells of the earliest animals. These cells used these chemicals for general communication and metabolic purposes. Over millions of years, as animals became more complex, the genes for these enzymes and receptors were copied and modified. This process of duplication allowed the system to become more specialized, with dedicated enzymes making specific signals and dedicated receptors reading them with high precision. The complex, high-speed communication system of the human brain is therefore not a brand-new invention, but a highly refined version of an ancient, general-purpose system that has been in use since the dawn of animal life.

The researchers confirmed these findings by looking at the genetic blueprints of these animals. They traced the evolutionary history of the genes responsible for making and moving these chemicals, showing that the specialized versions found in humans are direct descendants of the broad, flexible versions found in sponges and jellyfish. They also used computer modeling to predict how the receptors in the polyp would behave, confirming that they are structurally capable of binding acetylcholine just as strongly as human receptors do. This convergence of chemical detection, genetic analysis, and structural modeling provides a robust picture of the past. It shows that the transition from a simple, general chemical signal to a complex, specialized nervous system was a gradual process of specialization, not a sudden leap.

The implications of this work extend beyond just understanding the past. It suggests that the fundamental mechanisms of cellular communication are deeply conserved across the animal kingdom. The ability to use small molecules to influence cell behavior is a property that dates back to the very first multicellular animals. The specialized systems we see in humans are built upon this ancient foundation. By studying the simplest animals, scientists can see the raw materials from which our own complex biology was constructed. The study concludes that the chemical signaling systems we rely on for thought, movement, and sensation are not unique to us, but are an inherited trait from a common ancestor that lived hundreds of millions of years ago, long before the first bilateral animal ever existed.