Some of the most primitive animals have no nerves or neurons... how do they know what is going on?
We often think of our brains as computers, but while human-made computers are (so far) strictly electrical, our brains have a significantly different basis. The electrical component is comparatively slow, and confined to conduction along the membranes of single cells. Each of these neurons communicate with others using chemicals, mostly at specialized synapses, but also via other small compounds, neuropeptides, and hormones. That is why drugs have so many interesting effects, from anesthesia to anti-depression and hallucination. These properties suggest that the brain and its neurons began, evolutionarily speaking, as chemically excitable cells, before they became somewhat reluctant electrical conductors.
Thankfully, a few examples of early stages of animal evolution still exist. The main branches of the early divergence of animals are sponges (porifera), jellies and corals (ctenophora, cnidiaria), bilaterians (us), and an extremely small family of placozoa. Neural-type functions appear to have evolved independently in each of these lineages, from origins that are clearest in what appears to be the most primitive of them, the placozoa. These are pancake-like organisms of three cell layers, hardly more complex than a single-celled paramecium. They have about six cell types in all, and glide around using cilia, engulfing edible detritus. They have no neurons, let alone synaptic connections between them, yet they have excitable cells that secrete what we would call neuropeptides, that tell nearby cells what to do. Substrances like enkephalins, vasopressin, neurotensin, and the famous glucagon-like peptide are part of the managerie of neuropeptides at work in our own brains and bodies.
 |
| A placozoan, about a millimeter wide. They are sort of a super-amoeba, attaching to and gliding over surfaces underwater and eating detritus. They are heavily ciliated, with only a few cell types divided in top, middle, and bottom cell layers. The proto-neural peptidergic cells make up ~13% of cells in this body. |
The fact is that excitable cells long predate neurons. Even bacteria can sense things from outside, orient, and respond to them. As eukaryotes, placozoans inherited a complex repertoire of sense and response systems, such as G-protein coupled receptors (GPCRs) that link sensation of external chemicals with cascades of internal signaling. GPCRs are the dominant signaling platforms, along with activatable ion channels, in our nervous systems. So a natural hypothesis for the origin of nervous systems is that they began with chemical sensing and inter-cell chemical signaling systems that later gained electrical characteristics to speed things up, especially as more cells were added, body size increased, and local signaling could not keep up. Jellies, for instance, have neural nets that are quite unlike, and evolutionarily distinct from, the centralized systems of animals, yet use a similar molecular palette of signaling molecules, receptors, and excitation pathways.
Placozoans, which date to maybe 800 million years ago, don't even have neurons, let alone neural nets or nervous systems. A recent paper labored to catalog what they do have, however, finding a number of pre-neural characteristics. For example, the peptidergic cell type, which secretes peptides that signal to neighboring cells, expresses 25 or more GPCRs, receptors for those same peptides and other environmental chemicals. They state that these GPCRs are not detectably related to those of animals, so placozoans underwent their own radiation, evolving/diversifying a primordial receptor into hundreds that exist in its genome today. The researchers even go so far as to employ the AI program Alpha Fold to model which GPCRs bind to which endogenously produced peptides, in an attempt to figure out the circuitry that these organisms employ.
This peptidergic cell type also expresses other neuron-like proteins, like neuropeptide processing enzymes, transcription regulators Sox, Pax, Jun, and Fos, a neural-specific RNA polyadenylation enzyme, a suite of calcium sensitive channels and signaling components, and many components of the presynaptic scaffold, which organizes the secretion of neuropeptides and other transmitters in neurons, and in placozoa presumably organizes its secretion of its quasi-neuropeptides. So of the six cell types, the peptidergic cell appears to be specialized for signaling, is present in low abundance, and expresses a bunch of proteins that in other lineages became far more elaborated into the neural system. Peptidergic cells do not make synapses or extended cell processes, for example. What they do is to offer this millimeter-sized organism a primitive signaling and response capacity that, in response to environmental cues, prompts it to alter its shape and movement by distributing neuropeptides to nearby effector cells that do the gliding and eating that the peptidergic cells can't do.
 |
| A schematic of neural-like proteins expressed in placozoa, characteristic of more advanced presynaptic secretory neural systems. These involve both secretion of neuropeptides (bottom left and middle), the expression of key ion channels used for cell activation (Ca++ channels), and the expression of cell-cell adhesion and signaling molecules (top right). |
Why peptides? The workhorse of our brain synapses are simpler chemicals like serotonin, glutamate, and norepinephrine. Yet the chemical palette of such simple compounds is limited, and each one requires its own enzymatic machinery for synthesis. Neuropeptides, in contrast, are typically generated by cleavage of larger proteins encoded from the genome. Thus the same mechanism (translation and cleavage) can generate a virtually infinite variety of short and medium sized peptide sequences, each of which can have its own meaning, and have a GPCR or other receptor tailored to detecting it. The scope of experimentation is much greater, given normal mutation and duplication events through evolutionary time, and the synthetic pipeline much easier to manage. Our nervous systems use a wide variety of neuropeptides, as noted above, and our immune system uses an even larger palette of cytokines and chemokines, upwards of a hundred, each of which have particular regulatory meanings.
 |
| An evolutionary scheme describing the neural and proto-neural systems observed among primitive animals. |
The placozoan relic lineages show that nervous systems arose in gradual fashion from already-complex systems of cell-cell signaling that focused on chemical rather than electrical signaling. But very quickly, with the advent of only slighly larger and more complex body plans, like those of hydra or jellies, the need for speed forced an additional mode of signaling- the propagation of electrical activity within cells, (the proto-neurons), and their physical extension to capitalize on that new mode of rapid conduction. But never did nervous systems leave behind their chemical roots, as the neurons in our brains still laboriously conduct signals from one neuron to the next via the chemical synapse, secreting a packet of chemicals from one side, and receiving that signal across the gap on the other side.
