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Developmental Biology - The Male Brain

Why Male/Female Brains Differ

How sex steroids sculpt prenatal male brain...


In a new study out of the University of Maryland School of Medicine (UMSOM), Margaret McCarthy PhD, in conjunction with her team of researchers, has discovered how brain differences between males and females begin in-utero. The group uncovered how androgens, male sex steroids, sculpt the brain resulting in behaviors such as aggression and rough play.
"We already knew that brains of males and females are different and that testosterone, produced during the second trimester in humans and late gestation in rodents, contributes to these differences but we didn't know exactly how testosterone influenced these effects."

Margaret M. McCarthy PhD, Director, Program in Neuroscience, Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA.

The research is published in the journal Neuron.
Key is a decrease in the number of newborn brain cells in the male amygdala. The amygdala is where emotions and social behavior are controlled. Newborn male rats have fewer amygdala cells than females. As testosterone increases in late rat gestation, scientists observed the rats neural receptors bound to endocannabinoids causing immune cells to eliminate those amygdala cells.

In female rats, newborn cells differentiated into a type of glial cell which becomes the most abundant cell in the central nervous system.

In male rats, testosterone prompts immune cells to eliminate amygdala cells that are bound to endocannabinoids.

Females rats in the study were unaffected by their immune system, suggesting that, in male rats, activation of immune cells by an increase in endocannabinoids was eliminating amygdala cells. In this respect, cannabis use, which stimulates endocannabinoids in the brain and nervous system, could impact brain development in the fetus. These results suggest androgen and endocannabinoid signaling may contribute to individual differences in brain development and translate as behavioral differences between the sexes.
"These discoveries in brain development are critical as we work to tackle brain disorders as early in life as possible even during pregnancy."

Dean E. Albert Reece, MD, PhD, MBA, who is also the Executive Vice President for Medical Affairs, University of Maryland, and the John Z. and Akiko K. Bowers Distinguished Professor.

Highlights
Microglia are more phagocytic in the male amygdala during neonatal development

Androgen-induced endocannabinoids increase phagocytosis in males

Microglia engulf viable newborn astrocytes in a complement-dependent manner

Developmental phagocytosis produces a sex difference in juvenile social play

Summary
Brain sex differences are established developmentally and generate enduring changes in circuitry and behavior. Steroid-mediated masculinization of the rat amygdala during perinatal development produces higher levels of juvenile rough-and-tumble play by males. This sex difference in social play is highly conserved across mammals, yet the mechanisms by which it is established are unknown. Here, we report that androgen-induced increases in endocannabinoid tone promote microglia phagocytosis during a critical period of amygdala development. Phagocytic microglia engulf more viable newborn cells in males; in females, less phagocytosis allows more astrocytes to survive to the juvenile age. Blocking complement-dependent phagocytosis in males increases astrocyte survival and prevents masculinization of play. Moreover, increased astrocyte density in the juvenile amygdala reduces neuronal excitation during play. These findings highlight novel mechanisms of brain development whereby endocannabinoids induce microglia phagocytosis to regulate newborn astrocyte number and shape the sexual differentiation of social circuitry and behavior.

Authors
Jonathan W. VanRyzin, Ashley E. Marquardt, Kathryn J. Argue, Haley A. Vecchiarelli, Sydney E. Ashton, Sheryl E. Arambula, Matthew N. Hill, and Margaret M. McCarthy.

The authors declare no conflict of interest.

Acknowledgements
This research was funded by NIH, Natural Sciences and Engineering Council of Canada, Canadian Institutes of Health Research, Alberta Innovates, and BranchOut Neurological Foundation.


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Mar 5 2019   Fetal Timeline   Maternal Timeline   News  




Brain sex differences are established before birth,
generating lasting changes in circuitry and behavior.


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