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Home , Sexual dimorphism

Sexual Dimorphism in

Brain and Behavior

Bi156 Bi 156 January 14, 2008 January 20, 2010 Paul Patterson Paul Patterson differences in the brain

The past 5–10 years have witnessed a surge of findings from animals and concerning sex influences on many areas of brain and behaviour, including emotion, memory, vision, hearing, processing faces, perception, navigation, neurotransmitter levels, action on the brain and disease states. Even otoacoustic emissions (audible ‘clicks’ made by the inner ear) differ reliably between the , being both louder and more frequent in than male adults, children and infants. The advent of brain-imaging techniques such as PET and fMRI has heightened awareness of sex differences by revealing sex influences on brain functions for which the sex of participants was previously assumed to matter little, if at all. Concurrently, animal research has increasingly documented new, often surprising, sex influences on the brain. L. Cahill, 2006

“Delusions of : how our minds, society and neurosexism create difference. The real science behind sex differences.” C. Fine 2010 “Brain storm: The flaws in the science of sex differences.” R. Jordan-Young 2010 Harvard president deposed for suggesting that brain differences between women and men underlie the low numbers of women in the sciences Questions on of mammalian brain and behavior

• Are there biologically based differences between males and in behavior? • Are there differences in the structure of male and female brains? • Are the brains of homosexuals and transsexuals different from heterosexuals? • What can we say about the mechanisms of such differences? Mammalian sex determination Default pathway scheme

• Postulates the female brain as the default pathway • Explains why genetically female exposed to during fetal development (“organizational” effect) do not certain female behaviors such as receptivity to males, but do display certain male behaviors such as rough play • Explains why genetic males deprived of during early development display female-typical sexual receptivity when treated with appropriate steroids in adulthood • There are also “activational” effects of these after development – adult levels of regulate the frequency of male-type and territorial behaviors; females given testosterone mount females as readily as males. However: Key role for estrogen in male behaviors

• In many , including mice, male patterns of differentiation in the brain, as well as male behavior, require estrogen as well as testosterone, even though estrogen is essentially undetectable in the male brain. • Testosterone is an obligate precursor of estrogen in the brain, and conversion is carried out by the aromatase enzyme. • Thus, testosterone has a dual role: activating its receptor to control male behaviors in adults, and serving as precursor for estrogen, which in turn influences circuits via its receptor during development. • Estrogen also acts in adult males: the loss of male behaviors following adult castration can be rescued by estrogen injection. Moreover, male mice null for the estrogen receptors, ER and ER, do not mate or fight. • Males null for aromatase exhibit deficits in mating and fighting. Roles for estrogen and androgen

• If estrogen is ultimately a masculinizing hormone, why is the female brain not masculinized? • Estrogen in the mother is sequestered by the protein -fetoprotein in the fetal circulation, which binds and sequesters estrogen, protecting the female brain from this influence. • At , there is a male-specific surge of testosterone that is converted into estrogen in the brain. • In females at birth, the ovaries are quiescent and the brain is not exposed to sex steroids. • Thus, only the male neonatal brain is exposed to both sex hormones, and the female brain may follow a default pattern that is set by patterning genes. • The present understanding is that estrogen sets up the male repertoire of sexual and territorial behaviors, and testosterone controls the extent of these behaviors. Circuits mediating sexually dimorphic behaviors

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* * *Areas of high aromatase and androgen receptor

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Neural pathways underlying sexually dimorphic behaviors. Many hypothalamic and amygdalar centers have been implicated in the control of sex specific behaviors. Each of these brain regions is sexually dimorphic and expresses one or more gonadal hormone receptors; in addition, the BNST, MeA, POA, and VMH also express aromatase, and represent sites of estrogen synthesis in the adult brain. Some of these nuclei and their connections, including with pheromone sensing neurons in the MOE and VNO, are illustrated in this Schematic. AOB, accessory olfactory bulb; BNST, bed nucleus of the ; MeA, medial ; MOB, main olfactory bulb; PLCO, posterolateral cortical amygdala; PMV, ventral premamillary nucleus; POA, preoptic ; VMH, ventromedial nucleus of the hypothalamus. Wu & Shah, 2011 Early estrogen masculinizes brain and behavior

(Top) The perinatal surge of testosterone in genetically male mice results in the development of male-type brain morphology. Conversion of testosterone to estrogen is a key step in this process. Testosterone is converted into estrogens by aromatase synthesized in the brain, causing the number and projection patterns of aromatase-expressing neurons to become sexually dimorphic. In adult males, estrogen derived from testosterone by aromatase activity acts through estrogen receptor-a (Era) to potentiate male-type aggressive and territorial behaviors. However, testosterone acting directly through androgen receptors (Ars) is required for the full robust expression of the total complement of these male-type behaviors. (Bottom) Treating female mice with estrogen neonatally results in a male-type pattern of aromatase-expressing neurons. In adulthood, estrogen is also required for expression of the male-type aggressive and territorial behaviors permitted by the neuronal changes caused by the neonatal hormone treatment.

