In animals with social structures, the drive to reproduce is a complex process; governed by the brain, it's influenced by both internal cues such as hormones and external factors such as interactions with potential mates.
One area long known to play a critical role is the prefrontal cortex (PFC). Located just behind the forehead, this node governs various aspects of social behavior. In a recent paper in Cell, researchers at Rockefeller University's Laboratory of Molecular Biology, led by Nathaniel Heintz, have determined how a subregion of the PFC influences the reproductive drive in mice: through a hormonally primed cortical circuit that controls how and when female mice seek to mate with males. The circuit, which connects to multiple layers of the brain, is stimulated by both the "love hormone" oxytocin and ovarian hormones.
"The circuit integrates hormonal states with the recognition of potential mates to orchestrate complex cognitive behaviors," says Ines Ibañez-Tallon, research associate professor in the lab and co-author of the study.
Intriguingly, male mice also have this circuit, but its activation has the opposite effect in them: they become less interested in mating.
"This shared circuitry is flexibly sculpted by both hormonal state and biological sex to produce sex-specific patterns of social behavior," says senior co-author Kun Li, a former Ph.D. student in the lab and now an associate professor in the School of Life Sciences at Tsinghua University. "It could help explain why sexual motivation and social interest fluctuate across reproductive states and differ between sexes."
Sexual dimorphism in the brain
The paper builds upon earlier findings from the lab. In 2014, the researchers discovered a new type of brain cell in the medial prefrontal cortex (mPFC) that they dubbed oxytocin receptor-expressing neurons (OxtrINs). Oxytocin is a hormone linked to bonding of all kinds-maternal, familial, romantic, social. In mice, the team found, the OxtrINs cortical circuit promoted receptivity to mating-but only in females, and only during estrus, or the fertile period.
Intrigued by the idea that a cell type identical in male and female mice could affect them very differently, the researchers, led by Heintz and Ibañez-Tallon, conducted additional studies that further documented OxtrIN's uneven influence. In a 2016 study, they found that the activation of OxtrINs reduce anxiety-related behavior in male mice but not in female mice. While it did not alter anxiety levels in female mice, it did, however, cause the females to show more social preference for male mice.
While both discoveries pointed to a critical role for the mPFC in adaptive social behaviors dependent on reproductive states, "how the mPFC senses internal hormonal states and regulates flexible control over social behavioral outputs remained unclear," Li says.
For the current study, some of which was conducted at Tsinghua University, the researchers aimed to dive into those details.
The circuit
The previous research had located oxytocin-sensitive neurons in multiple layers of the mPFC. For the current study, Li and colleagues homed in on layer 5, which sends information to other areas of the brain. They identified neurons in this layer that expressed the Cacna1h gene, which produces calcium channels-electrical switches that neurons use to communicate. They then traced its connections into the anterior hypothalamic nucleus (AHN) region of the hypothalamus, an ancient, hormonally driven part of the brain that regulates basic needs such as hunger, thirst, and sleep, as well as sexual behaviors.
They then used a variety of advanced techniques to monitor neural activity in the female mice's brains as they went through a full estrus cycle-the equivalent of a human menstrual cycle-and interacted with male mice. The Cacna1h+ neurons turned out to be highly responsive to ovarian hormones, lighting up when the mice were fertile. During this period, the female mice sought out the male mice more, rejected them less, and showed heightened sexual receptivity.
Putting it all together, the team determined that Cacna1h+ neurons are a hormonally influenced critical subset of neurons that respond to prompts from oxytocin via OxtrINs, receiving social cues, and the AHN, which reads internal signals, resulting in sociosexual behavior.
However, manipulating the neurons changed that behavior in diametrically opposed ways in the mice. When Li turned on the Cacna1h neurons in female mice during the nonfertile period, the mice began to act as if they were hormonally prepped to mate. And when she inhibited the neurons during estrus, the mice lost all interest.
The opposite was true for the male mice, whose brain activity was also monitored. Silencing the Cacna1h+ neurons in male mice spiked their interest in female mice, and they were quicker to try to mate with them. And activating the neurons suppressed male sexual behaviors.
The circuit seems to have a feedback loop as well. That is, not only can Cacna1h+ neural activity initiate behavior, but behavior can activate the neurons themselves.
In estrus females, these neurons were strongly activated by male cues and promoted sociosexual interest and sexual receptivity, while in males these neurons did not respond to female cues, and the male mice showed reduced interest.
"It's fascinating," Ibañez-Tallon says. "Even when the neural circuitry, neuronal populations, and molecular components are identical-differing only in their levels of expression-the system can produce remarkably distinct functional outcomes."
While this study focused on ovarian hormones, in the future they'll look into the influence of testosterone, which has well-established links to depression, schizophrenia, anxiety, and other disorders.
"Given the strikingly different functional roles of Cacna1h+ neurons in males, it's likely that testosterone plays a key role in their development or responsiveness," Li says. "This line of research could provide valuable insights into the sex-specific regulation and vulnerability of social and emotional behaviors."
