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Monday, December 28, 2015

How Sexual Dimorphism Arises: The Cellular Level

Developmental masculinization of the brain leads to significant structural differences in the brains of the two sexes.
Some brain regions are larger in males; others are smaller. Collections of cells that constitute nuclei or subnuclei of the brain differ in overall size due to differences in cell number and/or density, as well as in the number of neurons expressing a particular neurotransmitter.
One of the most well studied brain regions that differs between male and female mice is the preoptic area, a region of the hypothalamus that is essential for sexual behavior in males.
In addition to the anatomical differences between the male and female brain, researchers have uncovered variation at the cellular level where microglia regulate the development of sexual differences
We also find that similar events take place during the ongoing neurogenesis that takes place everyday along with each experience and continues to shape our neurons and astrocytes.
It's important to note that we are not made just once at birth with a male or female bodily and brain makeup. Our cells in all parts of the body including the brain constantly die and new ones are born and take their place.
To be male or female your cells must continue to make those differences in the brain that arose in the womb, and much the same process and the same cells must keep doing that job of making sure all our new cells are either male or female.
This is from the Mary McCarthy Lab, perhaps the most advanced researchers in uncovering the origin and nature of sex differences in the brain.
Here is a video of hers:
The text we use here (below) is directly from the Scientist Article on her work:…
In the mPN of male mice, neurons have twice as many dendritic spines (potential synapses) as do neurons in females; synapse number correlates with male copulatory behavior in adulthood.
The male mPN also has more innate immune cells known as microglia, and these cells are in a more activated state, with shorter and thicker processes. In contrast, the microglia in female brains have long, thin processes indicative of a quiescent state.
Astrocytes in this part of the male brain are “bushy,” with more abundant processes than those in the same region of the female brain
The length and branching patterns of dendrites and the frequency of synapses also vary between males and females—in specific ways in specific regions—as does the number of axons that form projections between nuclei and across the cerebral hemispheres.
Even nonneuronal cells are masculinized. Astrocytes in parts of the male brain are more “bushy,” with longer and more frequent processes than those in the same regions of the female brain.
And microglia, modified macrophages that serve as the brain’s innate immune system, are more activated in parts of the male brain and contribute to the changes seen in the neurons.
Steroid hormones induce such changes by binding to transcription factors that then translocate to the cell nucleus to initiate gene transcription.
For example, estradiol binds to its receptor to induce expression of the gene for cyclooxygenase, which mediates the rate-limiting step in the production of a short-lived signaling molecule called prostaglandin E2 (PGE2).
A little more than 10 years ago, my colleagues and I made the surprising discovery that PGE2 is both necessary and sufficient for the fetal masculinization of the preoptic area, a brain region that is essential for sexual behavior in male mice.
In males, levels of PGE2 are upregulated selectively in this brain region by estradiol-induced synthesis of the cyclooxygenase enzyme.
PGE2 then initiates a signal transduction cascade that leads to activation of AMPA glutamate receptors and the formation and stabilization of synapses on the dendrites of neurons in this brain region.
As a result, male mice have twice the density of excitatory synapses in the preoptic area as females, and this positively correlates with expression of male copulatory behavior in adulthood.
We subsequently discovered that microglia, which have recently begun to be appreciated for their role in sculpting neuronal circuits,6 are the predominant source of PGE2.
Not only are there more of these innate immune cells in young male brains, their morphology reflects a more activated state, and they produce more PGE2 than do the microglia in female brains.
Pharmacological treatments given early in development to shift microglia away from an activated state resulted in lower PGE2 production and prevented masculinization induced by estradiol.5
Thus, a nonneuronal cell, microglia, and an inflammatory mediator, PGE2, are essential for the normal masculinization of the preoptic area in mice.
To quote from that earlier article on PGE2:
"Adult male sexual behavior in mammals requires the neuronal organizing effects of gonadal steroids during a sensitive perinatal period.
During development, estradiol differentiates the rat preoptic area (POA), an essential brain region in the male copulatory circuit.
Here we report that increases in prostaglandin-E2 (PGE2), resulting from changes in cyclooxygenase-2 (COX-2) regulation induced by perinatal exposure to estradiol, are necessary and sufficient to organize the crucial neural substrate that mediates male sexual behavior.
Briefly preventing prostaglandin synthesis in newborn males with the COX inhibitor indomethacin permanently downregulates markers of dendritic spines in the POA and severely impairs male sexual behavior.
Developmental exposure to the COX inhibitor aspirin results in mild impairment of sexual behavior. Conversely, administration of PGE2 to newborn females masculinizes the POA and leads to male sex behavior in adults, thereby highlighting the pathway of steroid-independent brain masculinization.
Our findings show that PGE2 functions as a downstream effector of estradiol to permanently masculinize the brain"

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