brain complexity: chemical controls (Introduction)

by David Turell @, Saturday, January 11, 2020, 20:00 (184 days ago) @ David Turell

The subject of this article is serotonin:

"The serotonergic system has widely been shown to control many aspects of neuroregeneration. In some regions, it facilitates neurogenesis, while in others, it seems to inhibit it. In the case of inhibition, a recent example has been published in PLOS Biology. The authors used a zebrafish model of Alzheimer's disease to show that amyloid-induced interleukin-4 (IL4) promotes neurogenic stem cell proliferation by suppressing the production of serotonin. In these animals, there is a unique neuro-immune interaction through which IL4 secreted by dying neurons activates microglia. In turn, microglia reciprocate by revving up neural stem cell proliferation.


"It is now commonly appreciated that peripheral immune stem cells (and even fetal cells from pregnant moms circulating in maternal blood) can migrate across the adult BBB [blood brain barrier] and fuse with local neurons to create all kinds of new hybrid entities. The opposite migration, however, is still largely unknown in nature. Surprisingly, researchers have recently discovered that neural progenitor cells in the developing mouse brain can exit through the BBB to join the general circulation.


"Everyone knows that serotonin is one of the major transmitters used in the brain. The perplexing states of mind resulting from use of many popular hallucinogenic drugs that mimic serotonin are believed to act specifically at the 5-HT2A receptor variety. But what might serotonin do that good old glutamate, dopamine or acetylcholine are not known to do? One thing serotonin does, and accomplishes specifically through 5HT2A receptors is control the minting of new mitochondria. That's not to say that the primary occupation of other transmitters is not somehow controlling mitochondria as well, we just don't yet know fully how they might do it.

"Discussing the biogenesis of mitochondria and the neurogenesis of new brain cells entails an instructive dilemma: Mitochondria are forced into competition with their own local master nucleus for access to nucleotides—necessary for both DNA repair and replication.


"The larger body-wide tryptophan ecosystem is responsible for maintaining levels of other important products, including nicotinamide adenine dinucleotide (NAD), and to a lesser extent, the peptide hormone melatonin.

Although NAD can be generated by the so-called "Preiss-Handler" pathway from niacin or from salvage pathways through nicotinamide, its "de novo" synthesis from tryptophan is an essential contributing pathway in the nervous system. Being able to synthesize NAD on demand from scratch is convenient, but also very expensive. The conversion ratio for the synthesis pathways is roughly 67 mg of tryptophan to make 1 mg of niacin.

"The decision to route essential tryptophan stores into either serotonin, or to NAD is made locally in every part of the brain. Diverse anatomical nuclei and specialized cell types use restricted subsets of enzymes which little but the potluck of cell differentiation has apportioned to each them. Deficiencies in the intracellular metabolic circuits that synthesize both nucleotide stores and the many transmitter products required by neural cells and their mitochondria are made whole through the establishment of macrocellular transport circuits between them. Although these resultant neural structures give rise to high effects scarcely imaginable from their comparatively low enzymatic origins, many of their characteristics can now be intuitively comprehended through simple principles of metabolic supply and demand.

"What is still far less certain territory today, but may soon be determined, is that the neural activity supported by different circuits should be explainable in similar terms. In other words, spikes themselves have an intrinsic meaning more basic than that of transmitting information to and from the external world. It has been suggested that other transmitters capable of acting through G-protein receptors, like, for example, GABA, have a primary function of controlling the availability of nucleotides to synaptic mitochondria. In particular, the second messenger systems of these transmitters continually lock and release variously phosphated purines between their cyclic and non-cyclic forms.

"If the largely post-mitotic brain derives much of its singular structure and function (compared to other organs) as a result of a more or less artificially maintained scarcity of nucleotides, it is not much of a stretch to imagine that the fuss and chatter of spikes is largely what we might call nucleotide micromanagement. Any higher-level "signaling" function of spikes and the subsequent transmitter release from vessicles across synapses is therefore merely superimposed on top of what is essentially the corralling, release, and likely also repair, of nucleotides."

Comment: this shows how difficult it is to understand how the brain does its amazing work as the result of neurogenic and chemical coordinated activities. Not by chance

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