It isn’t often that a single paper can change the way we think the brain works. But such is the case for the paper described in the previous post (full copy below *** ) if the implications I draw from it are correct.
Unfortunately this post requires a deep dive into neuroanatomy, neurophysiology, neuropharmacology and cellular molecular biology. I hope to put in enough background to make some of it comprehensible, but it is really written for the cognoscenti in these fields.
I’m pretty sure that some of these thoughts are both original and unique
Briefly, the paper provided excellent evidence for one axon causing another to fire an impulse (an action potential). The fireror was from a neuron using acetyl choline as a neurotransmitter, and the fireree was a dopamine axon going to the striatum.
Dopamine axons are special. They go all over the brain. The cell body of the parent neuron of the axon to be synapsed on uses dopamine as a neurotransmitter. It sits in the pars compacta of the substantia nigra a fair piece away from the target they studied (the striatum). “Individual neurons of the pars compacta are calculated to give rise to 4.5 meters of axons once all the branches are summed” — [ Neuron vol. 96 p. 651 ’17 ].” These axons release dopamine all over the brain. There aren’t many dopamine neurons to begin with just 80,000 which is 1 millionth of the current (probably unreliable) estimate of the number of neurons in the brain 80,000,000,000.
Now synapses between neurons are easy to spot using electron microscopy. The presynaptic terminal contains a bunch of small vesicles and is closely apposed (300 Angstroms — way below anything the our eyes can see) to the post synaptic neuron which also looks different, usually having a density just under the membrane (called, logically enough, post-synaptic density). Embedded in the postsynaptic membrane are proteins which conduct ions such as Na+, K+, Cl- into the postsynaptic neuron triggering an action potential.
But the dopamine axons going all over the brain have a lot of presynaptic specialization, but in many of the cases the post-synaptic neuron and its postsynaptic density is nowhere to be found (or the receptors for dopamine aren’t near the presynaptic specialization). This is called volume neurotransmission.
However, in the nuclei studied (the striatum) dopamine synapses on dendrites of the major cell type (the medium spiny neuron) are well described and the 5 receptors for dopamine (called G Protein Coupled Receptors — GPCRs) are found there. None of the GPCRs conduct ions or trigger action potentials (immediately anyway). Instead, they produce their effects much more slowly and change the metabolism of the interior of the cell. This is true for all GPCRs, regardless of the ligand activating them — and humans have 826 GPCR genes.
Note also that volume neurotransmission means that dopamine reaches nonNeuronal tissue — and there is good evidence that dopamine receptors are present on glial cells, pericytes and blood vessels.
The story doesn’t end with dopamine. There are 3 other similar systems of small numbers of neurons collected into nuclei, using different neurotransmitters, but whose axons branch and branch so they go all over the brain.
These are the locus coeruleus which uses norepinephrine as a neurotransmitter, the dorsal raphe nucleus which uses serotonin and the basal nucleus of Meynert which uses acetyl choline. There is excellent evidence that the first two (norepinephrine and serotonin) use volume neurotransmission. I’m not sure about those of the basal nucleus of Meynert.
What is so remarkable about the paper, that it allows the receiving neurons to (partially) control what dopamine input it gets.
All norepinephrine receptors are GPCRs, while only one of the 16 or so serotonin receptors conducts ions, the rest being GPCRs.
Acetyl choline does have one class of receptors (nicotinic) which conducts ions, and which the paper shows is what is triggering the axon on axon synapse. The other class (muscarinic) of acetyl choline receptor is a GPCR.
Addendum 29 September — it goes without saying (although I didn’t say it) that any molecule released by volume neurotransmission doesn’t confine itself to finding targets on neurons. Especially with norepinephrine, it could bind to receptors for it on the vasculature causing circulatory effects. They could also bind to GPCRs on pericytes and glia.
Now the paper tested axon to axon firing in one of the four systems (dopamine) in one of the places its axons goes (the striatum). There is no question that the axons of all 4 systems ramify widely.
Suppose axon to axon firing is general, so a given region can control in someway how much dopamine/serotonin/norepinephrine/acetyl choline it is getting.
Does this remind you of any system you are familiar with? Perhaps because my wife went to architecture school, it reminds me of an old apartment building, with separate systems to distribute electricity, plumbing, steam heat and water to each apartment, which controls how much of each it gets.
Perhaps these four systems are basically neurological utilities, necessary for the function of the brain, but possibly irrelevant to the computations it is carrying out, like a mother heating a bottle for her baby in water on a gas stove on a cold winter night. The nature of steam heat, electricity, water and gas tell you very little about what is going on in her apartment.
