Caltech Neuroscientists Unlock Secrets of How the Brain Is Wired for Sex

PASADENA--There are two brain structures that a mouse just can't do without when it comes to hooking up with the mate of its dreams--and trying to stay off the lunch menu of the neighborhood cat. These are the amygdala, which is involved in the initial response to cues that signal love or war, and the hypothalamus, which coordinates the innate reproductive or defensive behaviors triggered by these cues.

Now, neuroscientists have traced out the wiring between the amygdala and hypothalamus, and think they may have identified the genes involved in laying down the wiring itself. The researchers have also made inroads in understanding how the circuitry works to make behavioral decisions, such as when a mouse is confronted simultaneously with an opportunity to reproduce and an imminent threat.

Reporting in the May 19 issue of the journal Neuron, David Anderson, Caltech's Roger W. Sperry Professor of Biology and a Howard Hughes Medical Institute investigator, his graduate student Gloria Choi, and their colleagues describe their discovery that the neural pathway between the amygdala and hypothalamus thought to govern reproductive behaviors is marked by a gene with the rather unromantic name of Lhx6.

For a confirmation that their work was on track, the researchers checked to see what the suspected neurons were doing when the mice were sexually aroused. In male mice, the smell of female mouse urine containing pheromones was already known to be a sexual stimulus, evoking such behaviors as ultrasonic vocalization, a sort of "courtship song." Therefore, the detection of neural activity in the pathway when the mouse smelled the pheromones was the giveaway.

The idea that Lhx6 actually specifies the wiring of the pathway is still based on inference, because when the researchers knocked out the gene, the mutation caused mouse embryos to die of other causes too early to detect an effect on brain wiring. But the Lhx6 gene encodes a transcription factor in a family of genes whose members are known to control the pathfinding of axons, which are tiny wires that jut out from neurons and send messages to other neurons.

The pathway between the amygdala and hypothalamus that is involved in danger avoidance appears to be marked by other genes in the same family, called Lhx9 and Lhx5. However, the function of the circuits marked by these factors is not as clear, because a test involving smells to confirm the pathways was more ambiguous than the one involving sexual attraction. The smell of a cat did not clearly light up Lhx9- or Lhx5-positive cells. Nevertheless, the fact that those cells are found in brain regions implicated in defensive behaviors suggests they might be involved in other forms of behaviors, such as aggression between male mice.

The researchers also succeeded in locating the part of the mouse brain where a circuit-overriding mechanism exists when a mouse is both exposed to a potential mate and perceives danger. This wiring is a place in the hypothalamus where the pathways involved in reproduction and danger avoidance converge. The details of the way the axons are laid down shows that a mouse is clearly hard-wired to get out of harm's way, even though a mating opportunity simultaneously presents itself.

"We also have a behavioral confirmation, because it is known that male mice 'sing' in an ultrasonic frequency when they're sexually attracted," Anderson explains. "But when they're exposed to danger signals like predator odors, they freeze or hide.

"When we exposed the mice to both cat odor and female urine simultaneously, the male mice stopped their singing, as we predicted from the wiring diagram," he says. "So the asymmetry in the cross-talk suggests that the system is prioritized for survival first, mating second."

The inevitable question is whether this applies to humans as well. Anderson's answer is that similarities are likely, and that the same genes may even be involved.

"The brains of mice and humans have both of these structures, and we, like mice, are likely to have some hard-wired circuits for reproductive behavior and for defense," he says. "So it's not unreasonable to assume that some of the genes involved in these behaviors in mice are also involved in humans."

However, humans can also make conscious decisions and override the hard-wired circuitry. For example, two teenagers locked in an amorous embrace in a theater can ignore a horrid monster on the screen and continue with the activity at hand. In real-life circumstances, they would be more inclined to postpone the groping until they were out of danger.

"We obviously have the conscious ability to interrupt the circuit-overriding mechanism, to see if the threat is really important," Anderson says.

Gloria Choi, a doctoral student in biology, did most of the lab work involved in the study. The other collaborators are Hongwei Dong and Larry Swanson, a professor at USC who in the past has comprehensively mapped the neural wiring of the rat brain, and Andrew Murphy, David Valenzuela, and George Yancopoulos at Regeneron Pharmaceuticals, in Tarrytown, New York, who generated the genetically modified mice using a new high-throughput system that they developed, called Velocigene.