Serotonin the happy hormone act as a growth factor for the stem cells in the fetal human brain that determine brain size
During the evolutionary journey, the size of the brain increased, especially in a particular part called the neocortex. The neocortex enables us to speak, dream and think. In the search of the causes underlying 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, identified a number of molecular players. These players typically act cell-intrinsically in the so-called basal progenitors, the stem cells in the developing neocortex with a pivotal role in its expansion.
The researchers now report an additional, novel role of the happiness neurotransmitter serotonin which is known to function in the brain to mediate satisfaction, self-confidence and optimism – to act cell-extrinsically as a growth factor for basal progenitors(BPs) in the developing human, but not mouse, neocortex (Ncx). Due to this new function, placenta-derived serotonin likely contributed to the evolutionary expansion of the human neocortex.
The team of Wieland Huttner at the Max Planck Institute of Molecular Cell Biology and Genetics, who is one of the institute’s founding directors, has investigated the cause of the evolutionary expansion of the human neocortex in many studies. In a new study from his lab focuses on the role of the neurotransmitter serotonin, the happiness neurotransmitter, because it transmits messages between nerve cells that contribute to well-being and happiness, for a potential role in brain development during in the developing embryo. In humans and mice the placenta produces serotonin, which then reaches the brain via the blood circulation, however, the function of this placenta-derived serotonin in the developing brain has been unknown.
The findings of the study has been published in the Cell Press journal Neuron, their study revealed that the serotonin receptor HTR2A was expressed in fetal human, but not embryonic mouse, neocortex (Ncx). Serotonin needs to bind to this receptor in order to activate downstream signaling. To explore if this receptor could be one of the keys to the question of why humans have a bigger brain.” The researchers induced the production of the HTR2A receptor in embryonic mouse neocortex, and found that serotonin, by activating this receptor, caused a chain of reactions that resulted in the production of more basal progenitors in the developing brain. More basal progenitors can then increase the production of cortical neurons, which paves the way to a bigger brain. 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.
Significance for brain development and evolution
According to Wieland Huttner, supervisor of the study, "the present study uncovers a novel role of serotonin as a growth factor for basal progenitors in highly developed brains, notably humans and implicates serotonin in the expansion of the neocortex during development and human evolution". He continues: “Abnormal signaling of serotonin and a disturbed expression or mutation of its receptor HTR2A have been observed in various neurodevelopmental and psychiatric disorders, such as Down syndrome, attention deficit hyperactivity disorder and 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.”
Lei Xing, Nereo Kalebic, Takashi Namba, Samir Vaid, Pauline Wimberger, Wieland B. Huttner. Serotonin Receptor 2A Activation Promotes Evolutionarily Relevant Basal Progenitor Proliferation in the Developing Neocortex. Neuron, 2020; DOI: 10.1016/j.neuron.2020.09.034
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