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Genes, not just hormones, make sexes behave differently

Differences between males and females in behaviour are usually chalked up to sex-specific hormones, but a study released Sunday shows that genes play a critical role too.
Experiments at Yale University with mice revealed that sex chromosomes alone are enough to account for the fact that females, for example, are more likely to be creatures of habit.

The results, published in the British journal Nature, have important implications for understanding the origins of addiction, and could one day lead to treatments targeting the genes involved.

"This is the first time that any behaviour has been associated specifically with sex chromosomes independent of gonadal hormones," the study's lead author, Jennifer Quinn of Yale University.

Scientists have long observed that female mammals -- whether four-legged ones that squeak or two-legged one that talk -- tend more than males toward habit-forming behaviour, including addiction.

Sex-specific hormones regulated by gonadal organs explained part of the difference, but not all.

To find out whether genes also played a role in the Mars-Venus divide, a team of scientists led by Yale's Jane Taylor devised an elaborate set of experiments involving made-to-order mutant mice.

Through genetic manipulation and breeding, the researchers came up with two mice variants in addition to normal males and females: one mouse with male gonads but female sex chromosomes, and another with female gonads and male sex chromosomes.

This made it possible to measure the impact of hormones and genes separately.

In the experiments, mice in each of the four groups figured out on their own which of three side-by-side openings led to food.

What started out as goal-directed behaviour -- the search for something to eat -- rapidly became habit: within days, all the mice scampered straight to the correct door without even hesitating.

The mice with XX chromosomes -- normal females, and mice with a mix of female chromosomes and male gonads -- learned the drill more quickly, a first indication that genes help explain the difference in habit formation across the sexes.

At the end of a nine-day training period, half of each group was subjected to what the researchers call "conditioned taste aversion" -- three daily injections of lithium chloride right after a free meal, in a new setting.

"The drug makes the animals feel sick," causing them to shy away from food associated with that feeling, said Quinn, offering an analogy.

"If you drink too much creme de menthe, in the future you may want to avoid anything that has a minty flavour. It is something humans experience all the time," she said.

Two days after the last shot, the mice were given a "test" to see if they would poke their noses in the same hole where they found food during the training period, except that this time there was none.

The two variants of XX mice with female chromosomes -- one with male, the other with female gonads -- who had been given the nausea-inducing drug both made a beeline for the right opening. The XY mice performed less well.

This showed not only the the XX chromosome mice developed stronger habits, but that these habits were independent of hormones.

Just to be sure, the researchers repeated the experiments after removing the rodents' gonads.

Interestingly, when the experiment was repeated with a longer training period -- 15 days instead of nine -- the XY, or male, mice showed the same level of habit formation as females, highlighting the delicate balance between rote behavior and more "thoughtful" goal-oriented action.

Quinn said the study points in two directions for future research.

"We think the results may be applicable to addiction and its compulsive nature, but nobody has tested whether there is such a sex difference independent of hormones in a drug habit," she said.

Building on previous research showing that mice become addicted more easily to alcohol than to sugar, Quinn and her colleagues would like to see if that is more true for females than males.

The second line of inquiry concerns a possible treatment for addiction.

"So far, we have established that genes are involved independent of hormones, but we don't know yet which ones," Quinn said.

Once they are identified, drugs targeting those genes "could potentially revert someone from a habitual responder" -- an addict -- "back to a goal-directed responder," she added.

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