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

Andrew Huberman and Nirao Shah discuss the complex orchestration of genetic and hormonal factors that determine biological sex, emphasizing the importance of the SRY gene and the impact of hormones during development.

Sry Gene on Y Chromosome Determines Biological Sex

Sry Gene Triggers Testes Development, Secreting [restricted term] and Androgens to Masculinize Body and Brain

The determination of biological sex revolves around the presence of the SRY gene, which is typically located on the Y chromosome. This gene is responsible for the initial differentiation of the fetal gonads into testes. When testes develop, they secrete hormones such as [restricted term] and androgens, which masculinize the fetus's genitalia, brain, and body. Shah emphasizes that the SRY gene's presence promotes maleness and overrides the default pathway to feminization that occurs in its absence.

It is notable that the Y chromosome alone isn't the sole determinant for maleness; rather, it is the SRY gene that dictates this. This is evident as SRY can be transferred to an autosome, resulting in an XX male if the SRY gene is present. Conversely, without the SRY gene or when it has mutations, XY individuals can develop as females. Furthermore, Shah points out that there is no parallel gene for femaleness; in the absence of SRY, the default genetic pathway for mammals is female development.

Hormonal Exposure During Development Shapes Brain and Body Permanently

Early Development: [restricted term] and Androgens Can Masculinize Genetically Female Individuals

During critical periods of development, exposure to hormones like [restricted term] and androgens has the potential to permanently influence the brain and body, leading to masculinization. Huberman and Shah discuss how this hormonal presence during early development can have a profound impact on individuals with XX chromosomes. Shah talks about how congenital adrenal hyperplasia, a condition resulting in increased androgen production, can cause female babies to be born with masculinized external genitalia that can be surgically corrected. Similarly, Huberman references instances where individuals with XX chromosomes exposed to excessive androgens during development experience a disconnection from their genetic sex, suggesting a misalignment with their gender identity.

In cases of intersex conditions, deficiencies in enzymes involved in the processing of hormones, such as 5-alpha reductase, can alter physical sex characteristics as individuals mature. For example, a mutation that prevents the conversion ...

Nirao Shah and Andrew Huberman's discussions reveal that there are profound differences between male and female brains in terms of structure, connectivity, and gene expression, influenced by hormones and genetics.

Sex Differences in Neuronal Connectivity in Brain Regions

Neuron Survival and Pruning in Male and Female Brains Differ By Sex Hormones

Shah's lab has discovered notable disparities between the brains of female and male mice—including structure, neuron numbers, and gene expression. Hormones during prenatal development play a crucial role, with [restricted term] and estrogen contributing to cell loss in one sex, a process Shah emphasizes cannot be reversed in adulthood. [restricted term], which is converted into estrogen in the brain, prompts certain cells to survive in the male brain—this cell survival relates directly to behavioral differentiation between the sexes.

Brain Structure Sex Differences May Underlie Behavioral and Functional Differences

In specific brain regions that drive innate behaviors, such as mating or aggression, these sex-based differences emerge starkly, sometimes showing a twofold to threefold difference in cell numbers between sexes. Shah notes that there is a pathway that is practically nonexistent in the male brain but dimorphic in the female brain, suggesting this could be the basis for varied behaviors and functionality between the sexes.

Sex Hormones Reshape Neural Circuits, Especially In Females

Estrous Cycle Influences Female Sexual Behavior Circuits

Hormonal fluctuations linked to the estrous cycle significantly alter the female rodent's brain function, analogous to the human menstrual cycle. Estrogen-responsive neurons change the number of dendritic spines, thereby impacting neural communication. These neurons show threefold activity fluctuations during the cycle, reflecting profound neural circuitry changes.

Brains Use Distinct Sex Recognition Pathways

Shah delves into the importance of sex recognition in social interactions and elucidates that separate brain circuits in males and females enable them to identify the sex of other individuals effortlessly. He indicates that male and female mice utilize different brain circuits for this purpose, effectively creating distinct perceptions of reality based on the reception of ...

