|The Two Brains|
The battle between the sexes has been an eternal one. No one likes to lose the battle and it is more pleasant to believe that men and women are of equal ability and equal mind. In the past, sexual differences in the brain have been especially disregarded due to the belief that they are of little to no significance. However, in recent research, an increasing amount of evidence suggests otherwise. Differentiated hippocampal and hypothalamic responses to stress and stimulating imagery can be found between males and females, with further differences between heterosexual and homosexual individuals. Sexually dimorphic brain systems are useful to understand when tailoring more efficient therapies to those with disease states where sexual differences have been found. These disorders include a wide array involving emotional imbalance, such as schizophrenia  and depression . Additionally, the neurological processes underlying sexual orientation and identification allow one to more objectively analyze how different sexual experiences arise and their associated social implications.
Table of Contents
1. Differences in brain structure and neurobiology
1.1 Anatomical Differences
Differences in the brain anatomy between the sexes have not been conclusively defined. However, numerous studies have consistently found sexual dimorphisms in similar regions of the brain. In earlier studies in the area, the anatomy of animal brains (often rats) were used and research concentrated on the effects of sex hormones on the structure of the brain. The introduction of magnetic resonance imaging (MRI) brought the ability to analyse the brain in vivo, which also helped establish the idea of sex differences in the brain.
Overall, adult men have larger cerebrum volumes compared to women  in the frontal medial cortex, the hippocampus and the amygdala. However, women had higher gray matter to white matter ratios . The lateralization of different functions, especially of language, contributes to the asymmetry in all brains. Specifically, males have more of this asymmetry in the brain. Males also have more cerebrospinal fluid volume and a greater loss in brain volume with age (especially in the frontal and temporal lobes) . Women have larger cerebrum volumes in the frontal and medial limbic cortices. Women also have higher ratios of gray matter to whole brain volume and regions involved in language. Women have a larger splenium (the end of the corpus callosum). Differences in glucose metabolism and local blood flows can be detected between males and females as well .
Upon further investigation, greater amounts of sexual dimorphism can be found in regions where higher amounts of sex steroid receptors were located in animal models. In fact, after the differentiation of sexual organs is finalized, sexual differentiation of the brain occurs  under the driving effects of the sex steroid hormones. This kind of data can be utilized when determining relationships between sex steroid hormones and sexual dimorphisms in the human brain.
It is important to consider the interactions among genes, hormones, and developing neurons contribute to sexual anatomical differences in the brain.
1.2 Developmental differences via other factors
MicroRNAs (miRNAs) are becoming more known as prominent regulatory factors for almost all processes that occur in the body. They are implicated in sexual differentiation of the brain; seven significantly different miRNA forms were found between male and female rat brains immediately after birth . Interestingly, an injection of aromatase inhibitor, which prevents the testosterone to estradiol hormone conversion, was enough to stimulate a female-like miRNA profile in the male rat brains (with larger microglial bodies and shorter proceses) . This propounds the idea that miRNAs in the rat brain, and possibly the human one, can affect genes that specifically control sexual differentiation.
Sexually dimorphic miRNAs controlling hormone activity are found in all parts of the brain, especially in the adult mouse hippocampus, cerebellum and cortex . Further analysis has shown specific miRNAs in the hippocampus, paraventricular nucleus and the amygdala were receptive to estradiol  with a few of them dependent on age. miRNAs are likely heavily implicated in memory, learning, and stress responses, which are all processes with marked sexual dimorphisms. It is hypothesized that the internal differences in estradiol levels are what affect miRNA profiles between males and females .
*A detailed analysis of hormones and signalling pathways involved in sexual function is discussed elsewhere
2. Differences in normal brain physiology (including any physiochemical differences)
2.1 Male vs. Female
In rodents, sexual differentiation of the brain is a consequence of the testicular androgen flow around childbirth. The preoptic area (POA) of the hypothalamus is already known to be an area of the brain required for the expression of adult male sex behaviour and receives information from almost all sensory modalities . (It is also known as the sexually-dimorphic-nucelus of the POA, or SDN-POA) It is 5-7 times larger in males and male neurons have 2-3 more dendritic spines than females . In the POA, estradiol aromatized from testosterone stimulates the production of prostaglandin E2 (PGE2) to further delineate sex-specific areas in the brain. Inhibitors of PGE2 prevent this masculinisation. However, the method underlying this process is not as clear.
