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Androgens increase excitatory neurogenic potential in human brain organoids.

ABSTRACT: The biological basis of male-female brain differences has been difficult to elucidate in humans. The most notable morphological difference is size, with male individuals having on average a larger brain than female individuals^1,2, but a mechanistic understanding of how this difference arises remains unknown. Here we use brain organoids³ to show that although sex chromosomal complement has no observable effect on neurogenesis, sex steroids-namely androgens-lead to increased proliferation of cortical progenitors and an increased neurogenic pool. Transcriptomic analysis and functional studies demonstrate downstream effects on histone deacetylase activity and the mTOR pathway. Finally, we show that androgens specifically increase the neurogenic output of excitatory neuronal progenitors, whereas inhibitory neuronal progenitors are not increased. These findings reveal a role for androgens in regulating the number of excitatory neurons and represent a step towards understanding the origin of sex-related brain differences in humans.

SUBMITTER: Kelava I

PROVIDER: S-EPMC7612328 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Androgens increase excitatory neurogenic potential in human brain organoids.

Kelava Iva I Chiaradia Ilaria I Pellegrini Laura L Kalinka Alex T AT Lancaster Madeline A MA

Nature 20220119 7895

The biological basis of male-female brain differences has been difficult to elucidate in humans. The most notable morphological difference is size, with male individuals having on average a larger brain than female individuals<sup>1,2</sup>, but a mechanistic understanding of how this difference arises remains unknown. Here we use brain organoids<sup>3</sup> to show that although sex chromosomal complement has no observable effect on neurogenesis, sex steroids-namely androgens-lead to increased ...[more]

PMID: 35046577

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Project description:BACKGROUND: Prevailingly, adult mammalian neurogenesis is thought to occur in discrete, separate locations known as neurogenic niches that are best characterized in the subgranular zone (SGZ) of the dentate gyrus and in the subventricular zone (SVZ). The existence of adult human neurogenic niches is controversial. METHODS: The existence of neurogenic niches was investigated with neurogenesis marker immunostaining in histologically normal human brains obtained from autopsies. Twenty-eight adult temporal lobes, specimens from limbic structures and the hypothalamus of one newborn and one adult were examined. RESULTS: The neural stem cell marker nestin stained circumventricular organ cells and the immature neuronal marker doublecortin (DCX) stained hypothalamic and limbic structures adjacent to circumventricular organs; both markers stained a continuous structure running from the hypothalamus to the hippocampus. The cell proliferation marker Ki-67 was detected predominantly in structures that form the septo-hypothalamic continuum. Nestin-expressing cells were located in the fimbria-fornix at the insertion of the choroid plexus; ependymal cells in this structure expressed the putative neural stem cell marker CD133. From the choroidal fissure in the temporal lobe, a nestin-positive cell layer spread throughout the SVZ and subpial zone. In the subpial zone, a branch of this layer reached the hippocampal sulcus and ended in the SGZ (principally in the newborn) and in the subiculum (principally in the adults). Another branch of the nestin-positive cell layer in the subpial zone returned to the optic chiasm. DCX staining was detected in the periventricular and middle hypothalamus and more densely from the mammillary body to the subiculum through the fimbria-fornix, thus running through the principal neuronal pathway from the hippocampus to the hypothalamus. The column of the fornix forms part of this pathway and appears to coincide with the zone previously identified as the human rostral migratory stream. Partial co-labeling with DCX and the neuronal marker ?III-tubulin was also observed. CONCLUSIONS: Collectively, these findings suggest the existence of an adult human neurogenic system that rises from the circumventricular organs and follows, at minimum, the circuitry of the hypothalamus and limbic system.

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Androgens increase excitatory neurogenic potential in human brain organoids.

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Androgens increase excitatory neurogenic potential in human brain organoids.

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