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Behavioral Neuroscience Introduction to Neuroscience:
Sexual Dimorphism in Brain and Animal Behavior (Hormonal mechanism of behavior)
Tali Kimchi Department of Neurobiology [email protected]
Sexual Dimorphism
Sexual dimorphism is the difference in form between male and female members of the same species
Sexual dimorphism in body character
Sexual Dimorphism in Animal Behavior
Sexual Dimorphism in Social and Sexual Behavior
Territoriality (aggressive) Behavior
Pup Nursing and Maternal aggression
Courtship Behavior Sexual Behavior
Nature versus Nurture
“Males Toys” “Females” Toys
Tim
e c
onta
ct
(%)
The role of sex hormones in regulation of
sexual dimorphism in Behavior
Arnold A. Berthold (1803-1861)
In 1849, Berthold conducted the first formal experiment in behavioral endocrinology
Hypothesis: Intact testes are necessary for the development of male-typical morphological and behavioral characters.
Castration Castration +
Transplantation
in the same body
Castration +
Transplantation
in other body
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).
The first experiment in Neuroendocrinology (Berthold, 1849)
Ernest Henry Starling (1866-1922), English Psiologist
Starling (1905); Lancet
The first to use the term hormone. “Hormones” from Greek “ to excite”
Hormones: Blood borne chemical communication molecules
Sexually dimorphic social and sexual behaviors in rodents are all regulated by hormones
Aggressive behavior
Sexual behavior Maternal behavior
Maternal behavior in postpartum female rats
Pup retrieval Pup licking
Nest building Pup nursing
Terkel and Rosenblatt (1968)
Lactating female
Virgin 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.
The maternal behavior of the virgin toward newborn pups was facilitated when compared to the response of a virgin female that was transfused with virgin blood.
Prolactin level during pregnancy and postpartum
• Removal of litters from mother rats in the beginning of postpartum resulted in a rapid decline in serum prolactin, reaching pregnancy levels 3 hr later.
• Pregnancy levels: 8.3 ±0.1 ng/ml.
• 8-14 Postpartum days: 65.5 ±19.0 ng/ml
• ~15 Postpartum days: 25.7 ±5.5 ng/ml
• When litters of 10 pups each were returned to their mothers for 3 hr of suckling after 12 hr of non-suckling, serum prolactin increased precipitously to 130.3 ±19.6 ng/ml,
Amenomori et al 1970; Endocrinology
The role of prolactin in maternal behavior
It was showed that hypophysectomy (removing the pituitary gland) delayed the onset of maternal behavior in estrogen-treated females.
When the hypophysectomized females were injected
with prolactin or were implanted with a pituitary gland in the kidney capsule, where it secretes large amount of prolactin, short-latency maternal behavior was restored in females that had been primed with estrogen.
Bridges et al. 1990; PNAS
Vasopression Oxytocin
Adrenocorticotropic hormone (ACTH) Thyroid-stimulating hormone (TSH) Follicle-stimulating hormone (FSH) Luteinizing hormone (LH) Growth Hormone (GH) Prolactin (PRL)
The Hypothalamus-Pituitary-Gonadal Axis
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
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
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.
Steroid Hormones
Males: The Hypothalamus-Pituitary-Gonadal Axis
Intact males
Castrated males
Testosterone treatment
Effect of castration & testosterone treatment on male rodent (guinea pigs)
•In all rodents (mammals), gonadectomy decreases (abolish) male courtship and sexual behavior.
•Testosterone replacement reinstates sexual behavior in males.
Females: The Hypothalamus-Pituitary-Gonadal Axis
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.
The Hypothalamus-Pituitary-Gonadal Axis and estrous cycle of female rat
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.
William C. Young (1899-1965)
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.
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
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.
- Genetic disease (CAH)Congential Adrenal Hyperplasia
Elevated exposure to testosterone during development
Male-typical games
ק שח
מן מז
)%(
Girl with CAH
Healthy Girls
Healthy Boys
Boys with CAH
Female-typical games
Embryonic gonads
-
SRY
+ Testes Ovary
XX ♂ XY
FEMALE MALE
Organizing hormonal effects (development)
Activating hormonal effects (adult)
Feminization Masculinization
The organization and activation prevailing model (morphology characterization)
XY XX Sry XY XX XX Sry
Genotypically Female Mice Transgenic for SRY are Phenotypically Male
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
The organization and activation prevailing model of the brain
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.
Testosterone (Estrogen)
Low Estrogen
XY XX
Feminization Masculinization
Gender-specific phenotype
Testosterone
Brain Differentiation
Brain Activation
Estradiol
Sex Chromosome Genes P
erinatal
Adult
Organizing hormonal effects
Activating hormonal effects
SRY
♂ ♀
Hormones Hormones
Organization Activation
How sexually dimorphic behaviors are encoded in the brain of males and females?