Recently, microglia have been implicated in this mechanism. Microglia are the main immunocompetent cells in the brain . They contribute to normal brain development and work in tandem with prostaglandins. Newborn (neonatal) male rodents have double the amount of microglia than their female counterparts. Microglial inhibition during the critical period of sexual differentiation stops microglial sex differences. The masculinisation of dendritic spine density and adult sex behaviour are also inhibited. Additionally, the upregulation of PGE2 is halted since this inhibition also restrained estradiol’s function on PGE2 . Therefore, the communication among the immune cells (microglia), the developmental nervous and endocrine systems are vital for sexual differentiation of the brain and behaviour.
2.2 Reproductive cycles
The brain is required for normal reproductive cycles in chicken chimeras, independent of steroid hormones. Midbrain dopamine levels in rodents are sexually dimorphic and are controlled by the SRY gene . Female chimeras with male brains exhibited later sexual maturation and uncoordinated oviposition (egg-laying) cycles. However, their behaviour and sex steroid concentrations in the blood were normal. Male chimeras with female brains displayed characteristics similar to typical male chickens . The male brain cells preserved male identity even when exposed to a female environment (consisting of normal hormone levels present in female development).
2.3 Stress and Pharmacological Models
|Visual explanation of the HPA axis|
It is well documented that females are more vulnerable to stress-related disorders than males. The ratio of depression in females to males is approximately 2:1 . Stress can induce depression through inflammatory signalling in the brain itself. During adolescence, stress can further interrupt the activation and regulation of the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) pathways . Both of these axes control inflammatory paths and brain areas affecting behaviour.
In a recent study from Pyter et al (2013), adolescent stress was analysed and found to affect brain inflammatory signalling differently between males and females. Male and female rats were initially put under mixed stress conditions during adolescence. 4.5 weeks later (adulthood) they were subjected to either an injection of lipopolysaccharide (LPS) or saline. Although previous studies often demonstrated that adolescent stress largely affected females, Pyter’s group showed an increase in hippocampal inflammatory responses to LPS in only males . The differences in inflammatory signalling in the brain therefore do not wholly control the different behaviours between males and females. The sex differences in the inflammatory markers were also not correlated with differences in corticosterone. Intriguingly, in females under the adolescent stress condition, LPS was associated with estradiol levels. Estradiol was positively related to hippocampal microglial gene expression in the experimental female rats, but negatively related in the control group. Estradiol may be a protective factor against stress-induced neuroinflammation.
Depression can have specific effects on pregnancy. Depression during and after pregnancy affects up to 20% of women . Selective serotonin reuptake inhibitor (SSRI) medications are often used to treat this depression. SSRIs, however, are able to cross the placental barrier and be present in breast milk so that both  mother and child can be affected. Serotonin itself is involved in the development of the HPG axis and the effects  of drugs affecting it are not yet very clear.
In recent research, Fluoxetine (Prozac ®) during development, along with prenatal stress, affect sexual differentiation of the brain and reproductive behaviour in male rats. The area of the SDN-POA is reduced with exposure to fluoxetine or prenatal stress. Prenatal stress alone decreases the number of tyrosine-hydorxylase cells (precursor to serotonin) in the anteroventral periventricular nucleus of males; the volume of the posterior bed nucleus of the stria terminalis is also reduced in the offspring . Effects of both drug treatments and maternal stress are likely involved in the sexual dimorphic brain development of offspring.
*For specific sex differences in depression, please refer to Section 3.2
3. Differences in abnormal brain physiology
3.1 Emotional Behaviour
Endocrine-disrupting chemicals (EDCs) can permanently damage the development of both sexual dimorphic behaviours and structures of the brain. EDC exposure can affect a varied array of factors depending on dose, timing, age and sex. Currently, Bisphenol A (BPA) is one of the most examined EDCs due to its almost ubiquitous use in everyday items, including food and drink packages .
Developmental exposure to low doses of BPA has also been found to affect emotional behaviour. Both prenatal and postnatal exposure to BPA reduced or reversed the sex differences in emotional behaviour in mice. Novelty tests, free exploratory open field and elevated maze tests were used to identify the different behaviours in the mice. Females consistently showed increased anxiety and less likely to explore novel environments relative to the control females . Females exposed to BPA also showed behaviours more similar to those of males. EDCs must be further explored in their effects on not only behaviours, but also areas of the brain, to better understand how these sexually dimorphic profiles function and apply to humans.
