Introduction to Neuroscience: Behavioral Neuroscience

Transcription

1 Introduction to Neuroscience: Behavioral Neuroscience Hormones and Behaviors: Mechanisms underlying sexual dimorphic reproductive behaviors Tali Kimchi Department of Neurobiology * Presentation Materials for Personal Use ONLY

2 Sexual Dimorphism Sexual dimorphism is the difference in form between male and female members of the same species

3 Sexual dimorphism in body character

4 Sexual Dimorphism in Animal Behavior

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9 The role of sex hormones in regulation of sexual dimorphism in Behavior

10 Arnold A. Berthold ( ) German physiologist and zoologist In 1849, Berthold conducted among the first experiments in behavioral endocrinology Research question tested: Do the effects of prepubertal castration of male are dependent on neural connection to the testes

11 Castration Castration + Transplantation in the same body Castration + Transplantation in other body

12 Berthold s experiment: Summary and Conclusion Findings summary: Males that were castrated as juveniles later showed deficits as adults in males-typical body characters and in behaviors such as aggression, mating and crowing. -All of these effects could be reversed if the subject s testes, or the testes of another male, were implanted into the body cavity. Conclusion: Testes influence morphology and behavior NOT by the actions of nerves, but by secreting a substance into the bloodstream (i.e. hormones).

13 Ernest Henry Starling ( ), English physiologist The first to use the term hormone. Hormones from Greek to excite Starling (1905); Lancet Hormones: Blood borne chemical communication molecules

14 Sexually dimorphic social and sexual behaviors in rodents are all regulated by hormones Aggressive behavior Sexual behavior Maternal behavior

15 Maternal behavior in postpartum female rats Pup retrieval Pup licking Nest building Pup nursing

16 Terkel and Rosenblatt (1968) Virgin female Lactating female Blood was transfused from a parturient female (one that had given birth within 30 min of the onset of the transfusion) into a virgin female.

17 Maternal behavior of virgin females toward newborn pups is facilitated following blood transfusion from maternal females

18 Prolactin level during pregnancy and postpartum Pregnancy levels: 8.3 ±0.1 ng/ml Postpartum days: 65.5 ±19.0 ng/ml ~15 Postpartum days: 25.7 ±5.5 ng/ml Removal of litters from mother rats resulted in a rapid decline in serum prolactin level, reaching pregnancy levels 3 hr later When litters were returned to their mothers for 3 hr of suckling after 12 hr of non-suckling, serum prolactin increased sharply Amenomori et al 1970; Endocrinology

19 Prolactin release from the pituitary gland It was showed that hypophysectomy (removing the pituitary gland) delayed the onset of maternal behavior in estrogen-treated females. Rescue of the maternal behavior in hypophysectomized females: -prolactin injection -implantation with a pituitary gland in the kidney capsule (primed with estrogen) Bridges et al. 1990; PNAS

20 The Hypothalamus-Pituitary-Gonadal Axis Adrenocorticotropic hormone (ACTH) Thyroid-stimulating hormone (TSH) Follicle-stimulating hormone (FSH) Luteinizing hormone (LH) Growth Hormone (GH) Prolactin (PRL) Vasopression Oxytocin

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22 The Hypothalamus-Pituitary-Gonadal Axis The brain is the overall controller of circulating gonadal steroids Gonatopropin Releasing Hormone release by hypothalamus to stimulate anterior pituitary Gonatoproph cells in anterior pituitary release Luteinizing Hormone (LH) & Follicle- Stimulating Hormone (FSH). LH and FSH stimulates the gonads (Testes and Ovaries). Sex hormones (testosterone, estrogen, progesterone) release from the gonads feedbacks to influence brain function, particularly those relating to reproduction

23 The Sex Hormones Male (andrerogenic) sex hormone -Also being secreted by the adrenal gland Female (estrogenic) sex hormone * Both are steroid hormones and secreted in both sexes

24 Steroid Hormones Steroids are lipophilic, low-molecular weight compounds derived from cholesterol that are synthesized in the endoplasmic reticulum of cells in the gonads and adernal cortices and are then released into the blood circulation.

