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Sexual Differentiation of Brain & Physiology:
Pfeiffer (1933)
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Known: The pituitary and ovary were important for ovulation.
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Question: Are there differences between males and females in ability to
support ovulation?
ovarian fragments
(able to ovulate)
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eyes
of female
rats
show
ovulation
eyes
of male
rats
could not
show
ovulation
Concluded: Males and female rats differ in their ability to support
ovulation.
Concluded (although incorrectly): Male rat’s pituitary was unable to
support ovulation.
Sexual Differentiation of Brain & Physiology:
Pfeiffer (1933)
•
Question: Are testicular secretions during first few days of life involved
in making male rats unable to support ovulation?
newborn male
newborn
female
•
castrated
at birth
implanted
w/testicular
tissue
at birth
implanted
w/ovaries
as adults
as adult,
w/own ovaries
or implanted
ovaries
male could
show
ovulation
female
could not
show
ovulation
Concluded: Testicular secretions act early in development to make male
rats (and even female rats) unable to support ovulation.
Sexual Differentiation of Brain & Physiology:
Harris (1952)
•
Known:
– species that are “induced ovulators”--ovulation is triggered by copulation
(e.g., rabbit, cat); implied that the NS was involved in the process of
ovulation (via sensory input associated with copulation)
– hypothalamus (in the brain) was the likely source of control
•
Question: Are differences in the ability to support ovulation between
male and female rats the result of differences in the pituitary or brain?
removed
pituitary
from
female rat
implanted
pituitary
from
male rat
female rat with a
male pituitary
could show
ovulation
•
Concluded: The difference between male and female rats in the ability
to support ovulation was not due to differences in the pituitary.
•
Instead, differences must lie within the brain--hypothalamus.
Ovulation and GnRH Surge in Rats:
Ovulation:
• as follicles develop in ovary
GnRH Neuron
HYPO
– increasing levels of estrogen
are released
+
GnRH
– in female rats, increases in
estrogen lead to a GnRH
surge (positive feedback)
ANT
PIT
FSH
LH
– GnRH surge leads to LH
surge
– LH surge leads to ovulation
OVARY
Estrogen
GnRH: gonadotropin-releasing hormone
FSH: follicle stimulating hormone
LH: luteinizing hormone
•
male rats are unable to show
a GnRH surge in response to
increases in estrogen
Sexual Differentiation of Brain & Behavior:
Males & females of a variety of species show differences in behavior.
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One example is the display of lordosis by female rodents during mating.
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Lordosis--posture shown by female rodents in which the female arches her
back to elevate the rump and head.
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Background:
– estrogen and progesterone have activational effects on female sex behavior
– ovariectomize (OVX) adult female rats-->females don’t show lordosis
– OVX adult female rats + [estrogen followed by progesterone]-->female will
show lordosis
– castrate adult male rats + [estrogen followed by progesterone]-->don’t see
lordosis
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Basic observation: the nervous system of adult males and females are
different in their behavioral responsiveness to hormones.
Sexual Differentiation of Brain & Behavior:
Phoenix and associates (1959)
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Studied female sex behavior in guinea pigs--display of lordosis.
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Question: Does exposure to androgens early in development alter the
display of female sex behavior in the adult?
•
newborn
male
castrated
at birth
newborn
female
given
androgens
at birth
given
estrogen &
progesterone
as an adult
given
estrogen &
progesterone
as an adult
male can
show lordosis
in response to
mounting
female cannot
show lordosis
in response to
mounting
Concluded: Testicular secretions act early in development to make male
rats (and androgenized females) unable to show female sex behavior
(lordosis). Instead, androgen exposure “organizes” the brain so that
males will show male sex behavior in the adult.
Process of Sexual Differentiation:
MALES
FEMALES
masculinized
feminized
defeminized
demasculinized
Role of androgens in males:
• permanently masculinize the brain
– male specific responses (sex behavior)
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permanently defeminize the brain
– inability to support ovulation (no GnRH surge in male rats)
– inability to show female sex behavior in presence of ovarian hormones
What about females?
• Dogma: no androgens-->brain & behavior becomes feminized (passive)
• However, recent evidence suggests that some estrogen is needed for
“active”
development of female brain and display of female-specific responses.
– block interaction of estrogen with ER (antagonist) during development-->
individual that shows no female sex behavior nor ovulation
Critical Periods:
•
brief “windows of time” when steroids can alter development of body
and nervous system
Rats:
• injections of testosterone on day of birth or up to around the
10th day of life can render a female anovulatory and unlikely to
display lordosis
• however, injections of testosterone by day 12th (or after) has
little effect on these measures
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multiple “windows” are seen during development
– prenatal, perinatal and postnatal periods
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these “windows” reflect transient changes in steroid levels and require
the presence of steroids receptors (ARs or ERs) and possibly converting
enzymes (aromatase or 5α-reductase)
Paradox:
Early exposure of newborn females to elevated levels of estrogen could
masculinize the brain, behavior & physiology of these individuals as adults.
