Dr. Nirao Shah on Huberman Lab: How SRY Gene Shapes Sex

Humans have 22 pairs of autosomes plus a pair of sex chromosomes (XX in females, XY in males). The critical factor is not the Y chromosome per se, but the SRY gene on it. SRY encodes a transcription factor that turns on a gene program in a bipotential gonad, driving it to become testes instead of ovaries. Testes then secrete testosterone and anti-Müllerian hormone, masculinizing internal and external genitalia and suppressing female reproductive tract development. If SRY is missing or nonfunctional, an XY individual develops as female; if SRY is ectopically present on an autosome, an XX individual can develop as male.

In a species-specific critical window (embryonic in humans, perinatal in mice), testosterone, estrogen, and progesterone organize brain circuits along male- or female-typical lines. This includes differential neuron survival, cell death, and connectivity in key hypothalamic regions. After this window, gonads go quiescent until puberty, when hormones return and ‘activate’ those pre-wired circuits to produce adult behaviors like mating, territorial aggression, and parental care. Adult hormone changes can modulate activity but generally cannot recreate circuits that were never organized in development.

In hypothalamic regions like the ventromedial hypothalamus (VMH) and preoptic area, males and females differ in neuron number, gene expression, and connectivity, especially in circuits for mating, aggression, ovulation, and maternal behaviors. Some regions show near-binary differences (e.g., neuron counts two- to threefold higher in one sex), particularly for innate behaviors. Others show overlapping continua. Crucially, some female-typical circuits (e.g., lordosis receptivity) are absent or nonfunctional in males, while some male-typical circuits (mounting) are latent but present in females and can be unmasked by testosterone or specific circuit manipulations.

Complete androgen insensitivity syndrome (CAIS) results from nonfunctional androgen receptors; XY individuals with CAIS develop as externally feminized, identify and are raised as girls, and only discover their XY karyotype when they fail to menstruate at puberty. Conversely, 5α-reductase deficiency impairs conversion of testosterone to DHT; affected XY individuals are born with feminized genitalia, raised as girls, but ‘sprout a penis’ at puberty when high testosterone levels masculinize external genitalia, and many spontaneously adopt a male identity. These natural experiments suggest strong developmental hormone effects on brain organization and identity, beyond socialization alone.

In male mice, testicular testosterone enters the brain and is converted by aromatase into estradiol in specific neuronal populations. Estradiol then acts via nuclear estrogen receptors to regulate gene expression, neuron survival, and connectivity, masculinizing key circuits. Male mice lacking aromatase show impaired male-typical sexual behavior despite normal peripheral testosterone, underscoring that local brain estrogen—not just circulating testosterone—is crucial for organizing male behavior circuits. In humans, aromatization likely plays a role, but its relative contribution vs. direct androgen action is less clear.