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26 Males: The Hypothalamus-Pituitary-Gonadal Axis

27 Effect of castration & testosterone treatment on male rodent (guinea pigs) Intact males Castrated males Testosterone treatment In all rodents (mammals), gonadectomy decreases (abolish) male courtship and sexual behavior Testosterone replacement reinstates sexual behavior in males

28 Females: The Hypothalamus-Pituitary-Gonadal Axis

29 The Hypothalamus-Pituitary-Gonadal Axis and estrous cycle of female rat Estrous cycle begins with secretion of gonadotropins from the hypothalamus, which stimulate the growth of ovarian follicles, and ovulation; the ruptured ovarian follicle becomes a corpus luteum and produces estrodiol and progesterone

30 Hormonal activation of female-typical sexual behavior In all rodents, gonadectomy decreases (abolish) female sexual receptivity Estrogen and progesterone replacement reinstates sexual behavior of females

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32 William C. Young ( ) Endocrinology, 1959 Young demonstrated that perinatal exposure of female guinea pigs to elevated androgens permanently suppressed their capacity to display feminine sexual behavior (defeminization) and significantly enhanced their display of masculine sexual behavior (masculinization). It was suggested that the exposure to prenatal androgens had permanently altered the brain tissues underlying sexual behavior and that, similarly to the peripheral sexual organs, androgens organized the developing nervous system at a critical period of early development.

33 The organization/activation hypothesize Sex hormones act during prenatal stage to permanently (irreversibly) organize the nervous system in a sex-specific manner During adult life, the same hormones have activation effects, causing it to function sex-typical manner in adulthood

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35 Organization and activating effects of hormones Sex hormones can have the following effects: 1. Organizing effects- occur mostly at sensitive stages of development. -Determine whether the brain and body will develop male or female characteristics 2. Activating effects- occur at any time of life and temporarily activate a particular response.

36 Gynadromorphic Finch Male Female Agate et al 2003 PNAS

37 Testis Ovary ZZ (male) ZW (female) ZZ (male) ZW (female) Gene that expresses on the W chromosome Gene that expresses on the Z chromosome

38 Male Female Brain region that responsible to male singing Typical song of male Agate et al 2003 PNAS

39 The organization and activation prevailing model (morphology characterization) MALE XY XX FEMALE Embryonic gonads Testes + - Ovary SRY Masculinization Organizing hormonal effects (development) Activating hormonal effects (adult) Feminization

40 Genotypically Female Mice Transgenic for SRY are Phenotypically Male XY XX XX Sry XY XX Sry

41 The Klinefelter syndrome, also known as the XXY genetic disorder symptoms include: 1. reduced fertility or full infertility to some extent. 2. Female-typical body charectristics

42 The organization and activation prevailing model of the brain Perinatal Adult Testosterone (Estrogen) XY Masculinization Testosterone SRY Brain Differentiation Brain Activation XX Feminization Gender-specific phenotype Low Estrogen Estradiol Sex Chromosome Genes Organizing hormonal effects Activating hormonal effects The default sex in mammals is female. The differences between male and female behaviors are almost entirely a consequence of early-age exposure to testosterone.

43 Hormones Hormones Organization Activation

44 Sexual Dimorphic Brain Nuclei in Rodents (rat/hamster) Bed Nuclei of the Stria Terminalis (BNST) Sexual Dimorphic-Nucleus of Preoptic Area (SDN-POA) Posterodorsal Medial Amygdala (MePD) Larger in male Anteroventral Periventricular Nucleus (AVPV) Larger in Female AVPV

45 Sexual Dimorphism in Brain Morphology Cell number in the AVPV Axonal projection from the BNST

46 Sexual Dimorphism in Brain Gene Expression Vasopression fiber in the Lateral Septum (LS) Tyrosine Hydroxylase Estrogen Receptor β AVPV Androgen Receptor POA BNST

47 Xu et al 2012; Cell

48 Xu et al 2012; Cell

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50 Steroid Hormones Steroids are lipophilic, low-molecular weight compounds derived from cholesterol that are synthesized in the endoplasmic reticulum of cells in the gonads and adernal cortices and are then released into the blood circulation.

51 Testosterone, Estradiol Estradiol masculinizes or DHT masculinizes the brain the brain? Testosterone treatment in neonatal rats is blocked by prior administration of specific estrogen receptor antagonist DHT does not mimic the effect of testosterone Radio-labeled testosterone is recovered from the brain as radio-labeled estradiol Aromatase inhibitors counteract the effect of testosterone administration

52 Why female brain is not masculinized by estrogen? Estradiol production by the fetal ovaries is minimal Circulation of α-fetoprotein (AFP) is present at high levels in embryos AFP = Fetal plasma protein that binds estrogens with high affinity and prevents it s passage through the placenta.

