性与大脑课件.pptx

性与大脑鸟与鸣叫鸟与鸣叫成千上万种成千上万种鸟通过歌唱鸟通过歌唱来交流信息：来交流信息：求偶，宣称求偶，宣称领地领地通常仅雄性通常仅雄性会唱会唱斑胸草雀斑胸草雀鸟类鸣叫/歌唱是最好的人类语言模型金丝雀：雄性比雌性唱歌强斑胸草雀：仅雄性会唱歌，雌性与歌唱相关神经核团 退化或无法辨识斑胸草雀：仅雄性会唱歌.雌性与歌唱相关神经核团 退化或无法辨识斑胸草雀需要早期类固醇激素来组构他的与鸣叫相关的早期类固醇激素来组构他的与鸣叫相关的神经核团环路神经核团环路，晚期需要雄激素来激活这些核团晚期需要雄激素来激活这些核团.刚孵化的雌鸟给予雌激素或雄激素处理，他们的与鸣叫相关的神经核团会比正常雌鸟的大。成年时，给予这些雄性化的雌鸟雄激素，他们的与鸣叫相关的神经核团会变得更大，他会像雄鸟那样歌唱（如果年幼时没有给予雌激素或雄激素处理，那么成年后他们不会对雄激素产生反应！）但金丝雀的歌唱系统并不依赖于早期性激素的接触！春夏是金丝雀的繁殖季节（斑胸草雀生活在条件恶劣的沙漠地带，没有固定的繁殖季节，一旦食物充沛，条件合适，就可交配），每年春季，雄鸟雄激素激增，刺激与鸣叫相关神经核团增大2倍，神经元形成更大的树突，更多的突触，尤其在雄鸟成年期每年都有新生神经元的不断产生并参与到歌唱的神经环路。到了秋天，雄鸟的雄激素下降，与鸣叫相关神经核团萎缩.鸟儿如何学会了歌唱鸟儿如何学会了歌唱先天本能与后天学习共同作用，最终才能炼就成先天本能与后天学习共同作用，最终才能炼就成熟动听的歌曲熟动听的歌曲（鸣叫）早期感觉阶段，早期感觉阶段，年轻的雄鸟学习和记忆住老师学习和记忆住老师（通常是父亲）的歌唱。（通常是父亲）的歌唱。感觉运动阶段感觉运动阶段，年轻的雄雄鸟开始唱鸟开始唱起他那不成熟的歌曲，他通常使用听觉反馈来比较自己的歌与听觉反馈来比较自己的歌与记忆中老师的歌记忆中老师的歌。通过反复试错，他唱起的歌逐渐接近老师的歌了如果鸟儿在早期感觉阶段，听觉隔离，他还是能唱最基本的歌，反映出唱歌或鸣叫是鸟的本能行为。如果鸟儿在早期感觉期，仅能听到其它种类的鸟儿的歌唱，那他就唱别种鸟儿的歌，这反应出后天环境学习的影响。如果不仅能听到其它种类的鸟儿的歌唱还能听到同种类鸟儿的歌唱，那么鸟儿更倾向于学习同种类鸟儿的歌在感觉期之后，在感觉运动期之前。如果鸟儿聋了。他的歌将保持不成熟状态.对歌唱而言，感觉运动阶段是重要的，年轻的雄鸟开始唱起他那不成熟的歌曲，他通常使用听觉反馈来比较自己的歌与记忆中老师的歌。通过反复试错练习，他唱起的歌逐渐接近老师的歌了The song motor pathway(red),consisting of HVC(high vocal center高高级发声中枢级发声中枢)，RA(robust nucleus of the arcopallium弓状皮质栎核弓状皮质栎核),and the brainstem motor nuclei that regulate muscle contraction in the vocal and respiratory systems,is responsible for song production.歌唱的神歌唱的神经环路经环路高级发声中枢高级发声中枢弓状皮质弓状皮质栎栎l核核发声器官发声器官The anterior forebrain pathway(black),consisting of LMAN(巢巢皮质巨皮质巨细胞核外侧部细胞核外侧部)，area X(前脑基底神经节前脑基底神经节 X区区),and DLM(medial dorsolateral thalamus内背外侧丘脑内背外侧丘脑),is essential forsong learning.Dopamine neurons project to and modulate neurons in area X.巢皮质巨细胞核外侧部巢皮质巨细胞核外侧部前脑基底神经节前脑基底神经节 X区区歌唱学歌唱学习的习的神神经环路经环路高级发声中枢高级发声中枢弓状皮质弓状皮质栎栎l核核内背外侧丘脑内背外侧丘脑HVC(high vocal center高级发声中枢高级发声中枢)and RA(robust nucleus of the arcopallium弓状皮质栎核弓状皮质栎核),这这两个大脑皮层的神经核团类似于哺乳动物的运动皮层,对歌唱非常重要HVC neurons project to the RA,and RA neurons project to brainstem motor nuclei that control muscle contraction in the vocal organ and breathing center for song production.歌唱学习脑区：歌唱学习脑区：forebrain nuclei LMAN(lateral magnocellular nucleus of the anterior nidopallium巢皮质巨细胞核外侧部巢皮质巨细胞核外侧部)and area X(前脑基底神前脑基底神经节经节 X区区)老鼠的性与性行为老鼠的性行为Male rodents mount females，males show aggressive behavior toward intruders(particularly sexually mature males)in order to defend their territory.对雌性骑跨行为，为保护领地对入侵者攻击female rodents exhibit lordosis behavior when sexually aroused,assuming a posture that facilitates sexual intercourse.Females exhibit maternal behavior after giving birth to pups,including nest building,pup retrieval,and nursing.脊柱前突，分娩后的母性行为：筑巢，数幼崽，养育.Male Sexual Behavior.下丘脑内侧视前区下丘脑内侧视前区MPA是雄鼠的性行为控制中枢是雄鼠的性行为控制中枢 This schematic diagram shows a possible explanation of the interacting excitatory effects of pheromones,genital stimulation,and testosterone on male sexual behavior.延髓旁延髓旁巨细胞核巨细胞核下丘脑腹内侧核下丘脑腹内侧核VMH是雌性性行为控制中心是雌性性行为控制中心Female Sexual Behavior.This schematic diagram shows a possible explanation of the interacting excitatory effects of pheromones,genital stimulation,and estradiol and progesterone on female sexual behavior.旁巨细胞核旁巨细胞核in most mammals(including mice and humans),sex is determined by the presence or absence of the Y chromosome.People with a single X chromosome but no Y chromosome develop into females(Turner syndrome,occurring in 1 out of 2500 girls)。people with two X chromosomes and a Y chromosome develop into males(Klinefelters syndrome,occurring in 1 out of 1000 boys).性分化关键事件发生在胚胎发生中期（此时，生殖脊在雌性分化为卵巢，雄性分化为睾丸）It was discovered in the 1950s that when the genital ridge was removed in utero prior to overt sexual differentiation,all embryos differentiated as females.This experiment suggested that female differentiation follows a default pathway,and the presence of testes instructs the male differentiation pathway.