When our tools were blunt, the brain looked a lot simpler than it does now.
Example #1: Locus coeruleus (LC). This is a tiny group of neurons deep in the brain. It looks blue to the naked eye, if you’ve gone to medical school as I have and dissected a brain. This is held to be due to neuromelanin produced by the neurotransmitter it uses (norepinephrine). Neurons using dopamine as a neurotransmitter also produce neuromelanin but it’s brown. The two differ by just one oxygen atom.
The LC is tiny in primates, only 15,000 – 50,000 neurons depending on species and who you read.. The rat (where most experiments are done) has only 1,500 in a space 1000 microns (1 millimeter) x 200 x 500 microns.
So until now any attempt to stimulate the locus coeruleus with an electrode alerted the animal.
Why? Two reasons.
1. The LC is so small that any electrode stimulating it, stimulated every neuron.
2. Because that tiny nucleus sends fibers all over the brain, releasing norepinephrine everywhere, and not just at synapses. This is called volume neurotransmission. Most places on the axons of a LC neuron showing synaptic vesicles (where norepinephrine is found), don’t have a dendrite or any sort synaptic specialization next to them. So the LC innervates the whole brain, in the same way that our brain innervates our muscles.
Stimulate the LC of a rat and the brain is flooded with norepinephrine and the animal wakes up.
Well that was the case until technology marched on and miniaturization of electrodes allowed us to record from a 10 – 20 neurons at a time in the LC when stimulation was applied. Those responding to a given stimulus were called ensembles. Of 285 single LC neurons studied in 15 rats, 115 participated in multiple ensembles, 149 participated only in a single ensemble and 21 didn’t participate in any. Activity of different ensembles produced different brain states — not all were wide awake. You can read all about this in Proc. Natl. Acad. Sci. vol. 119 e21116507119 ’22.
Volume neurotransmission 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.
For instance, “human serotonergic neurons, which are estimated to extend axons for 350 meters” [ Science vol. 366 3aaw9997 p. 4 ’19 ], so the fibers are everywhere in the brain. I couldn’t find a statistic for axons of the locus coeruleus but those of neurons using acetyl choline as a neurotransmitter are estimated to have axons extending for 31 meters.
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.
Maybe be we’ll be able to slice and dice these nuclei in the future to produce more subtle effects on brain function.
Example #2: Dendritic diversity — that’s for next time. This post is long enough.
Chemiotics II 