How the brain is wired for sex

Two brain structures a mouse just can’t do without when hooking up with its dream mate—and trying not to become lunch for the neighborhood cat—are the amygdala and hypothalamus. The former is involved in the initial response to cues that signal love or war, while the latter coordinates innate reproductive or defensive behaviors triggered by these cues.

Now, neuroscientists have traced out the wiring between the amygdala and hypothalamus, and may have identified the genes involved in laying down the wiring itself. The researchers have also gained an understanding of 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.

In the May 19 issue of the journal Neuron, David Anderson, Caltech’s Sperry Professor of Biology and a Howard Hughes Medical Institute investigator, his graduate student Gloria Choi, and colleagues Hong-wei Dong and Larry Swanson (USC) and Andrew Murphy, David Valenzuela, and George Yancopoulos (Regeneron Pharmaceuticals) describe their discovery that the neural pathway between the amygdala and hypothalamus thought to govern reproductive behaviors is marked by a gene with the unromantic name of Lhx6.

To confirm their work, the researchers checked the suspected neurons when the mice were sexually aroused. In male mice, the smell of female mouse urine containing pheromones is a sexual stimulus, evoking such behaviors as ultrasonic vocalization, a sort of “courtship song.” Therefore, the detection of neural pathway activity when the mouse smelled the pheromones was the giveaway.

The idea that Lhx6 actually specifies the pathway wiring 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 that are known to control the pathfinding of axons—tiny wires that jut out from neurons and send messages to other neurons.

The pathway between the amygdala and hypothalamus involved in danger avoidance appears to be marked by other genes, Lhx9 and Lhx5, in the same family. However, the function of these circuits 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 located the brain area in the hypothalamus where a circuit-overriding mechanism exists when a mouse is exposed both to a potential mate and to danger. The layout of axons in the wiring shows that, in such a situation, a mouse is clearly hardwired to get out of harm’s way. The researchers’ prediction was also behaviorally confirmed.

Mice are known to freeze or hide when they sense danger, and when exposed to cat odor and female urine simultaneously, the male mice stopped their pheromone-induced “singing.” “So the asymmetry in the cross talk suggests that the system is prioritized for survival first, mating second,” Anderson says.

Anderson believes similarities are likely in humans, as mice and humans both have these brain structures, “and we, like mice, are likely to have some hardwired circuits for reproductive behavior and for defense,” he says.

However, humans can also consciously override the hardwired circuitry. For example, two teenagers in an amorous embrace in a theater can ignore an on-screen monster. In real-life circum-stances, they would more likely 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.

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