生殖脊在明显性分化之前从子宫移除，则胚胎都发育为雌性，说明雌性为缺省分化路径Thus,the Y chromosome must contain some genetic factor(s)that exert its sex determination effect by promoting testis development.A single gene,Sry(Sex determining region Y),was identified in the 1990s.In humans,XY subjects with loss-of-function Sry mutations develop into females despite having the rest of the Y chromosome intact;this indicates that Sry is necessary for male differentiation.仅仅Sry 基基因突变，因突变，XY染色体的个体就会发育为雌性染色体的个体就会发育为雌性Moreover,XX mice carrying an Sry transgene on an autosome develop into males,with characteristic male reproductive system and male sexual behavior;this indicates that the presence of Sry in females is sufficient to convert them into males.仅仅将将Sry 基因转入常染色体，基因转入常染色体，XX染色体染色体的个体就会的个体就会发育发育为为雄雄性性The Sry gene on the Y chromosome determines male differentiation via testosterone productiona gene called the sex-determining region of the Y chromosome (SRY),which codes for a protein called testis-determining factor(TDF).Y 染色体性别决定区染色体性别决定区（SRY)编码睾丸决定因子，通编码睾丸决定因子，通过睾酮的产生来决定雄过睾酮的产生来决定雄性的分化性的分化A major function of the testes during embryonic development is to produce testosterone,a steroid hormone that promotes the development of the male reproductive system(masculinization)and inhibits the development of the female reproductive system(de-feminization).Testosterone and estradiol are the major sex hormonesSexually inexperienced,castrated males(that is,males with the testes removed)do not exhibit male-typical sexual behaviors,such as mounting of females and aggression toward intruder males.Acute injection of testosterone into adult castrated males can restore these behaviors,indicating an activational effect of testosterone in male sexual behavior.无性经验的阉割雄鼠不会展示雄性性行为无性经验的阉割雄鼠不会展示雄性性行为，但是注但是注射睾酮后他们会恢复这些行为，反应出睾酮对射睾酮后他们会恢复这些行为，反应出睾酮对雄性雄性性行为的激活效应性行为的激活效应Testosterone is synthesized from cholesterol in the testes.Because of its hydrophobic nature,testosterone can freely diffuse across the plasma membrane to enter target cells,where it binds to the androgen receptor.This binding triggers nuclear translocation of the testosteroneandrogen receptor complex,which acts as a sequence-specific DNA-binding transcription factor to activate or repress target gene expression.A testosterone metabolite,dihydrotestosterone(DHT),is a more potent activator of the androgen receptor and is responsible for external genital masculinization during development.Estradiol，the major estrogen(female sex hormone),is a steroid hormone made by the ovaries of sexually mature females.While estradiol is often regarded as the female counterpart of testosterone，it also plays important roles during male development.Like the effect of testosterone on castrated males,application of estradiol to ovariectomized females(that is,females from which the ovaries have been removed)can restore female-typical sexual behavior,such as lordosis.(Co-application of progesterone,another steroid hormone that regulates female sexual behavior,augments the effect of estradiol.)雌激素维系雌性性行为起重要作用雌激素维系雌性性行为起重要作用cells that express an enzyme called aromatase can convert testosterone(but not DHT)to estradiol.In these cells,therefore,testosterone can exert its action by two means:(1)by binding to an androgen receptor directly.(2)by binding to an estrogen receptor after being converted to estradiol.Early exposure to testosterone causes females to exhibit male-typical sexual behavior胚胎期第18天出生后第出生后第10天天This sensitive period coincides with peak testosterone production in male rodents.Testosterone exerts its organizational effect mainly through the estrogen receptors in rodentsDuring embryonic development in rodents,the testosterone produced by the testes of male fetuses can circulate through the blood to reach the brain.