Sexual Dimorphism in Brain and Behavior

Sexual Dimorphism in Brain and Behavior

Sexual Dimorphism in Brain and Behavior Bi156 Bi 156 January 14, 2008 January 20, 2010 Paul Patterson Paul Patterson Sex differences in the brain The past 5–10 years have witnessed a surge of findings from animals and humans concerning sex influences on many areas of brain and behaviour, including emotion, memory, vision, hearing, processing faces, pain perception, navigation, neurotransmitter levels, stress hormone action on the brain and disease states. Even otoacoustic emissions (audible ‘clicks’ made by the inner ear) differ reliably between the sexes, being both louder and more frequent in female than male adults, children and infants. The advent of human 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 gender: 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 sexual differentiation of mammalian brain and behavior • Are there biologically based differences between males and females 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 rodents exposed to androgen during fetal development (“organizational” effect) do not display certain female behaviors such as receptivity to males, but do display certain male behaviors such as rough play • Explains why genetic males deprived of androgens during early development display female-typical sexual receptivity when treated with appropriate steroids in adulthood • There are also “activational” effects of these hormones after development – adult levels of testosterone regulate the frequency of male-type mating and territorial behaviors; females given testosterone mount females as readily as males. However: Key role for estrogen in male behaviors • In many vertebrates, 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 this 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 birth, 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 * * * *Areas of high aromatase and androgen receptor * 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 stria terminalis; MeA, medial amygdala; MOB, main olfactory bulb; PLCO, posterolateral cortical amygdala; PMV, ventral premamillary nucleus; POA, preoptic hypothalamus; 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 allele 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 finch A bilateral gynandromorphic finch in which the right half of the body (a), gonads (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 sex chromosome genes and independent from gonadal sex hormones. Role of sex chromosomes – 4 core genotype model Jazin & Cahill, 2010 Hormone-independent sexual differentiation • The Y chromosome gene SRY is transcribed in the hypothalamus and frontal and temporal cortex of the adult human brain. • 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 Corpus callosum 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 cycle. 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.

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