In a nuanced discussion, Huberman and Shah explored the complexities surrounding biological sex, gender identity, and the separate concept of sexual orientation, noting the significant variances and influences that contribute to each.

Biological Sex Differs From Self-Identified Gender

Mismatch Between Biological Sex and Gender Identity

The conversation highlighted that biological sex might not always align with societal binary categories, a concept historically recognized in various cultures through the acknowledgement of intersex individuals. Huberman and Shah noted instances beyond the SRY gene's effect, where individuals might be raised in a gender that contradicts their genetics but still willingly choose to affirm their gender identity at puberty, aligning more closely with their genetic makeup.

Nirao Shah illustrated this with androgen insensitivity syndrome cases, where individuals are unresponsive to [restricted term] and biologically feminized, behaving as females despite their genetic sex. Notably, individuals with congenital adrenal hyperplasia, a condition affecting genital appearance, could experience a potential mismatch between biological sex and gender identity.

Andrew Huberman recounted the transition of neurobiologist Ben Barres, born Barbara, who felt discontent with his biological sex from a young age and chose to transition. Barres, who had speculated the influence of pro-[restricted term] properties from an anti-miscarriage drug taken during gestation, exemplifies that one’s self-identified gender might conflict with biological sex despite the organizing effects of sex hormones.

Mismatch Can Occur Despite Sex Hormones' Organizing Effects

Huberman and Shah also discussed cases implying mismatches between biological sex and gender identity, despite the usual sex hormones' organizing effects during developmental stages. Gender is characterized as encompassing a constellation of behaviors and societal roles beyond biological sex, indicating that gender identity can manifest divergently from hormonal influences.

Sexual Orientation Is Separate From Biological Sex and Gender Identity

Sex Hormone Levels Similar in Homosexuals and Heterosexuals

Huberman pointed out that sexual orientation does not seem to correlate with the levels of sex hormones in adulthood. He cited data showing no significant difference in androgens or estrogen between heterosexual and homosexual individuals. This disassociation reinforces the ...

The structure and function of mouse and human brains share both striking similarities and remarkable differences, particularly in the evolutionary conservation of certain brain regions and in the expansion and flexibility provided by the human cortex.

Evolutionary Conservation of Hypothalamus and Deep Brain Regions in Mice and Humans

Nirao Shah and Andrew Huberman discuss the deep conservation of the hypothalamus and related brain structures in both mice and humans, evidencing the preservation of critical survival and behavioral functions across species.

Circuits Controlling Behaviors Like Sex, Aggression, Parenting Are Conserved

The hypothalamus in mice, containing the ventromedial hypothalamus and the preoptic area, controls behaviors such as aggression, female sexual behavior, maternal actions, and male sexual behavior, and these structures are identifiable counterparts in the human brain. Shah notes that these regions are conserved because they regulate essential survival functions including reproduction, aggression, care for young, thirst, and temperature control.

Nirao Shah mentions that in mice, the brain is bipotential at birth but is influenced by hormones like [restricted term], leading to differences in neuron survival in male and female mice, with specific brain regions developing more neurons in one sex compared to the other. Experiments have shown that altering the hormonal environment can change territorial and sexual behavior in mice, a pattern likely conserved in humans.

Furthermore, Shah discusses the relevance of non-sex determining genes, like the hox genes, Pax6, which are highly conserved from birds to humans, and the periaqueductal gray (PAG), involved in innate behaviors such as fight or flight and lordosis behavior.

Shah's research provides evidence for a hierarchy of behaviors, including mating, aggression, and protecting the young, which suggests regulatory structures for these behaviors are conserved in both mice and humans. He describes activating certain brain cells in mice to induce aggressive behavior unless the context suggests danger or a non-territorial situation, which could inhibit aggression. This implies that similar neural circuits are likely to ...