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Developmental Biology - Stem Cells

Happiness and the Evolution of The Human Brain

Serotonin is the growth factor in fetal brain stem cells which determines human brain size

During the extent of human evolution, approximately six million years until now, the size of our brain has increased, especially in a part of the brain called the neocortex, which enables us to speak, dream and think.

In search of causes that stimulated neocortex expansion, researchers at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, together with colleagues at the University Hospital Carl Gustav Carus Dresden, previously identified a number of molecular players.
These players typically act in the so-called basal progenitor cells the stem cells of the developing neocortex playing a pivotal role in its expansion.

Researchers now report an additional, novel role of the happiness neurotransmitter serotonin known to function in the brain to mediate satisfaction, self-confidence and optimism to act cell-extrinsically as a growth factor for basal progenitors in the developing human, but not mouse, neocortex.
Due to this newly observed function, placenta-derived serotonin likely contributed to the evolutionary expansion of the human neocortex.

The research team of Wieland Huttner at the Max Planck Institute of Molecular Cell Biology and Genetics, one of the institute's founding directors, has investigated the cause of the evolutionary expansion of the human neocortex in many studies. A new study from his lab focuses on the role of the neurotransmitter serotonin in this process.
Serotonin is often called the happiness neurotransmitter because it transmits messages between nerve cells that contribute to well-being and happiness. However, a potential role of such neurotransmitters during brain development has not yet been explored in detail.

In the developing embryo, the placenta produces serotonin, which reaches the brain via blood circulation. This is true for humans as well as mice. Yet, the function of this placenta-derived serotonin in the developing brain had been unknown.

Postdoctoral researcher Lei Xing, in the Huttner group, studied neurotransmitters during his doctoral work in Canada. When he started his research project in Dresden, he was curious to investigate neurotransmitters' role in the developing brain.
"Exploring datasets generated by the group in the past, I found that the serotonin receptor HTR2A was expressed in fetal human, but not embryonic mouse, neocortex. Serotonin needs to bind to this receptor in order to activate downstream signaling. I wondered if this receptor could be one of the keys to the question of why humans have a bigger brain? To explore this, we induced the production of the HTR2A receptor in the embryonic mouse neocortex.

We found by activating serotonin, we caused a chain of reactions resulting in production of more basal progenitor cells in the developing mouse brain. More basal progenitors can increase the production of cortical neurons, which paves the way to a bigger brain.

Lei Xing PhD, Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse, Dresden, Germany.
'Our study uncovered a novel role of serotonin as a growth factor for basal progenitors in highly developed brains, notably human. Our data implicates serotonin in the expansion of the neocortex during development and human evolution.

Abnormal signaling of serotonin and a disturbed expression or mutation of its receptor HTR2A has been observed in various neurodevelopmental and psychiatric disorders, such as (1) Down syndrome, (1) attention deficit hyperactivity disorder and (3) autism. Our findings may help explain how malfunctions of serotonin and its receptor during fetal brain development can lead to congenital disorders and may suggest novel approaches for therapeutic avenues."

Wieland Huttner PhD, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany and lead author.

This research was published in Neuron, 19 October 2020

Abstract Highlights

5-HT receptor HTR2A is expressed in developing ferret and human, not mouse, neocortex

HTR2A is required for, and suffices to increase, basal progenitor (BP) proliferation

HTR2A activation increases proliferative BPs at the expense of neurogenic BPs

HER2 and ERK1/2 signaling are required for HTR2A-induced BP proliferation

Evolutionary expansion of the mammalian neocortex (Ncx) has been linked to increased abundance and proliferative capacity of basal progenitors (BPs) in the subventricular zone during development. BP proliferation is governed by both intrinsic and extrinsic signals, several of which have been identified. However, a role of neurotransmitters, a canonical class of extrinsic signaling molecules, in BP proliferation remains to be established. Here, we show that serotonin (5-HT), via its receptor HTR2A, promotes BP proliferation in an evolutionarily relevant manner. HTR2A is not expressed in embryonic mouse Ncx; accordingly, 5-HT does not increase mouse BP proliferation. However, ectopic HTR2A expression can increase mouse BP proliferation. Conversely, CRISPR/Cas9-mediated knockout of endogenous HTR2A in embryonic ferret Ncx reduces BP proliferation. Pharmacological activation of endogenous HTR2A in fetal human Ncx ex vivo increases BP proliferation via HER2/ERK signaling. Hence, 5-HT emerges as an important extrinsic pro-proliferative signal for BPs, which may have contributed to evolutionary Ncx expansion.

Lei Xing, Nereo Kalebic, Takashi Namba, Samir Vaid, Pauline Wimberger and Wieland B. Huttner.

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Nov 3 2020   Fetal Timeline   Maternal Timeline   News

The placenta in "soil" supplies the brain with serotonin, helping the brain to grow.

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