Gagnidze & Pfaff., 2009 Estrogen promotes cell survival in the BNST & MeA

P1 P4

(A–D) Coronal sections through the brain of P1 male and female mice bearing the aromatase-IPIN stained for bgal activity. Scale bars equal 250 mm. (E) No sex difference in the number of bgal+ cells at P1. Mean ± SEM; n = 3; p R 0.63. (F–I) Adjacent coronal sections through the MeA of P4 male and female mice bearing the aromatase-IPIN allele immunolabeled for bgal or stained for apoptosis with TUNEL (arrows). Arrowhead (I) indicates autofluorescent material. Scale bars equal 100 mm. (J) There are more apoptotic cells in the BNST and MeA in control (NV) females and aromatase–/– (KO) ± males compared with control (WT) males and estrogen-treated (NE) females. Mean SEM; n = 3; *p % 0.004. Wu et al., 2009 Bilateral gynandromorphic

A bilateral gynandromorphic finch in which the right half of the body (a), (b), sex-chromosome-linked gene expression in the brain (c), and volume of sexually dimorphic nuclei (d) have male characteristics, while the left half is female-like. Striking sex differences have developed and are maintained in each side of the brain although they have been exposed equally to circulating gonadal hormones. This result supports the existence of cell-autonomous information provided by genes and independent from gonadal sex hormones. Role of sex chromosomes – 4 core genotype model

Jazin & Cahill, 2010 Hormone-independent sexual differentiation

• The gene SRY is transcribed in the hypothalamus and frontal and temporal cortex of the adult . • It will be very interesting to identify the genes responsible for hormone-independent sex effects on the brain. • Recently, a large set of imprinted genes, many of which are imprinted in a sex-specific manner, were found in the brain. • Previously identified imprinted genes in the brain regulate social interactions, so this new set of imprinted genes may also be involved in such functions. Sex differences in the human brain

Larger in the male Parts of the bed nucleus of the stria terminalis Second and third interstitial nuclei of the anterior hypothalamus Sexually dimorphic nucleus of the preoptic area Onuf’s nucleus in the spinal cord

Larger in the female Anterior commisure Massa intermedia

Greater asymmetry in the male Planum temporale

Shape differences Splenium of the corpus callosum more bulbous in female Suprachiasmatic nucleus more elongated in female Sexual dimorphisms in human cognition I

• Although there is considerable overlap in performance between the sexes, and not all studies agree, evidence suggests that men perform better on visuospatial tasks, and women perform better on verbal tasks. • Some of these differences are likely due to traditional methods of raising kids. • Some are likely due to both organizational and activational activities of sex hormones. Sexual dimorphisms in human cognition II

• In men, spatial tasks are performed better at times of low testosterone levels - spring, evening. • Women perform better on spatial tests in the low-estrogen phase of the menstrual . But their verbal performance is better during the high estrogen phase. • These correlations are supported by experiments administering estrogen to post-menopausal women. • Moreover, spatial learning in ovariectomized rats is enhanced by injection of estrogen. • fMRI of post-menopausal women show that estrogen injections can alter brain activation patterns. • Estrogen can alter synaptic density and neurite outgrowth. Effect of estrogen on human brain activation during verbal working memory

Brain activation patterns can be modified in mature women by estrogen treatment to resemble those seen in younger women for these learning tasks.

Shaywitz et al.,’99 Imaging female and male verbal learning

Shaywitz et al., ‘95 Dimorphism in lateralization of function

• Boys develop specialization of right hemisphere as early as age 6, while girls display bilateral representation until 13. This suggests of the brain during a very significant period of schooling. • Natural lesions (strokes) show that males have more lateralization of function than females. • fMRI shows clear sex differences in cortical localization of activity evoked during language tasks. acutely enhances memory by female rats in the water maze Synaptic density changes during the estrus cycle Gene expression changes in the aging brain are sexually dimorphic

Gene expression profiles across the lifespan undergo sexually dimorphic and region-specific changes. Patterns of global gene changes over 20-year increments were compared independently for males and females in each brain region. Pronounced sexually dimorphic patterns are apparent in the SFG and PCG, whereas the HC and EC show less dramatic differences between males and females. Berchtold et al., 2008 5-HT synthesis is higher in males

11C-methyl-tryptophan is the tracer Both incidence and of brain diseases differ between the sexes

Plus, autoimmune diseases such as multiple sclerosis are much more common in females, and autism is much more common in boys Sex differences can be graded Some sex-specific effects in KO mice

