Sex Differences in the Brain

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Written by Brett Weiss

October 2019

Image by Clker-Free-Vector-Images from Pixabay

Biological differences clearly exist between males and females.  Major biological differences that distinguish the sexes relate to brain structure and hormonal regulation of brain activity, which result in differences in behavior.  Defining these differences has proven difficult and very complex.  The following will present information on sex differences in brain structures, hormonal effects in the brain, resulting behavior, genetics, and disease presentation.

The first major anatomical sex difference discovered in the mammalian brain, named the sexually dimorphic nucleus of the preoptic area, has cells that that express a protein (Calbinidin-D28k) that distinguishes this region from others (McCarthy et al., 2015).  Located in a region toward the front of the brain and above the eyes, this brain region has similar numbers of neurons between sexes at birth.  Early in development, though, the region becomes smaller in females between postnatal days six and nine due to higher numbers of cells undergoing cell death (apoptosis) and DNA fragmentation in females (McCarthy et al., 2015).  To date, the origins of this sex difference remain somewhat of a mystery; however, many researchers speculate that cellular mechanisms related to estradiol (major sex hormone of females) play a role in size of this structure (McCarthy et al., 2015).  After the discovery of sex differences in volume of the sexually dimorphic nucleus of the preoptic area, researchers discovered other regions in ferret, sheep, and primates including humans that differed in size between sexes.  Several of the regions were found to be larger in one sex than the other, the majority of larger structures present in males.  Another such region differing in volume between the sexes includes the anteroventral periventricular nucleus, which is actually larger in females (McCarthy et al., 2015).  Studies have shown that this cluster of neurons (nucleus) in the brain plays a role in reproductive physiology with control over the release of reproductive hormones (gonadotropin-releasing hormone which also controls release of luteinizing hormone) (McCarthy et al., 2015).

Hormone levels in the brain influence density of brain cell connections (synapses) which may then influence behavioral patterns (McCarthy et al., 2015).  For instance, studies of the hippocampus (regions on either lower side of the brain) have revealed that differences exist in dendrite (end of neurons receiving signals) morphology and synapse patterning (McCarthy et al., 2015).  The preoptic area of the brain has been studied in mice with interesting findings related synapse patterning as well.  The studies have related synaptic patterning to adult male sexual behavior (McCarthy et al., 2015).  In mice, the researchers found that estradiol, after aromatization from testosterone, activates expression of genes, Cox-1 and Cox-2, which increases the production of a prostaglandin, PGE2 (McCarthy et al., 2015).  Although prostaglandins normally associate with inflammation and fever, PGE2 acts through a cellular cascade which results in the formation and stabilization of dendritic spines of synapses (McCarthy et al., 2015).  The result of this cascade includes dendritic spine density twice as high in males compared to females, which remains stable throughout life.  The higher spine density per unit of dendrite in males has correlated with male copulatory behavior such as frequency and latency to mounting receptive females (McCarthy et al., 2015).  Interestingly, injecting female pups with PGE2 into the brain during the ‘critical period’ of development fully masculinized the synaptic patterning of the pups, which also resulted in the display of male copulatory behavior in adulthood in the absence of hormonal treatment (McCarthy et al., 2015).  This study constituted the first report of a chemical other than testosterone or estradiol which was both necessary and sufficient for masculinization of a neuroanatomical and a behavioral endpoint (McCarthy et al., 2015).  The injection of PGE2 had specific behavioral effects and did not affect female maternal behavior or emotionality (McCarthy et al., 2015).

Microglia display differences in males and females.  Microglia constitute the primary immune cells of the brain and the central nervous system in general.  Microglia act as macrophages (cells which phagocytose or ‘eat’ stressed or dying neurons).  Microglia also respond to and produce prostaglandins, which means that they may very well positively reinforce the effects of the prostaglandin PGE2 (McCarthy et al., 2015).  Microglia have an ameboid-like shape when inactivated or “quiescent” and have a highly ramified shape when “activated” or “surveying” for injured or dying neurons (McCarthy et al., 2015).  In males, in studies of the preoptic area, more microglia were found with ameboid or round shape that produced more of the prostaglandin PGE2 than those in females (McCarthy et al., 2015).  When female mice were treated with a masculinizing dosage of estradiol or PGE2, their microglia took on an “activated” shape and increased their production of the prostaglandin, PGE2, a positively reinforcing response (McCarthy et al., 2015).  Thus, microglia also appear to play a role in the masculinization of behavior in mice, which could very likely translate into the masculinization of synapses and subsequent behavior in humans.

