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Brains apart: The real difference between the sexes
http://www.newscientist.com/article.ns?id=mg19926651.600&print=true
16 July 2008
Hannah Hoag

ANYONE in a long-term relationship will tell you that, at times, men
are indeed from Mars, and women are almost certainly from Venus.
It's common knowledge that the sexes often think very differently,
but until recently these differences were explained by the action of
adult sex hormones or by social pressures which encouraged males and
females to behave in a certain way. For the most part, the basic
architecture of the brain, and its fundamental workings, were
thought to be the same for both sexes.

Increasingly, though, those assumptions are being challenged.
Research is revealing that male and female brains are built from
markedly different genetic blueprints, which create numerous
anatomical differences. There are also differences in the circuitry
that wires them up and the chemicals that transmit messages between
neurons. All this is pointing towards the conclusion that there is
not just one kind of human brain, but two.

It's giving neuroscientists something of a headache. Most of what we
know about the brain comes from studies of male animals and male
human volunteers. If even a small proportion of what has been
inferred from these studies does not apply to females, it means a
huge body of research has been built on shaky foundations. Working
out exactly how women are different could explain some long-running
mysteries, such as why men and women are prone to different mental
health problems and why some drugs work well for one sex but have
little effect on the other.

It has long been known that some differences exist between male and
female brains, but they were widely believed to be restricted to the
hypothalamus, which is involved in regulating food intake and
controlling sex drive, among other things. Unless they were studying
the hypothalamus, researchers generally avoided using female animals
in their experiments because the ups and downs of oestrogen and
progesterone during the female menstrual cycle made interpreting
results more complicated. So, hypothalamus aside, neuroscientists
continued to believe that male and female brains were the same.

But it's becoming obvious that the hypothalamus is only the
beginning of the story. For a start, the relative sizes of many of
the structures inside female brains are different from those of
males. In a 2001 study, Jill Goldstein of Harvard Medical School and
colleagues measured and compared 45 brain regions in healthy men and
women. They found that parts of the frontal lobe, which houses
decision-making and problem-solving functions, were proportionally
larger in women, as was the limbic cortex, which regulates emotions.
Other studies have found that the hippocampus, involved in
short-term memory and spatial navigation, is proportionally larger
in women than in men, perhaps surprisingly given women's reputation
as bad map-readers. In men, proportionally larger areas include the
parietal cortex, which processes signals from the sensory organs and
is involved in space perception, and the amygdala, which controls
emotions and social and sexual behaviour. "The mere fact that a
structure is different in size suggests a difference in functional
organisation," says neurobiologist Larry Cahill at the University of
California, Irvine.

Cahill has found evidence that sex also influences how some brain
regions are used. In brain-imaging experiments, he asked groups of
men and women to recall emotionally charged images they had been
shown earlier. Both men and women consistently recruited the
amygdala - a pair of almond-sized bundles of neurons which make up
part of the limbic system - for the task. However, the men enlisted
the right side of it, whereas women used the left. What's more, each
group recalled different aspects of the image. The men recalled the
gist of the situation whereas the women concentrated on the details.
This suggests men and women process information from emotional
events in very different ways, using different mechanisms, says
Cahill.

The same may be true for the brain circuits used to dampen pain. It
is well known that women are more likely to seek help for chronic
pain than men. Some of this can be chalked up to the fact that women
use healthcare services more than men, but even taking this into
account, there's strong evidence that women - and female animals -
experience more pain than males. Not all studies show sex
differences but, when they do, it's always the females that feel
more pain.

Anne Murphy at the University of Georgia in Athens is trying to find
out why chronic pain affects women more than men. She is
particularly interested in a pain-suppressing circuit that links two
parts of the brain - the periaqueductal grey (PAG) and the rostral
ventromedial medulla (RVM) - with the spinal cord. When this circuit
is activated by a pain signal it can dampen pain by setting off a
chain reaction that leads to the release of endorphins, which bind
to opioid receptors and inhibit the pain signal. "This circuit is
the Mecca of pain modulation in humans and all vertebrates, yet no
one has asked how it is organised in females," says Murphy.

There is no clear answer yet, but Murphy's investigations have
yielded some intriguing results. Females have a denser connection
between PAG and RVM than males, yet Murphy's work suggests that this
pathway is not activated in females to suppress pain. "This pathway
is obviously not being used for pain in females, so what's the
function for it and why is it so much bigger?" she asks.

That question remains unanswered for now, but Jeff Mogil at McGill
University in Montreal, Canada, thinks he may have found at least
part of the female pain circuitry. In experiments in mice, he
chemically blocked a particular receptor found on neurons in the
mouse PAG and spinal cord. Mogil discovered that male mice use these
N-methyl-D-aspartate (NMDA) receptors to dampen pain, but that
blocking this pathway had little impact on females' ability to deal
with pain. "It suggests that females have a separate pathway that
doesn't involved the NMDA receptor," he says.

Genetic experiments in mice have since led him to suspect that
female pain inhibition may be linked to sex-specific variations in
the gene for the melanocortin-1 receptor (Mc1r), which regulates
hair and skin colour in humans and is also expressed in the PAG.
Female mice that lacked a functional version of these genes were
less able to block pain, as were female human volunteers with red
hair, who also lack functional Mc1r genes. Male redheads had no
problems blocking pain, presumably because they were using the NMDA
circuit instead.