The paper is so new (the Neuron issue of 21 September) that more implications are sure to present themselves.
Quibbles are sure to arise. One is that fact that the gray matter of our brain doesn’t contain much in the way of neurons using acetyl choline as a neurotransmitter. What it does have is lots of neurons using GABA which we know can act on axons, inhibiting axon potential generation. This has been well worked out with synapses where the axon emerges from the neuron cell body (the initial segment). However the different ionic composition of axons in the developing brain results in GABA having an excitatory effect. Perhaps ionic composition varies in different parts of the neuron.
The work was done in living animals, so the paper contains no electron micrographs. Such work is sure to be done. No classical presynaptic apparatus may be present, just two naked axons touching each other and interacting by ephaptic transmission (the term does not appear in the paper).
So a lot of work should be done, the first of which should be replication. As the late Carl Sagan said “extraordinary claims require extraordinary evidence”.
Finally:
As Mark Twain said ” There is something fascinating about science. One gets such wholesale returns of conjecture out of such a trifling investment of fact.”
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Every now and then a paper comes along which shows how little we really know about the brain and how it works. Even better, it demands a major rethink of what we thought we knew. Such a paper is — Neuron vol. 110 pp. 2949 – 2960 ’22 https://www.cell.com/neuron/fulltext/S0896-6273(22)00656-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627322006560%3Fshowall%3Dtrue
which I doubt you can get unless you are a subscriber to Neuron. What [ Neuron vol. 110 pp. 2889 – 2890 ’22 ] does is pretty much prove that an axon from one neuron can synapse on an axon of another neuron. When one neuron is stimulated the axon of another neuron fires an impulse (an action potential) as measured by patch clamping the second axon. This happens way too fast after stimulation to be explained by volume neurotransmission (about which more later). Such synapses are well known on the initial segment of the axon as it leaves the cell body (the soma) of the neuron.
But these synapses occur very near to the end of the axon in the part of the brain (the striatum) the parent neuron (a midbrain dopamine neuron) innervates (the striatum). The neurotransmitter involved is acetylcholine and the striatum has lots of neurons using acetylcholine as a neurotransmitter. There are two basic types of acetylcholine receptor in the brain — muscarinic and nicotinic. Muscarinic receptors are slow acting and change the internal chemistry of the neuron. This takes time. Nicotinic receptors are ion channels, and when they open, an action potential is nearly immediate. Also using a drug to block the nicotinic acetyl choline receptor, blocks action potential formation after stimulation.
Why is this work so radical? (which of course means that it must be repeated by others). It implies that all sorts of computations in the brain can occur locally at the end of an axon, far away from the neuron cell body which is supposed to be in total control of it. The computations could occur without any input from the cell body, and spontaneous activity of the axons they studied occur without an impulse from the cell body. If replicated, we’re going to have to rethink our models of how the brain actually works. The authors note that they have just studied one system, but other workers are certain to study others, to find out how general this.
Neuropil, is an old term for areas of the brain with few neuron or glial cell bodies, but lots of neural and glial processes. It never was much studied, and our brain has lots of it. Perhaps it is actually performing computations, in which case it must be added to the 80 billion neurons we are thought to have.
Now for a bit more detail
The cell body of the parent neuron of the axon to be synapsed on uses dopamine as a neurotransmitter. It sits in the pars compacta of the substantia nigra a fair piece away from the target they studied. “Individual neurons of the pars compact are calculated to give rise to 4.5 meters of axons once all the branches are summed” — [ Neuron vol. 96 p. 651 ’17 ].” These axons release dopamine all over the brain, and not necessarily synapsing with a neuron. So when that single neuron fires, dopamine is likely to bathe every neuron in the brain.This is called volume neurotransmission which is important because the following neurotransmitters use it — dopamine, serotonin, acetyl choline and norepinephrine. Each has only a small number of cells using them as a transmitter. The ramification of these neurons is incredible.
So now you see why massive release of any of the 4 neurotransmitters mentioned (norepinephrine, serotonin, dopamine, acetyl choline) would have profound effects on brain states. The four are vitally involved in emotional state and psychiatric disease. The SSRIs treat depression, they prevent reuptake of released serotonin. Cocaine has similar effects on dopamine. The list goes on and on and on.
Axons synapsing on other axons is yet another reason to modify our rather tattered wiring diagram of the brain — https://luysii.wordpress.com/2011/04/10/would-a-wiring-diagram-of-the-brain-help-you-understand-it/