神经生物学：大脑的性分化

1、0246810203040506070 andoverOffenders as a percentage of the population:England & Wales 2004Age (years) % populationSocial Trends 2006Sexual Differentiation of the Mammalian Reproductive System Fertilization by an X or Y spermSex Determining Region of the Y Chromosome (SRY) leads to production of the

2、 Testis Determining Factor and the formation of the testesThe rest of sexual differentiation depends on 1. Hormone production by the testis: Testosterone (which may lead to formation of Dihydrotestosterone or Estradiol) and Mullerian Duct Inhibiting Hormone.2. Tissue response to appropriate hormone.

3、Current DogmaFig. 11-3, p. 328Differentiation of human genitals. The males SRY gene (Sex-determining Region Y, SRY) causes the gonad to become a testis, and the testis produces testosterone, which masculinizes development. In the absence of testosterone, development follows the female pattern. (Sour

4、ce: Based on Netter, 1983)Alexander GM, Hines M. 2002. Sex differences in response to childrens toys in nonhuman primates (Cercopithecus aethiops sabaeus). Evolution and Human Behavior 23:467-479.肾上腺肾上腺congenital adrenal hyperplasia (CAH)Fig. 11-12, p. 342CAH girls were intermediate between unaffect

5、ed girls and boys. These data show results when the children played alone. (Source: Based on data of Pasterski et al., 2005)Iijima M, Arisaka O, Minamoto F, Arai Y. 2001. Sex differences in childrens free drawings: a study on girls with congenital adrenal hyperplasia. Horm Behav 40:99-104.Iijima M,

6、Arisaka O, Minamoto F, Arai Y. 2001. Sex differences in childrens free drawings: a study on girls with congenital adrenal hyperplasia. Horm Behav 40:99-104. I899T S888I P892L P817A P817T d 1nt (N848) stop 881 F827S R855C* R855H* T860I V866M* splice G-A (+1 int. 7)(somatic) splice A-C (+4 intron 7)CA

7、IS12346785 del 5nt (E79) stop 89 i 1 nt (G104) stop 110 i 11 nt (P378) stop 481 d 2 nt (Y267) stop 301 del 23 nt (L341) stop 492 Q63X Q67X E153X G371X Y393X Q487X duplic. 8nt stop 563 Y571C C579Y V581F V581L R585K del exon 3 C614S R615H* L616P C619Y d 13nt (R707) stop 787 L677P V684I D695N N705S L70

8、7R G743E M749K M749V R752X F754V A765T P766S splice G-A(-1 int. 4) del ex5 d 1nt (P766) stop787 D767E subst. 10 nt (-12/-3 int. 5)by 8 b nt del ex 6 i 1 nt (P801) stop 828 d 2 nt (V785) stop 827(somatic inthe mother, transmittedtwice) R774C R779W R786X G795X T800P腹股沟疝腹股沟疝The sexual differentiation o

9、f the genitals takes places much earlier in development (i.e. in the first two months of pregnancy) than sexual differentiation of the brain (that starts in the second half of pregnancy and becomes overt upon reaching adulthood), these two processes may be influenced independently. programming or or

10、ganizing effects (permanent modification ), and activating effects (transient modification)Ratios for women over men suffering from a selection of neurological and psychiatric diseasesNote: abbreviations: REM = rapid eye movement ; ADHD = attention deficit hyperactivity disorder. (for references see

11、 (Swaab 2003)Hofman and Swaab, J Anat. 1989; 164:55-72.the sexually dimorphic nucleus of the preoptic area (SDN-POA). Is it Nature OR Nurture?In the late 1950s/early 1960s there was a well accepted concept championed by Dr. John Money: HOW ONE IS RAISED OR REARED FOR ABOUT THE FIRST TWO YEARS OF POS

12、TNATAL LIFE IS WHAT DETERMINES ONES PSYCHOSEXUALITY“Gender identity is sufficiently incompletely differentiated at birth as to permit successful assignment of a genetic male as a girl. Gender identity then differentiates in keeping with the experience of rearing-J. Money, 1975Epispadias：尿道上裂；：尿道上裂；

13、innominate osteotomy：骨盆切骨术：骨盆切骨术Three Challenges to the Nurture Hypothesis1.Hormone-dependent sexual differentiation of brain function and structure well established in lab animals.2.Structural sex differences appear to exist in the human brain as well.3.The report by Money which demonstrated the ma

14、rked effectiveness of Nurture and actually dictated clinical management for more than 2 decades, was seriously challenged in the 1990s.Effects of neonatal castrationThe normal adult gonadal steroidsEffects of exogenous steroidsNo changeFemaleCyclic LH release Frequent lordosisNo cyclic LH releaseLor

15、dosis rareCyclic LH releaseFrequent lordosisMale No cyclic LH releaseLordosis rareNo changeInfluence of the perinatal hormonal environment on adult neuroendocrine function in the ratPotential Mechanisms StudiedSteroids increase neuronal mitotic( (有丝分裂有丝分裂) ) activity.No positive evidence, as yet.Ste

16、roids alter apoptotic neuronal death.In the SDN-POA, which is larger in male rats, Testosterone treatment suppresses apoptotic neuronal death. - But not the only mechanism!Sexual Differentiation of the Rat BrainNatures Blueprint for the internal and external genitalia and the brain is female.A males

17、 brain must be exposed to testicular hormones during a critical period of early development to attain the masculine characteristics in terms of brain structure and function.One mechanism for the alteration in brain structure may be an alteration in apoptosis.The process of apoptosis may define one c

18、ritical period. Prenatal factors that influence gender identity that may result in transsexualityNote: abbreviations: CAH = congenital adrenal hyperplasia; DES = diethylstilbestrolThe bed nucleus of the stria terminalisSex differences in BSTc of human brainZhou,Hofman,Gooren,Swaab.Nature 378:68-70,

19、1995.Kruijver et al. J.Clin.Endocr.Metab.85:2034-2041, 2000Fig. 11-17, p. 349Figure 11.17: Volumes of the interstitial nucleus 3 of the anterior hypothalamus (INAH-3).Samples are females (F), heterosexual males (M), and homosexual males (HM). Each filled circle represents a person who died of AIDS;

20、each triangle represents a person who died from other causes. The one open circle represents a bisexual man who died of AIDS. (Source: Reprinted with permission from “A difference in hypothalamic structure between heterosexual and homosexual men,” by S. LeVay, Science, 253, pp. 10341037. Copyright 1

21、991 American Association for the Advancement of Science.)Sex differences in (INAH)-3 of human brainPrenatal factors that may influence sexual orientation Note: abbreviations: CAH = congenital adrenal hyperplasia; DES = diethylstilbestrol.Fig. 11-14, p. 346Sexual orientations in adult relatives of a

22、homosexual man or woman. Note that the probability of a homosexual orientation is highest among monozygotic twins of a homosexual individual, lower among dizygotic twins, and still lower among adopted brothers or sisters. These data suggest a genetic contribution toward the development of sexual orientation. (Source: Based on the data of Bailey & Pillard, 1991; Bailey, Pillard, Neale, & Agyei, 1993)1. There is a persistently occurring genomic mutation, since homosexual individuals are less likely to have children2. A sufficient number