An experiment with mice finds the switch of female sexual rejection

“Sexual rejection is not just the absence of receptivity, it is an active behavior,” explains Susana Lima, lead author and head of the foundation’s Neuroethology Laboratory. «Females show defensive actions such as fleeing, kicking or hitting the male. “We wanted to understand how the brain switches between these two drastically different behavioral states.”

To do this, they studied the ventromedial hypothalamus (VMH) of mice, an evolutionarily ancient brain region that controls social and sexual behavior in all species, including humans. The team focused on the anterior VMH, a less explored area, particularly on cells that respond to the hormone progesterone, which fluctuates throughout the reproductive cycle. “These neurons are ideal for studying how the female brain oscillates between acceptance and rejection during the cycle,” says first author Nicolás Gutiérrez-Castellanos. “It is a striking example of how the same stimulus (in this case, an anxious male) can provoke completely opposite behaviors, depending on the internal state of the female,” he adds.

Using advanced techniques such as fiber photometry (which tracks brain activity in real time by measuring calcium signals), the researchers observed the behavior of these progesterone-sensitive neurons in receptive and non-receptive female mice during interactions with males. In this way, they observed how anterior VMH neurons became very active in non-receptive females, which correlates with defensive actions such as kicking and boxing, but were much less active in receptive females.

“It appears that progesterone-sensitive neurons in the ventral anterior hemisphere act as gatekeepers of sexual rejection,” says co-senior author Basma Husain. «When a female is outside her fertile window, these neurons become very active, which causes rejection. But during fertility, their activity decreases, allowing mating to occur.”

On and off

How are these neurons activated or deactivated depending on fertility? To investigate this, the team performed electrophysiology experiments, measuring the activity of progesterone-sensitive neurons in brain slices. “We discovered that in non-receptive females, these neurons received more excitatory signals, which made them more likely to activate,” explains Gutiérrez-Castellanos. «In receptive females, they received more inhibitory signals, which reduced their probability of activation. “It’s a testament to how adaptable and flexible the neural connections in the hypothalamus (and brain) can be.”

The researchers artificially stimulated these neurons during the fertile phase, prompting rejection behaviors such as kicking and punching. “It’s like turning on a switch: although the females were fertile, they acted as if they were not,” says co-lead author Basma Husain.

In contrast, silencing these neurons with a chemical drug in non-receptive females reduced rejection behaviors, although interestingly it did not make them fully receptive, indicating that two distinct populations of neurons, one controlling rejection and the other receptivity, They work together to produce the appropriate behavior according to the internal state of the female.

“This setting gives the brain two ‘knobs’ to adjust,” Lima explains. “It is a more efficient and robust way for the brain to balance these behaviors, ensuring that mating occurs when conception is most likely, while minimizing the risks and costs of mating, such as exposure to predators or diseases.”

According to Husain, “this dual system is likely to add flexibility to the brain’s regulation of sexual behavior. Sex is not deterministic. “Even during the receptive phase, a female can reject males, so the ability to draw on both sets of neurons may allow for more nuanced and dynamic behaviors.”

Notably, these findings are consistent with recent research showing that progesterone-sensitive neurons in the posterior VMH, which drive sexual receptivity, undergo similar cycle-dependent changes, but in the opposite direction: active during the fertile phase and inactive outside. her.

“The VMH exists in humans and probably performs similar functions,” says Lima. «Recent studies in mouse models have shown that VMH changes in pathological conditions such as polycystic ovary syndrome. Furthermore, social isolation of female mice during development can lead to reduced sexual receptivity, with alterations in the same brain area, underscoring the clinical relevance of VMH.”

“We are just beginning to understand how the internal wiring of the brain organizes social behavior,” concludes the researcher. “There is much left to learn, but these findings bring us one step closer to understanding how neural mechanisms and internal states drive complex social interactions, from sexual behavior to aggression and beyond.”