53 Alpha-fetoprotein (AFP) role in female s brain development Tyrosine Hydroxylase (TH) gene expression in the hypothalamus (AVPV) ATD= Aromatase inhibitor Female-typical behavior Male-typical behavior Baker et al 2005; Nature neuroscience

54 Cell death and sexually dimorphic brain nucleus (SDN-POA) Cell number in the AVPV

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56 Cell death (Bax gene) is involved in brain developmental organization Cell Number in AVPV TH gene expression in AVPV Female-typical sexual behavior * Gonadectomized+ estrogen+progesterone treatment in adulthood Forger et al 2004; PNAS Jyotika et al 2007; Dev. Neurobiol.

57 Prenatal testosterone treatment increases SDN volume in female rats but do NOT lead to increase in masculine sexual behavior Treating males prenatally with aromatase inhibitor reduces SDN volume but do NOT (little) effect male sexual behavior or lead to increase in feminine sexual behavior

58 Evidence for the affect of Y-linked genes on sexual dimorphism SRY is needed for sexual dimorphism in TH expression De Vries et al 2002 J Neuroscience

59 Latency to follow intruder female Evidence for the affect of Y-linked genes and SRY on sexual dimorphism social interactions All animals were gonadectomized (i.e. equal hormones level) Gatewood et al 2008 McPhie-Lalmansingh et al 2008

60 Sexual dimorphism in human behavior: Nature versus Nurture

61 Sexual dimorphism in behavior: Nature versus Nurture

62 Time contact (%) Males Toys Females Toys

63 זמן משחק )%( Congential Adrenal Hyperplasia )CAH (- Genetic disease Elevated exposure to testosterone during development Female-typical games Male-typical games Girl with CAH Healthy Girls Boys with CAH Healthy Boys

64 The index fingers of most straight men are shorter than their ring fingers, and for most women they are the same length or longer. Gay men and lesbians tend to have reversed ratios. Male-like ratio Female-like ratio Williams, T. J. et al ( 2000) Nature

65 The boy who was raised as a girl Bruce's penis was damaged In unsuccessfully surgery for urinary problems Twins Bruce and Brian Reimer were born in Canada as two perfectly normal boys Suggested the ideal sex change experiment Dr John Money was a psychologist specializing in sex changes

66 The boy who was raised as a girl Dr Money genuinely believed that Bruce had a better chance of living a happy life as a woman than as a man without a penis Suggested the ideal sex change treatment Bruce raised as Brenda At the age of ~2 years old Bruce is castrated and treated with female sex hormones

67 The boy who was raised as a girl David got married but later had become depressed At the 38 years old David committed suicide (2 tears after his brother died from over a drug overdose) At the age of 15 Brenda switch again to male called David

68 Sexual dimorphism can NOT be explained just by sex hormones organization affects X Y

69 Imprinting genes Definition: A gene or chromosome region that is expressed when inherited from one (maternal or paternal) parent. But not when inherited from the other parent (i.e. parent-specific inactivation of a gene).

70 Imprinting genes Mechanism: Imprinting is determined by allele-specific DNA methylation at critical sites (e.g. promoter region) which represses the expression of the gene. DNA methylation is the convalent attachment of methyl to the cytosine using DNA methylase enzyme. Result: DNA methalation may inhibit transcription by mainly preventing the binding of transcription factors to the promoter region.

71 Imprinting genes Biology function: The battle of the sexes theory or parental conflict theory The father is more interested in the growth of the offspring, at the expense of the mother. The mother s interests is to conserve resources for her survival and provide sufficient nutrition to her pups. Parental genes are selected to extract resources from the mother to give to the fetus, while maternal imprinting genes are selected to inhibit this transfer of resources Maternal imprinting genes will repress growth of pups and paternal imprinting genes will enhance growth.

72 Paternally imprinted genes (Peg1/Mest) Normal animal Peg1 enhance maternal care Peg1 mutant female will exhibit deficiency in maternal behaviors Curley et al 2004 Proc R Soc B

73 Paternally imprinted genes (Peg3) Time to retrieve pups Mutant Wild type Postparum Virgin Latency of nest building Postparum Virgin Lefebvre et al 1998; Nature Genetics Keverne et al 1999; Science

74 Imprinting genes and human disease