Since the cortico-limbic-striatal neural system (amygdala, hippocampus, prefrontal cortex, and striatum) shows many sexually dimorphic markers and is key in the regulation of mood and emotions, it is not surprising to detect sex differences in major depressive disorder (MDD) . Gray matter morphology is significantly different between males and females in the left ventral prefrontal cortex, right amygdala, and right hippocampus when compared to the healthy control group.
Females with MDD show significant gray matter decreases in limbic regions when compared to healthy females. Males with MDD showed significant gray matter decreases in striatal regions when compared to healthy males . These differences contribute to the finding that more females with MDD are prone to anxiety, whereas males with MDD are more prone to impulsiveness. The prefrontal-limbic areas are involved with anxiety; the prefrontal cortex likely has a role in modulating the amygdala and the hippocampus, which may also affect the role of estrogen in anxiety . Conversely, the prefrontal-striatal areas are involved in disinhibition . This disinhibition is associated with increased suicidal thoughts, impulse dysregulation and psychomotor irregularities in males . Depressed males are also found to have smaller anterior cingulate cortex volumes, while depressed females have smaller amygdala volumes compared to their normal counterparts . The influence of medications on the cortico-limbic-striatal pathway and differential sex responses is important in understanding treatment possibilities for patients with MDD.
3.3. Other disorders with sexual dimorphic markers
There are many disorders with significant differences between females and males; these include Parkinson’s disease (PD), schizoprenia, Wilson’s Disease (WD) and Alzheimer’s Disease (AD). The hallmark of PD is the loss of dopinamergic neurons in the midbrain (from the substantia nigra). One of the enzymes metabolizing dopamine, catechol-O-methyltranferase (COMT), modifies age of onset (AOO) for PD and relates to a sexual dimorphism. Patients with the Val158 allele (Val/Val, Val/Met) have reduced dopamine availability due to higher enzymatic activity; patients with the Met/Met allele have more dopamine availability due to lower enzymatic activity (which delays motor symptoms). Interestingly, the low-enzymatically active COMT gene is associated with obsessive-compulsive disorder in males, but not in females . The dorsolateral prefrontal cortex of women also has lower COMT activity than men. . Estrogen again is thought to be involved in this process since it inhibits COMT mRNA expression . Another possibility is the monoamine oxidase B gene (MAOB), which is X-linked and is involved in dopamine metabolism. MAOB activity in the brain increases with age and changes with gender .
Individuals with schizoprenia have less functional and structural asymmetry in the brain than healthy individuals; this is thought to arise from a predisposition to psychosis related to language . An increase in white matter dispersion toward the anterior corpus callosum is generally found in male patients, similar to healthy females. This increase is analogous to a reduction in asymmetry of connecting fibres . Often, a reversal in the normal layout of brain surface asymmetry is identified in schizophrenia patients  where male patients’ brain layouts become closer to normal female brain layouts. The shapes and sizes of ventricles and cortical gyri also show reversal of sex differences (become larger in both cases in affected males) .
Specific information on gender differences in the brain of Alzheimer's Disease can be found here.
4. Sexual Orientation and Identification: How the Brain is involved
4.1 Anatomical and physiochemical differences between orientation and gender
Areas of the suprachiasmatic nucleus (SCN) , the anterior commissure (AC) , and the third interstitial nucleus of the anterior hypothalamus (INAH3) are appreciably different between the different genders and sexual orientations. The SCN and the AC are twice as large in homosexual males than heterosexual males , . Furthermore, the AC is also larger in females, which may help explain why females have different cognitive and language abilities when compared to men (the AC connects the left and right temporal cortices). The INAH3 is part of the POA discussed earlier and therefore it is understandable that it too has a role in sexually dimorphic markers. The INAH3 has been found to be smaller in homosexual males than heterosexual males  and of intermediate size between heterosexual males and heterosexual females , possibly indicating a gradient-like growth pattern of the area.
Less research has been done on heterosexual women and homosexual women, although some structural differences have been found in the research that exists. Homosexual women often exhibit less gray matter bilaterally in the temporal and basal cortex, ventral cerebellum and left ventral premotor cortex . This reduction in gray matter was most defined in the left perirhinal cortex . Indeed, the reduction is also found in heterosexual men when compared to heterosexual women implying homosexual women showed more male-like layouts in gray matter. The perihinal cortex is implicated in higher order multimodal inputs (both visual and olfactory) used in social and sexual behaviours .