胚胎发育期，雄性胎儿产生的睾酮到达大脑，在芳化酶的作用下胚胎发育期，雄性胎儿产生的睾酮到达大脑，在芳化酶的作用下转化为雌二醇，导致大脑发生雄性化转化为雌二醇，导致大脑发生雄性化By contrast,estradiol,which originates from the placenta,is bound to and sequestered by circulating-fetoprotein,a protein secreted by fetal liver cells into the bloodstream.胎儿肝脏产生的胎儿肝脏产生的-甲胎蛋白和卵巢及母体胎甲胎蛋白和卵巢及母体胎盘产生的雌二醇结合盘产生的雌二醇结合，导致，导致雌二醇无法达到大脑。雌二醇无法达到大脑。This means that estradiol cannot reach the brains of males or females via circulation.导致雌二醇无法到达雌，雄胎儿的大脑导致雌二醇无法到达雌，雄胎儿的大脑However,estradiol can be produced locally within the brain cells of males by the action of aromatase on testosterone.During the early postnatal period,while the testes continue to produce testosterone,estradiol production by female ovaries is negligible.Therefore,only male brains can be affected by estradiol during early development.出生后的早期阶段睾丸分泌睾酮，卵巢分泌雌二醇几乎可忽略，出生后的早期阶段睾丸分泌睾酮，卵巢分泌雌二醇几乎可忽略，导致仅雄性脑在发育早期阶段被影响！导致仅雄性脑在发育早期阶段被影响！The organizational effect of testosterone has a sensitive window of action.experiments on rats and mice revealed that their sensitive period starts shortly before birth and spans the first 10 days after birth.性行为的敏感期（窗口期）是出生后的前十天testosterone is aromatization to estradiol and subsequent activation of the estrogen receptors.First,female mice treated with estradiol during the first 10 days after birth exhibit male-typical behaviors such as territorial marking and aggression toward intruders.Early estradiol treatment also reduces female receptivity to mating.Second,aromatase knockout male mice exhibit profound defects in male-typical behaviors.Third,although androgen receptor is expressed in the adult brain,its brain expression during the sensitive period of organization appears negligible.Indeed,male mice with brain-specific knockout of the androgen receptor still exhibit qualitatively similar male-typical mating behavior,albeit at a reduced level.Territorial marking behavior in male,female,and neonatal estrogen treated female mice.Male mice urinate throughout their cages(top panel),a typical territory-marking behavior.Female mice urinate in a corner(arrow in the middle panel).Female mice treated neonatally with estrogen(NE)partially adopt the male urination pattern(bottom).Sex hormones specify sexually dimorphic neuronal numbers by regulating programmed cell death Sexual dimorphisms vary widely across species.In the brain,dimorphisms are sometimes found,but they are significant in some species and nonexistent in others.An example of an animal with a large dimorphism is the Icelandic stickleback fish,in which the male brain is much larger than the female brain,perhaps because of the cognitive demands of nest construction,courtship,and childcare，which are carried out only by the male.Dimorphism in brain size.These brains are from adult female(left)and male(right)three-spined stickleback fish that were the same length and weight.The male brain is larger and 23%heavier than the female brain.The scale bar indicates 1 mm.Sexual dimorphism in neuronal number was first discovered in the medial preoptic area(MPOA)in the anterior hypothalamus,an area implicated by lesion studies as essential for male courtship behavior including mounting,intromission(insertion of the penis into the vagina),and ejaculation.雄鼠下丘脑内侧视前区雄鼠下丘脑内侧视前区MPOA对求偶，对求偶，骑跨，插入，射精行为很重要骑跨，插入，射精行为很重要.该核团该核团在雄性明显比雌性大在雄性明显比雌性大Nuclear staining indicated that the MPOA was several-fold larger in male rats compared to female rats.Castration immediately after birth caused a reduction in the size of the male MPOA,whereas treating females with testosterone at birth caused an increase in MPOA size.Sexual dimorphism in the medial preoptic area(MPOA)of the hypothalamus.