[转贴]Brain gender

以下版权属于nature publishing group


Brain gender: prostaglandins have their say


Erich N Ottem, Damian G Zuloaga & S Marc Breedlove
The authors are in the Neuroscience Program and Department of Psychology, Michigan State University, East Lansing, Michigan 48824, USA. breedsm@msu.edu




New findings reveal that steroid hormones masculinize some aspects of the rat brain via prostaglandins. Blocking prostaglandin synthesis with drugs like aspirin can interfere with sexual differentiation of the brain and impair sexual behavior later in life.


Different though the sexes are, they intermix. In every human being a vacillation from one sex to the other takes place, and often it is only the clothes that keep the male and female likeness, while underneath the sex is the very opposite of what it is above.

–Virginia Woolf, Orlando, p. 133 (1928)

Scientists, the ultimate voyeurs, have been striving to peer not only beneath clothes, but well beneath the skin to ask how men and women come to be different. We know from studies in non-human mammalian models that the gonads are important during the perinatal period, when testes secrete hormones such as testosterone to masculinize the body, while in females, the absence of steroid secretions from ovaries permits the body to develop feminine traits. We have known for almost half a century that the same testicular steroids that masculinize the body can also masculinize the brain and therefore behavior in mammals1.

But if testosterone is the executive barking out orders ("Be a man!"), we would like to identify the underlings who scurry around to implement them. In other words, which genes are being regulated in which cell populations, and what are the molecular consequences of those changes? Amateau and McCarthy2 now show that steroids can masculinize the perinatal rat brain by inducing the production of prostaglandin-E2 (PGE2). Indeed, they found that inhibitors of this pathway (including aspirin) impair male sexual behavior later in life.

The authors examined a portion of the brain that has long been a hotbed of sexual neurobiology research—the preoptic area (POA). This region within the anterior hypothalamus is crucial for regulation of hormone secretion, and has been implicated in both female and male sexual behavior. Lesions of the POA disrupt ovulatory cycles in females and abolish copulatory behavior in males. Previous searches for possible sexual dimorphism in the brain also revealed a subregion of the POA—the sexually dimorphic nucleus of the POA (SDN-POA)—that is distinct in Nissl stains and many-fold larger in volume in males than in females3.

Amateau and McCarthy used levels of spinophilin (a protein highly expressed in dendritic spines) as a measure of the masculinizing effects of steroids on sprouting of dendritic spines in the POA. They found that treatment of newborn male rats with indomethacin, an inhibitor of cyclooxygenase-2 (COX-2), the rate-limiting enzyme for PGE2 synthesis, reduced the number of spines and levels of spinophilin in the POA. It also greatly reduced occurrence of male copulatory behaviors later in adulthood. Perinatal treatment of males with a less potent COX-2 inhibitor, aspirin, given to their mothers during pregnancy and lactation, also diminished adult copulatory behavior, albeit transiently. We do not know exactly how much aspirin the mothers ingested, as it was placed in their drinking water (one 81-mg baby aspirin per half-liter), but it is likely comparable to the dose a human would take for a headache.

Conversely, providing exogenous PGE2 to newborn female rats short-circuited the system, masculinizing their brains without the need for steroids. PGE2 therefore seems both necessary and sufficient for the masculinization of some aspects of morphology and function in the POA. PGE2 manipulations had no effect on spinophilin expression in the hippocampus, so the effect seems to be specific to brain regions prominently engaged in sexual differentiation. These data suggest a new and unexplored mechanism, downstream from gonadal steroids, that directs sexual differentiation of the brain.

Given their freewheeling ideas about gender, Virginia Woolf's famous Bloomsbury group might not have been surprised about one aspect of sexual differentiation of the brain—estrogen, the 'feminine' hormone crucial for female reproduction, also serves to masculinize the brain of male rats. The males' testes primarily secrete testosterone, but in the brain, a portion of that testosterone is converted to estradiol by a single reaction catalyzed by the enzyme aromatase. (Other androgens are similarly converted into other estrogens.) The estrogens then bind to estrogen receptors—not androgen receptors—to masculinize brain morphology and behavior. Research has shown this in several ways; for example, treating newborn female rats with estrogen causes them to behave in a masculine fashion in adulthood and also causes them to have a large SDN-POA3. Amateau and McCarthy found that PGE2 was just as effective as estrogen at inducing spine formation in the POA. Thus, coupled with the demonstration that perinatally blocking PGE2 demasculinizes the brains of males, the findings suggest that PGE2 acts downstream from estrogen to masculinize the rat brain.