From a genetic standpoint, males have an X and a Y sex chromosome, while females have two X chromosomes (males have XY and females have XX).  Direct sex chromosome effects include the effects of the SRY gene of the Y chromosome, known for its role as essential for development of the testis (McCarthy et al., 2017).  Genetically modified mice with XX genotype (female under typical circumstances) and with the Sry gene inserted into the genome resulted in XX individuals with testis (McCarthy et al., 2017).  The SRY gene has also associated with production of dopaminergic neurons, which may explain why males are more susceptible to dopamine disorders such as Parkinson’s disease and schizophrenia (McCarthy et al., 2017).  Furthermore, the powerful tool of translocating genes from sex chromosomes has provided evidence that many other sex differences in brain and behavior can be linked to specific loci on either sex chromosome, including neural tube defects and pain perception (McCarthy et al., 2017).  One may wonder also how these genetic differences between male and female affect brain structure and subsequent behavior.

In order to break down behavioral differences between males and females, an exploration of the evolution of sex differences, which shapes genetics, must ensue.  In species in which two cells (the gametes) must fuse for reproduction, two distinct sexes result which produce the two cell types.  Evolutionary pressures, which depend on the ecology of the species, acting on each sex drive further sex differences (Choleris et al., 2018).  In other words, different pressures from the environment act on each sex differently as they pursue survival and reproduction.  In order to explain these pressures on each sex, Charles Darwin, the father of evolutionary theory, proposed the theory of ‘sexual selection.’  In this theory, Darwin explained two evolutionary factors that drive the distinction between the sexes.  The first relates to intrasexual competition, usually among males, where access to reproduction is available to only a few members of the sex.  The second entails intersexual choice, which means that the mating preferences of one sex (often female) influences the evolution of specific traits in the opposite sex.  Although intrasexual competition and intersexual choice explain traits affecting mating success, which include differences in brain and mating behavior, it does not explain behaviors such as foraging strategies that do not necessarily relate to intrasexual and intersexual competition.  For this reason, it may be the case that life history strategies, which allow males and females to maximize reproduction over a lifetime, have a heavy impact on the evolution of sex differences (Choleris et al., 2018).  The resulting sex differences in traits influence physiology to behavior and also susceptibility to pathogens, stressors, and disease.  In fact, applying the study of evolutionary forces to sex differences in medicine constitutes a field of medicine referred to as “Evolutionary or Darwinian Medicine (Choleris et al., 2018).”

Some of the major differences between males and females explained in the light of and from the study of evolutionary science include that females tend to be more sensitive and responsive to stress and potential threats with enhanced defensive behaviors (Choleris et al., 2018).  From an evolutionary standpoint, this appears adaptive as females constitute the sex with greater reproductive and parental investment in mammals, with greater evolutionary cost (reduced offspring survival) associated with loss of females compared to loss of males (Choleris et al., 2018).  This adaptation with evolutionary advantages related to risk aversion in human females may contribute to explaining female predominance in psychiatric disorder that relate to stress system activation such as anxiety disorders, phobias, depressive disorders, and post-traumatic stress disorders (Choleris et al., 2018).  Males of many species, on the other hand, show greater territoriality and patrolling behaviors, which some biologists believe relates to males having generally better spatial abilities than females (Choleris et al., 2018).  Thus, with greater aggressive tendencies in defending territories and acquiring exclusive priority to resources, males may also have higher incidence of risk-taking disorders, impulsive behaviors, and disorders of social behavior such as autism spectrum disorders, schizophrenia, and violence and impulsive aggression (Choleris et al., 2018).

According to evolutionary theory, sex differences in the brain which include genetics, physiology, anatomy, behavior, and disease susceptibility result from evolutionary pressures.  Many gaps exist in scientific knowledge of how selective pressures have shaped differences in sexes.  A deeper understanding of the topic from research may result in optimized treatments based on sex.  Such deeper understanding may also facilitate social acceptance for the wide array of phenotypes (observable characteristics of an individual resulting from interaction of genotype and environment) that present in the human species.


Choleris E, Galea LAM, Sohrabji F & Frick KM (2018).  “Sex differences in the brain: Implications for behavioral and biomedical research.”  Neurosci Biobehav Rev.  85: 126-145.

McCarthy MM, Nugent BM, & Lenze KM (2017).  “Neuroimmunology and neuroepigenetics in the establishment of sex differences in the brain.”  Nat Rev Neurosci.  18(8): 471-484.

McCarthy MM, Pickett LA, Van Ryzin JW, & Kight KE (2015).  “Surprising Origins of Sex Differences in the Brain.”  Horm Behav.  76: 3-10.

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