What makes Mickey Mouse attracted to Minnie Mouse? It has been known that male rodents are allured by the scent of the opposite sex.But researchers have now discovered how a mechanism in the brain that processes behavior- changing chemical signals called pheromones determines the sexual preference of male mice – and motivating them to prefer females over males.Earlier studies in the lab of Prof. Tali Kimchi of the Weizmann Institute of Science’s neurobiology department focused on the link between sexual preference in mice and the vomeronasal organ (VNO), a scent-sensing system that unlike the nose, responds mainly to pheromones. The VNO has lost its function in humans, but plays a role in directing the behavior of numerous animals.Kimchi’s team had shown that genetically engineered male mice lacking a functioning VNO showed no aggression toward other males, and were equally interested in mating with males and females. When the researchers exposed them to negative conditioning against female pheromones, they began to avoid mating with females but continued to display a sexual behavior toward males. In other words, they were able to distinguish between genders.These findings suggested that without the pheromone signals processed by the VNO, male mice could easily lose interest in females.In the new Rehovot study just published in the journal Cell Reports, Dr. Yamit Beny- Shefer – who was a doctoral student at the time of the study – and other members of Kimchi’s team revealed the neural circuit responsible for the sexual preference of male mice.They showed that the female pheromones activate a reward mechanism which begins with the release of the neurotransmitter dopamine. This, in turn, stimulates a “pleasure center” – the neuronal cluster called nucleus accumbens. In the absence of this stimulus, the males showed no preference for females. Dr. Noga Zilkha, a member of the team, explained, “It’s been known that sexual stimuli activate the brain’s reward system. That’s not news. What’s new in our findings is that the activation of a certain reward mechanism plays a critical role in determining the sexual preference of male mice for females – a preference that’s essential for reproduction.In one set of experiments, the researchers let a female mouse into a cage housing a male that was engineered to lack a VNO.Dopamine levels rose sharply in the brains of regular males, but not in the brains of engineered mice. The behavior of the two groups of males differed accordingly: Regular mice exhibited a sexual behavior toward females and aggression toward males; the engineered mice, on the other hand, showed almost no aggression toward males and were equally sexual toward males and females.Next, the researchers managed to create a preference for females in the engineered mice by manipulating the pleasure center in their brain.They employed optogenetics, a method that makes it possible to activate or neutralize certain neurons with great precision by exposing them to a microscopic light beam. They were thus able to bypass the pheromone-processing mechanism lacking in these mice, directly simulating the effects of dopamine in their “pleasure center.”As the male mice were stimulated, they were placed in close proximity with females so that the reward mechanism was activated just when females were around, creating a kind of conditioning.Following such conditioning, these mice showed a marked sexual preference for females, similar to that of regular mice, although they retained a certain level of sexual interest in males and their behavior toward other males remained non-violent.After establishing the connection between activation of the “pleasure center” and sexual preference, the researchers further investigated this neuronal circuit in greater detail. They injected into the brains of non-engineered mice a molecule that blocks D1 dopamine receptors in the brain. The blockage of this neuronal circuit eliminated the sexual preference of the males toward females. Even some two weeks after the blockage, these mice still showed no preference for females.