Male vs. Female Brain Differences & How They Arise From Genes & Hormones | Dr. Nirao Shah

Dr. Shah’s group discovered these neurons by using optogenetics to activate a genetically defined set of cells in the preoptic area. The mouse strain used typically has a 4–5 day period after ejaculation during which he will not mate again, even with a new female. When they turned on these TACR1 neurons with light, the males began mating again within a second and could ejaculate again, continuously, as long as the light remained on. Moreover, if the mice were given an opportunity to self-stimulate these neurons by poking their nose into a port, they would do so repeatedly, even if they had never mated before—indicating the neurons inherently encode reward. These cells project to the ventral tegmental area, activating dopamine neurons and causing dopamine release in the nucleus accumbens, which likely mediates the pleasurable aspect of sex. When the neurons were activated in the presence of an object that merely resembled a mouse (like a test tube with a tail glued on), the mice would attempt to mount it, demonstrating that these cells lower the threshold for initiating mating behavior to the point where minimal sensory cues are sufficient.

Dr. Shah described the heroic effort it took to develop the technology to make a knockout prairie vole, a process that took 10–15 years. Once they succeeded in knocking out the oxytocin receptor, they found that these voles still formed pair bonds after mating, just like normal littermates. They remained monogamous and even rejected other potential mates. This suggests that the role of oxytocin may be redundant, with vasopressin being the prime candidate for compensation. Dr. Shah argued that if a behavior as crucial as pair bonding (vital for raising offspring) is so important, it would be surprising if evolution didn't build in redundancy. However, he contrasted this with the SRY gene, which has no redundancy—highlighting that nature doesn't always provide backup plans for essential functions. The story illustrates the complexity of translating pharmacological blocking studies to genetic loss-of-function.

Dr. Shah’s group found that in the adult female mouse, a specific pathway in the hypothalamus essentially grows and retracts by about three-fold over the 4–5 day ovulatory cycle. At the time of ovulation, when the pathway is fully present, if they artificially inhibited this pathway, the female stopped mating. This indicates that the structural changes are functionally relevant for reproductive behavior. In males, this pathway is essentially absent, consistent with it being required for female-specific behavior. The dynamic rewiring is driven by the fluctuating levels of estrogen and progesterone. This challenges the notion that brain circuits are fixed after a critical developmental period and shows that, at least in females, the adult brain can undergo rapid, hormone-dependent reorganization.

Dr. Shah’s lab recorded from these cells and found that their activity naturally encodes the sex of a conspecific within the first 5–10 seconds of interaction. In male mice, a robust signal persists for about 90 seconds when facing a female, and a smaller signal when facing a male. They then showed that by optogenetically activating these neurons for 90 seconds while a male encounters another male, the experimental mouse will treat the intruder as a female for the next 15–20 minutes—mounting him and attempting to mate, despite all sensory evidence indicating it's a male. Conversely, if they silence or kill these neurons, the male no longer shows preference for female odors and does not mate with females or attack other males; he becomes completely indifferent. This demonstrates that these few thousand cells are necessary and sufficient for guiding appropriate social behavior based on sex. Importantly, recording from the same cells in female mice showed they are quiescent, indicating that females use a different circuit for sex recognition, suggesting that male and female brains are wired to perceive social reality differently at a very fundamental level.

Dr. Shah recounted that David Edwards gave testosterone to adult female mice as a control and was surprised to see them display male-typical mounting. This indicated the circuit is present in females but requires testosterone to activate. Later work by Catherine Dulac showed that if pheromone sensing is ablated, females will also mount like males without any hormone treatment, as if there is a tonic inhibition from the olfactory system that suppresses male behavior. This dual control—lack of testosterone and active inhibition—keeps the male circuit silent in females. Conversely, the female sexual behavior circuit (lordosis) is not present in males, as giving estrogen and progesterone to adult males does not induce receptivity. This asymmetry suggests that evolutionary pressures may have conserved the male circuit in both sexes while allowing the female circuit to be lost in males.