(A)Nuclear staining of female(left)and male(right)rat brains revealed a striking size difference in a densely stained nucleus in the MPOA of the anterior hypothalamus(arrows).The absence of the suprachiasmatic nucleus(SCN)in the male brain is an artifact of the section plane.OC,optic chiasm.(B)Quantitative analyses show that the MPOA is eight times larger in males than females.The MPOA size is markedly reduced in males that were castrated as neonates,whereas females treated neonatally with testosterone have increased MPOA size.Further studies indicated that this difference is caused by programmed cell death that occurs only in females.In the male brain,sex hormones act during the sensitive period around birth to inhibit cell death programs in MPOA neurons.在敏感期，性激素（睾酮）阻断了下丘脑内侧视前区细胞的凋亡Since the discovery of sexual dimorphism in the MPOA,additional sexual dimorphisms have been found in other brain areas,including the medial amygdala and bed nucleus of stria terminalis(BNST).Both are basal nuclei in the forebrain that lesion studies have implicated in regulating male courtship behavior.内侧杏仁核，终纹床核为雄性求偶行为的脑区，雄性核团也比雌性的大Not all sexually dimorphic brain areas are bigger in males.The anteroventral periventricular nucleus(AVPV)in the hypothalamus is larger in females than males,consistent with its major role in regulating the female ovulatory cycle.Sex hormones also regulate sexually dimorphic neuronal connectionsaromatase-expressing neurons have denser projections to several parts of the brain in males than in females,including the ventromedial hypothalamic nucleus(VMH),a key center for regulating mating behavior.下丘脑腹内侧核下丘脑腹内侧核VMH是雌性性行为控制中心是雌性性行为控制中心Females that undergo neonatal estrogen treatment displayed male-typical neuronal number and projection patterns,indicating that these dimorphisms are largely produced by the neonatal action of estrogen.Sexual dimorphism of a penile muscle and its motor neurons.Sexual dimorphism in neurons of the spinal nucleus of the bulbocavernosus球海绵体肌脊髓核(SNB)is mediated by testosterone activation of the androgen receptor,which regulates gene expression to prevent programmed cell death of a penile muscle in males;trophic support provided by the muscle promotes the survival of its motor neurons.睾酮Sexual dimorphism in the spinal nucleus of thebulbocavernosus muscle.A.The spinal nucleus of the bulbocavernosus(SNB)is foundin the male lumbar spinal cord but is greatly reduced in thefemale.The motor neurons of the nucleus are present in bothsexes at birth but the lack of circulating testosterone in females leads to death of the SNB neurons and their target muscles.It is thought that testosterone in the male circulation promotesthe survival of the target muscles,which express the androgen receptor.In response to testosterone the muscles provide trophic support to the innervating SNB neurons.This musclederived survival factor is likely to be ciliary neurotrophic factor or a related member of the cytokine family.Thus testosterone acts on muscle cells to control the sexual differentiation of SNB neurons.Dendritic branching of SNB neurons is regulated by circulatingtestosterone in adult male rats.In males the dendritesarborize extensively within the spinal cord(upper photo).Thefact that the arbors are pruned in adult castrated male rats(lower photo)is evidence that this dendritic branching depends on androgens.The spinal cord is shown in transverse section and the SNB neurons and their dendrites are labeled by a retrograde tracer injected into target muscles.sex hormones can also regulate neuronal connections in adults.most of the excitatory synapses that provide input to cortical and hippocampal pyramidal neurons are formed on the dendritic spines.Thus,spine density can be used as a proxy for the density of excitatory synapses onto a pyramida