Jazin & Cahill, 2010 Natural experiment: Congenital Adrenal Hypoplasia

• Enzyme defect causes low corticosteroid levels, which lead to compensatory elevation of adrenal steroids with androgenic activity. Thus, there is excess androgenic activity before birth. • Girls with CAH display enhanced spatial abilities, and more often play with toys that are preferred by boys. • They also display a greater incidence of lesbianism. Sexually Dimorphic Nucleus (SDN)

• Essential for male sexual behavior in rats and monkeys. • Gross sexual dimorphism in size of nucleus is altered by perinatal hormones. • Effect of perinatal hormones is on apoptosis in the SDN. Hormone controls SDN size Spinal Nucleus of the Bulbocavernosus (SNB)

• The SNB (Onuf’s nucleus in humans) controls the muscles at the base of the penis. • These muscles and the neurons that innervate them develop in the fetus of both sexes. • Perinatal apoptosis occurs in SNB of both sexes but is more marked in females. • Perinatal injection of testosterone blocks loss of these neurons in females, while blocking androgen action in males increases neuronal death. • The same manipulations yield similar results in the muscles, and the muscles respond before the neurons. • The muscles express androgen receptors but the neurons do not, so the androgens save the muscles, which then save the neurons. Is homosexuality biologically driven?

• This question is controversial because of its moral and religious implications. If this behavior is not primarily one of free choice but is biologically driven, the morality issue should disappear. • Genetic factors are likely involved. • Several structural differences are found in brains of homosexuals: – SCN is larger, containing twice as many neurons in homosexuals compared to heterosexuals. – INAH-3 is larger in males than in females and twice as large in heterosexuals than in homosexuals. Concordance for homosexuality in twins Sexual orientation and brain differences

Swaab & Hofman, ‘90 Link between sexual orientation and hypothalamic neuronal activation by sexually dimorphic pheromones

Testosterone derivative (AND) and estrogen derivative (EST) are candidates for human pheromones. AND is found in male sweat while EST is found in female urine. In contrast to heterosexual men, and in congruence with heterosexual women, homosexual men display hypothalamic activation in response to AND. Maximal activation is in medial preoptic area/anterior hypothalamus, which is involved in animal sexual behavior. Male homosexual and heterosexual brains are also differentially activated by EST. In contrast to the pheromones, common odors are processed similarly in all 3 groups of subjects, and engage only the olfactory brain. [Savic et al., 2005] Is transsexuality biologically driven?

• Transsexuals are people of one genetic, gonadal and body sex who believe that they are psychologically of the other sex, and often choose to undergo a surgical as adults. • The brain area, BSTc (bed nucleus of the stria terminalis), is larger in men than in women, and is required for male sexual behavior in rats. • Neonatal but not adult castration of male and androgenization of female rats induce significant changes in the number of neurons in the BSTc, and suppress its sexual dimorphism. • A female-sized BSTc is found in male-to-female transsexuals. • Suggests not only choice of mate, but sexual identity, may be biologically driven. Sexual orientation and BSTc size

Zhou et al., ‘95 BSTc volume in homosexuals and transsexuals

The volume of the central part of the bed nucleus of the stria terminalis (BSTc) in four sexually diverse groups: presumed heterosexual and homosexual men, presumed heterosexual women, and six postoperative male-to-female transexuals. The volume of the nucleus was estimated by the density of vasoactive intestinal polypeptide innervation, which in turn was measured immunohistochemically. *Indicates significantly greater than females or transexuals. Based on Zhou et al., 1995. References

Background Kandel ER, Schwartz JH, Jessell TM (Eds.) Fourth edition (2000) “Principles of Neuroscience”, Chap. 57. • Wu MV, Shah NM (2011) Control of masculinization of the brain and behavior. Curr Opin Neurobiol 21:116-23. * Jazin E, Cahill L (2010) Sex differences in molecular neuroscience: from fruit flies to humans. Nature Rev Neurosci 11:9-17. Baron-Cohen S, Knickmeyer RC, Belmonte MK (2005) Sex differences in the brain: implications for explaining autism. Science 310:819-823.

Student papers * Liu Y, Jiang Y, Si Y, Kim JY, Chen Z-F, Rao Y (2011) Molecular regulation of sexual preference revealed by genetic studies of 5-HT in the brains of male mice. Nature 472:95-9. * Bradley KC, Boulware MB, Jiang H, Doerge RW, Meisel RL, Mermelstein PG (2005) Changes in gene expression within the nucleus accumbens and striatum following sexual experience. Genes Brain Behav 4:31-44. Toy preferences in vervet monkeys mimic those in human children

Alexander & Hines, 2002