It's early days, but if women do have a different pain-damping
circuit to men, it could explain why there are sex differences in
responses to opioid painkillers. Women get more relief from the
opioid painkiller nalbuphine compared to morphine, whereas in men
morphine is more effective and nalbuphine actually increases the
pain intensity. The findings could eventually lead to new
painkillers tailored to be more effective in women, but Mogil isn't
holding his breath. "For now there isn't a big enough and
uncontroversial enough literature in any of these differences to
justify drug development of any single one of them," he says.

Similar difficulties have blighted developments in mental health -
another area where there are known to be sex differences. Women are
diagnosed with depression twice as often as men, for example, and
their brains typically produce about half as much serotonin - a
neurotransmitter linked to depression. Earlier this year, Anna-Lena
Nordström, from the Karolinska Institute in Stockholm, Sweden, found
that healthy women have more of the most common type of serotonin
receptor than men but fewer serotonin transporters, which are needed
to recycle serotonin. It hasn't been shown that variations of this
set-up make some women more prone to depression, but Nordström
points out that transporter differences between men and women are of
particular interest because this is where antidepressants like
Prozac act, and because there is evidence that women respond better
to such drugs than antidepressants that act on neurotransmitters
other than serotonin.

Males may be less likely to suffer depression, but that doesn't mean
they get an easy ride. Boys are more likely to be diagnosed with
autism, Tourette's syndrome, dyslexia, stuttering, attention-deficit
disorder and early-onset schizophrenia. Margaret McCarthy of the
University of Maryland in Baltimore believes that hormone-like
substances called prostaglandins, which help masculinise the male
brain shortly before or after birth may be at least partly to blame.
Prostaglandins are also known to cause inflammation, so McCarthy is
investigating whether their action, if altered by infection or
certain drugs, could cause inflammation and damage to the developing
brain.

The ways in which men and women abuse drugs is another area that
could reveal brain differences. While men are almost twice as likely
as women to use cocaine, possibly due to social factors, when women
take it they get addicted more quickly and have a more severe habit
when they seek treatment.

Jane Taylor from Yale University suggested in 2007 that genetic
differences may help to explain why. She compared mice that were
engineered to either be genetically male with testes, genetically
male with ovaries, genetically female with testes or genetically
female with ovaries. She found that genetically female mice formed
drug habits more quickly than the genetically male mice, regardless
of which gonads they carried (Nature Neuroscience, vol 10, p 1398).

Jill Becker at the University of Michigan, Ann Arbor, has found
something similar. She trained rats to poke their noses into a hole
to get a dose of cocaine and compared the cocaine intake of female
rats which had had their ovaries removed with castrated male rats.
The females were bigger bingers. But when these females were given
oestrogen, their total intake nearly tripled. That means that a
genetic vulnerablility plus circulating sex hormones can add up to a
crippling addiction.

Several studies have since found that women report that cocaine has
a bigger positive effect when their oestrogen levels are high and
their progesterone levels low. Suzette Evans at the Columbia
University College of Physicians and Surgeons in New York City is
running a clinical trial to test whether cocaine-dependent women can
be treated by increasing their progesterone levels.

There's much left to learn, but as the evidence mounts for
sex-related influences on brain structure and function, the
development of medicines better suited to a woman's biology may yet
take off. Before that can occur, however, more work is needed to
uncover the differences between the brains of male and female
animals. Despite recent progress, such work is very much in the
minority.

Mogil, who has demonstrated big differences in pain processing in
males and females, is astonished that so many researchers have
failed to include female animals in their studies, especially when
it comes to pain research. "It's scandalous," he says. "Women are
the most common pain sufferers, and yet our model for basic pain
research is the male rat." On the flip side, it's also an area ripe
for exploration: "Every year or two we write a paper that says that
something someone reported earlier is actually only true in males.
We keep making people look bad. They are missing stuff completely."

The Human Brain - With one hundred billion nerve cells, the
complexity is mind-boggling. Learn more in our cutting edge special
report.

Myths and misconceptions

DON'T ASK A WOMAN FOR DIRECTIONS

Give a man a sheet of paper printed with tangled streets and he can
tell you where you need to go. But don't be afraid to ask a woman
for directions. Chances are she'll get you there, too, but using a
different technique. Drawing on her hippocampus, she'll offer you
physical cues like the bakery, the post office and the Chinese
restaurant.

MEN AREN'T EMOTIONALLY TUNED-IN

He might not remember the details of the big blow-up you had during
your honeymoon, ladies, but just because you can it doesn't mean
he's insensitive. Women are simply better at remembering the details
surrounding emotional events, because their amygdala is tuned to
capture them.

WOMEN ARE MORE TALKATIVE THAN MEN

Modern folklore claims women speak nearly three times as many words
as men. Don't believe the hype. Women and men both say 16,000 words
a day, on average.

OESTROGEN IS THE FEMALE HORMONE

While it's true that males mainly secrete testosterone from the
testes, oestrogen is important to male brain development in the
womb. In the male brain, testosterone is converted into oestradiol,
which acts on oestrogen receptors and sets the hypothalamus to
"male".

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Weblinks

Larry Cahill, UC Irvine
http://www.faculty.uci.edu/profile.cfm?faculty_id=3276
Anne Murphy, Georgia State University
http://www.biology.gsu.edu/people/faculty/person.cfm?person=3141
Jill Becker, University of Michigan
http://www.lsa.umich.edu/psych/people/directory/profiles/faculty/?uniquename=jbbecker
Society for Women's Health Research
http://www.womenshealthresearch.org