SEX
Beer
Commitment
neuron
NOTHING
LOBE
SPEECH
SKILLS
Male Brain Female Brain
Bed Nuclei of the Stria Terminalis (BNST) Sexual Dimorphic-Nucleus of Preoptic Area (SDN-POA) Posterodorsal Medial Amygdala (MePD)
Sexual Dimorphic Brain Nuclei in Rodents (rat/hamster)
Anteroventral Periventricular Nucleus (AVPV)
Larger in male
Larger in Female
AVPV
Axonal projection from the BNST
♂ ♀
♂ ♀
Sexual Dimorphism in Brain Morphology
Cell number in the AVPV
♂ ♀
Tyrosine Hydroxylase
Estrogen Receptor β
AVPV
POA
BNST
Androgen Receptor
♂ ♀
Vasopression fiber in the Lateral Septum (LS)
Sexual Dimorphism in Brain Gene Expression
Xu et al 2012; Cell
Xu et al 2012; Cell
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.
Steroid Hormones
• 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.
Estradiol masculinizes the brain Testosterone, Estradiol or DHT masculinizes the brain ?
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.
Why female brain is not masculinized by estrogen?
Alpha-fetoprotein (AFP) role in female’s brain development
Tyrosine Hydroxylase (TH) gene expression in the hypothalamus (AVPV)
ATD= Aromatase inhibitor
Baker et al 2005; Nature neuroscience
Female-typical behavior Male-typical behavior
Cell death and sexually dimorphic brain nucleus (SDN-POA)
Cell number in the AVPV
♂ ♀
Cell death (Bax gene) is involved in brain developmental organization
Forger et al 2004; PNAS Jyotika et al 2007; Dev. Neurobiol.
Cell Number in AVPV TH gene expression in AVPV
Female-typical sexual behavior
* Gonadectomized+ estrogen+progesterone treatment in adulthood
• Prenatal testosterone treatment increased SDN volume in female rats but do NOT lead to increase in masculine sexual behavior.
• Treating males prenatally with aromatase inhibitor reduced SDN volume but do NOT (little) effect male sexual behavior or lead to increase in feminine sexual behavior.
De Vries et al 2002 J Neuroscience
Nu
mb
er
of T
H c
ell
Evidence for the affect of Y-linked genes on sexual dimorphism of the brain
♂ ♀
♂ ♀
Chemical (odor) signals that are emitted by animals to communicate information to their own species
What are pheromones?
What are pheromones?
Pheromone signals are largely involved in the regulation of social and reproductive behaviors in most animals (including in human)
Attracting mate partner Pups recognition Male territoriality
Primer effects: induce sequence of slow long-lasting physiological and neuroendocrine responses
Releaser effects: induce relatively rapid, fixed, behavioral responses
Ultrasonic vocalization in the presence of female
Aggressive behavior toward intruder male
Mating behavior
Pheromone effects in rodents
Aggressive behavior of lactating female
Maternal behavior (e.g. pups retrieval)
Bruce effect: Recently mated female will return to estrous if exposed to strange male (pregnancy block)
Whitten effect: Induction of estrous in group-housed females by exposing to male (urine)
Lee-Boot effect: Grouping several (8-12 individuals) females in a cage results in suppression of their estrous cycles
Vandenbergh effect: Puberty acceleration caused by exposure to male, during female development.
Puberty-delay caused by group-housed females.
Endocrine effects: Intact male exhibit LH surge Following exposure to female mice. Female exhibit LH surge in response to male or its bedding
The olfactory systems
Liman et al. 1999
TRPC2 expression in the VNO
VNO
OB
Detection of chemosensory signals in mice
Typical male-female reproductive behaviors
♂
♀
Aggressive behavior Sexual behavior
TRPC2 mutant female (brown) with normal male (black)
Sexual behavior of TRPC2-KO lab female
Kimchi et al. 2007; Nature
♂
♀ WT
WT
TRPC2-KO
Male-typical sexual behavior in TRPC2-KO lab females
An
ima
l m
ou
nti
ng
(%
) M
ou
nti
ng
tim
e (
se
c)
Pe
lvic
th
rus
tin
g (
se
c)
♀
Kimchi et al. 2007; Nature
Female
Male
Social behavior under semi-natural environment
control
mutant
Maternal Behavior
Failure to discriminate between male and female
?
Male-typical sexual behavior (courtship and mounting behaviors)
Female mutant
Normal male
Female-typical behavior (maternal behavior)
Summary-part 1: Behavioral phenotype of TRPC2-KO lab females
4 mutant males
2 control (normal) males
Pheromone inputs repress neuronal circuit for female-typical nursing behavior in males
♂
Catherine Dulac
Social and sexual behaviors of male mutant mice
Failure to discriminate between male and female
?
Aggressive behavior
Normal testosterone level
Female-typical behavior (pup caring / nursing behavior)
Model: Pheromone inputs repress neuronal circuit for male-typical sexual behavior in females
♂ Sex-specific
pheromone signals
♀ Sex-specific pheromone signals
Dulac and Kimchi, 2007; CONB
♂