Summary: New research shows that estrogen produces lasting physical differences between male and female brains during development.
Source: CSHL
Sex hormones are powerful architects of behavior, and their influence begins early in life. Brief hormonal surges during development help shape neural circuits that direct behavior throughout an animal’s life.
Estrogen controls the activity of hundreds of genes in the brain. Changes in estrogen levels influence mood, energy balance, and behavior across the lifespan, and they also sculpt neural circuits during critical developmental windows. These effects occur when activated estrogen receptors bind directly to specific sites on cellular DNA to switch genes on or off.
Cold Spring Harbor Laboratory Assistant Professor Jessica Tollkuhn, graduate student Bruno Gegenhuber, and colleagues have created a detailed map of where estrogen receptors attach to DNA in mouse brain cells. They examined both male and female brains and compared mature adults to developing pups to track how hormone action changes with age.
Reported in the journal Nature, their study identifies the genomic targets of estrogen receptors in the brain and demonstrates that estrogen establishes structural sex differences during early development.
Tollkuhn emphasizes that estrogen is present in the brains of both sexes; some neurons synthesize estrogen locally from testosterone. In male mice, a surge of testosterone shortly after birth is converted into estrogen in the brain, and that converted estrogen directs the wiring of neural circuits during a narrow, sensitive period.
Because of this early hormonal influence, specific brain regions become larger and contain more cells in males than in females. Those anatomical differences help shape adult behaviors including mating, parental care, and aggression.
“There’s a critical developmental window when the brain must receive this hormonal input to produce lasting changes in circuit wiring,” Tollkuhn says. “Although the hormone surge is transient, its effects on brain structure and gene regulation endure.”
The team focused on the BNST, a sexually dimorphic brain area that is larger in males than females in both mice and humans. Using genomic techniques, they mapped where estrogen receptor alpha (ERα) binds across the genome within cells of this circuit and identified the downstream genes whose activity is regulated by estrogen.
Their analysis revealed many estrogen-regulated genes, including those involved in neural development, cell identity, and neuronal signaling. Importantly, while the estrogen molecule is present in the brain only briefly after the neonatal surge, the genes activated or reorganized by that signal remain altered for weeks, suggesting a molecular mechanism for long-lasting sex differences.
Based on genome-wide binding maps and gene expression data, the authors conclude that estrogen receptor signaling acts through two main mechanisms: promoting the emergence of male-biased neuron types and activating a persistent male-biased gene expression program. Together, these mechanisms direct sexual differentiation of the mouse brain.
With the estrogen receptor targets now defined, Tollkuhn’s group plans to investigate how individual target genes mediate estrogen’s diverse effects on brain wiring, adult behavior, and susceptibility to disease. Understanding these pathways may illuminate why sex differences appear in certain neurodevelopmental and psychiatric conditions.
About this neurodevelopment research news
Author: Press Office
Source: CSHL
Contact: Press Office – CSHL
Image: The image is credited to Bruno Gegenhuber/Tollkuhn lab/CSHL, 2022
Original Research: Open access.
“Epigenomic organization and activation of brain sex differences” by Jessica Tollkuhn et al. Nature
Abstract
Epigenomic organization and activation of brain sex differences
Oestradiol (a form of estrogen) establishes neural sex differences across many vertebrates and continues to influence mood, behavior, and energy balance in adulthood. In its canonical pathway, oestradiol acts through the transcription factor estrogen receptor alpha (ERα).
Although ERα has been well studied in contexts such as breast cancer, its neuronal genomic targets and their roles in creating brain sex differences have remained largely undefined.
This work produces a comprehensive map of ERα-binding sites within a sexually dimorphic neural circuit that helps regulate social behaviors.
The authors show that ERα directs sexual differentiation of the mouse brain by two coordinated actions: generating two male-biased neuronal cell types and initiating a sustained male-biased program of gene expression.
Overall, the findings indicate that sex differences in neural gene expression arise from hormone-driven activation of steroid receptors in specific neuron populations. The molecular targets identified in this study may explain how oestradiol shapes brain development, behavior, and disease vulnerability.