Studies on the olfactory system and pheromones in sexual attraction have shown differences among heterosexual and homosexual males and heterosexual females. The testosterone derivative 4,16-androstadien-3-one (AND) and the estrogen-like steroid estra-1,3,5(10),16-tetraen-3-ol (EST) are currently hypothesized to be human phremones ; AND is found in male sweat and EST is found in female urine. The regional cerebral blood flow (rCBF) in heterosexual individuals differed between females and males when smelling AND and EST. AND maximally activated the POA and ventromedial nuclei in women and EST activated the paraventricular and dorsomedial nuclei in men. When women smelled EST and men smelled AND, activation occurred in only the amygdala, piriform, anterior insular, orbitofrontal and anterior cingulated corticies . Homosexual men showed activation patters similar to heterosexual women with the similar hypothalamic activation in response to AND . Similarly, maximal activation was found in the POA. Although less conclusive, homosexual women were found to display more similar activation profiles as heterosexual men . When tested with common scents, unrelated to the candidate human phremones, all individuals showed activation in only the olfactory brain areas (amygdala, piriform, orbitofrontal, and insular cortex). The differences in brain activation between genders and orientations highly suggest a link between gender preference and hypothalamic processes .
Initially, the brain is believed to develop in either a male direction through testosterone acting on nascent neurons or a female direction if no testosterone is present. Many researchers believe that gender identity and sexual orientation may be programmed into brain structures while still in the womb. Moreover, since sexual differentiation of the genitals occurs in the first two months of pregnancy whereas that of the brain occurs in the second half of pregnancy, the two pathways can progress independently of one another . This may be what contributes to transsexuality for it appears that masculinisation of the brain does not always correspond to masculinisation of genitals .
*A detailed analysis of attraction and the brain is discussed elsewhere
4.2 Neuroimaging studies showing differential activation
The relationship between sexual behaviours (including gender preference, identification and sexual orientation) and brain anatomy is of much debate. Many researchers believe that gender differences in the brain may account for behavioural differences between not only the sexes but among sexual orientations as well.
Sexual arousal (SA) is described as the “readiness to perform sexual behaviours” on both psychological and physical fronts . It can be measured as the bilateral blood oxygen level dependent (BOLD) signal levels in different brain regions. SA is often higher in male than female individuals when viewing erotic stimuli and largely affects hypothalamic regions . As an extension to this, the SA levels in homosexual males are more similar to those of heterosexual females than males , , once again demonstrating a gradient-like pattern in hypothalamic function.
When viewing stimuli opposite to the individual’s sexual orientation, both homosexual and heterosexual males showed an absence of hypothalamic activation. However, the activation pattern that was found was an autonomic response, which may correspond to the pathway for aversive input (including fear and disgust) . It is clear from the evidence that has been presented, that although many patterns seem consistent, more research needs to be done on both homosexual and heterosexual males and females, especially the latter.
5. Practical and therapeutic application
5.1 Sex-specific vulnerability to disorders
It is clear from the research thus far that different sexes may respond to disorders in different ways. Understanding these differences are crucial in understanding how to treat various neuropsychiatric disorders. Irregularities in the prefrontal-limbic system are principally found in females with major depressive disorder, as opposed to the irregularities in the prefrontal-striatal system in MDD males . In male schizophrenia patients, testosterone has some effect on the brain as shown through the increased excitement and hostility levels and decreased ability in verbal memory, working memory and processing speed . Pharmacological treatments targeting different and specific areas may be required to best treat patients of different sexes. Knowing the neural circuitry and how it operates in the sexes will provide important clues when creating tailored treatment  options for disorders with sexually dimorphic markers.
5.2 Sexual Orientation and social implications
|The Kinsey scale is one representation of the heterosexuality-homosexuality continuum.|
Currently, there is little to no evidence that the social environment has any influence on gender identity, sexual orientation or even abnormal sexual preferences . Structural differences in the brain are hitherto the best correlates to the development of different sexual behaviours. In addition to different responses to disorders and treatments between the sexes, different responses are found among those of different orientations as well. Interestingly, the hypothalami of homosexual males do not respond as well to fluoxetine when compared to heterosexual males; this alludes to a divergence in how the serotonergic system works and the possible need for different treatment choices .
Moreover, not much is known about the neural foundation of sexual orientation in women . More research needs to be done in not only this area but in the area of other sexual behaviours falling along the heterosexual-homosexual continuum. For example, bisexuality is not an area that is well-researched, likely because of the complexity involved in recruiting participants and interpreting data. Understanding more about the neural foundation of different sexual behaviours will help people learn more about these behaviours and reduce unwarranted stigmas associated with them.