An important question is whether the authors inadvertently altered steroid production or metabolism when they manipulated PGE2. In that case, they would simply have found a complex way to manipulate perinatal steroids. But assays of testosterone a few days after the PGE2 treatment and at maturity gave no evidence that circulating steroids differed between experimental and control animals. Furthermore, the overall volume of the SDN-POA was unaffected by PGE2 manipulations. This is reassuring, as it indicates that the manipulations did not affect gonadal testosterone secretion or hypothalamic aromatase activity, because either would have affected SDN-POA volume. It is also curious, however, because it suggests that although PGE2 mediates estrogenic masculinization of dendritic spine formation in the POA, it cannot account for masculinization of the volume of the SDN-POA. Presumably steroids call for a different set of underlings, not PGE2, to enlarge SDN-POA volume.

As with any new finding, a host of questions arise. For example, which cells are responding to the estrogen to induce PGE2 production? There are plenty of hypothalamic neurons with estrogen receptors, so either the postsynaptic neurons forming the spines or their presynaptic partners might be the ones that detect estrogen and trigger some chain of events leading to increased PGE2. No synapse in the CNS is ever very far from a glial cell, and many glia possess estrogen receptors4, so it is also possible that a nearby astrocyte might respond to estrogen and release PGE2. For that matter, it is possible that some relatively distant neuron is affected by estrogen and changes its activity so that, several synapses away, PGE2 emerges.

Not knowing which cells respond to the steroid hormone seems to be a large gap in the story. For all our information about how steroids affect the developing brain morphologically and functionally, there is no evidence to show whether in these instances steroids affect neurons or glia (or even connective tissue). Once we learn where estrogen acts to induce PGE2 production, we can then investigate the mechanism by which PGE2 boosts dendritic spine formation. Is PGE2 acting on the postsynaptic neuron forming the spine, its presynaptic partner, or through some third party such as a nearby glial cell or a distant neuron that affects electrical activity in the POA? As with estrogen receptors, mapping the distribution of PGE2 receptors (EP) provides little help, as they seem to be almost everywhere. Furthermore, there is evidence that the transmitter glutamate and its numerous receptors may interact with PGE2 to regulate development of the POA. For example, pharmacological blockade of AMPA receptors blocks the ability of PGE2 to increase spinophilin in the POA5. PGE2 also induces Ca2+-dependent glutamate release from astrocytes, but only if AMPA and metabotropic glutamate receptors (mGluRs) are activated6. Glutamate receptors and a host of second messengers have been implicated in dendritic spine formation7, and new evidence suggests that astrocytes are capable of vesicular release of glutamate8. Thus, the list of interactions that may occur during estrogen-induced, PGE2-mediated brain masculinization suddenly suffers from an embarrassment of riches (Fig. 1).


Figure 1. Alternative mechanisms for estrogen-induced masculinization of the rat brain through prostaglandins.

(a) Estradiol (E2) interacts with estrogen receptors (ER), which are expressed in many neurons and glia, and could directly (as shown here) or indirectly increase the expression of cyclooxygenase-2 (COX-2), the rate-limiting enzyme for the production of prostaglandin-E2 (PGE2) from arachidonic acid (AA). (b) Newly formed PGE2 could promote dendritic spine formation by at least three different pathways. PGE2 and glutamate of presynaptic origin (blue arrows) may activate various prostaglandin receptors (EP) and glutamate receptors on the postsynaptic target to initiate new spine formation. PGE2 could also act on presynaptic EP receptors (green arrows) to augment glutamate release, thereby promoting new spine formation in the postsynaptic cell. Alternatively, PGE2 may trigger glutamate release from nearby glia to induce spine formation (yellow pathway). In each case, the postsynaptic cell assembles various proteins, including spinophilin, to support the new spines.



Full Figure and legend (60K)


These results also raise the question of whether widespread use of COX inhibitors such as indomethacin or aspirin may affect sexual behavior in humans. Although it might be tempting to try to relate these results to sexual orientation, the authors did not examine any measures of sexual orientation (such as partner preference). However, there was a distinct dampening of masculine performance in male rats exposed to COX inhibitors, indicating a reduced libido. Could a pregnant woman seeking relief from migraine through one of these drugs inadvertently hinder the masculinization of her fetal son's brain? Certainly these unexpected results reinforce the notion that pregnant women should strive to avoid ingesting any drugs, however benign they are thought to be today. Even now there may be some husband out there saying, in effect, "Sorry, dear, not tonight. My mother had a headache 30 years ago."

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