Estrogens are largely formed by the ovary and ovaries are found in females.
• Why would an ovarian hormone cause masculinization of the brain and
behavior?
Testosterone
(precursor)
estrogen
aromatase
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Aromatization is important for masculinizing the brain in some species
(rats).
– testosterone
estrogen
estrogen-ERs
produces an effect
– need testosterone, aromatase (which will produce estrogen), and ERs
•
If estrogens can masculinize the brain, how do females normally escape
masculinization?
– ovaries of female fetuses (in utero) secrete very little steroid
– both male and female fetuses see high levels of estrogen (source: maternal ovaries,
adrenal glands)
– normally, the brains of male fetuses are masculinized/defeminized but the brains of
females are not--why?
– presence of a protein: -fetoprotein (AFP)
– AFP binds to estrogen and appears to block estrogen’s ability to reach the brain
– however, AFP does not bind to testosterone; therefore, testosterone can enter the
brain and be converted to estrogen via aromatase--masculinization of brain
– the ability of exogenous estrogen to masculinize the brain requires--high levels-which presumably swamps the buffering capacity of AFP allowing some estrogen
to reach the brain
– estrogen and sexual differentiation:
• no estrogen
• some estrogen
”unisex brain”
feminized brain
• testosterone or lots of estrogen
masculinized brain
Species Differences:
There are species differences in what hormones masculinize and defeminize the
brain and behavior.
male sex
behavior
•
rats/hamsters
guinea pigs/primates
dependent
on
aromatization
not dependent
on
aromatization
In guinea pigs and primates:
– testosterone or other androgens (dihydrotestosterone) must interact with ARs to
masculinize/defeminize the brain
– of interest, a homologue to AFP has been identified in primates but does not
bind to estrogen (in rats, the AFP does bind to estrogen)
Species Differences:
There are species differences in what processes are masculinized and
defeminized.
Masculinized:
Defeminized:
male rats
male primates
male sex
behavior
true
no positive
feedback response
to estrogen; no
support of ovulation
not true
Sexual Dimorphisms within Adult Nervous System:
Sexual dimorphisms have been observed in the following parameters:
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number of neurons
size of neurons (large or small)
number and shape of synapses
length and branching of dendrites
amount and type of neurotransmitters, enzymes and receptors that are
expressed
Examples (shown in class):
• SDN-POA (sexually-dimorphic nucleus of the preoptic area)--sex
differences in the size of nucleus
• SNB (spinal nucleus of the bulbocaveronosus)--sex differences in the
presence/absence of brain nucleus
How do hormones affect sexual differentiation?
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drive neuronal cell differentiation (number of cells born), cell migration
and/or cell survival
– Ex. SDN-POA
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promote outgrowth of dendrites and axons of specific neurons
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provide target-derived neurotrophic action
– Ex. SNB
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regulate the expression of specific molecules--neurotransmitters, enzymes
and receptors
Hormones--Cell Survival:
Ex. Sexually Dimorphic Nucleus of the Preoptic Area (SDN-POA) (in rats)
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SDN-POA is 3-5 times larger in males than in females
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aromatization of testosterone to estrogen is important for masculinization
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originally thought--androgens were important in stimulating the number of
neurons born in males that will migrate to, and form, the SDN-POA (book)
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however--more recent data suggest that exposure to androgens perinatally act
to increase the number of neurons that survive in males than in females
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how can we follow cell birth/survival? tritiated thymidine autoradiography
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current view: (following injection of 3H-thymidine on day 18 of gestation)
– PN4--# neurons in SDN-POA: males=androgenized females= females
– PN7--# neurons in SDN-POA: [males=androgenized females]>females
–
neurons are lost in females at PN7 and PN10; exposure to testosterone (from E20
to PN10) can prevent this loss
– males have larger SDN-POA because more neurons survive into adulthood, and
also because of an increase in volume not associated with addition of more
neurons--increase in cell size (larger) and/or more connections
Tritiated Thymidine Autoradiography:
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neuroblasts in the ventricular
zone will divide, differentiate
into neurons, and migrate to
specific areas in the brain
during cell division, DNA is
being synthesized
3H-thymidine will be
incorporated into newly
synthesized DNA
if 3H-thymidine is injected on
day 18 of gestation, then all
neurons “born” on day 18 will
have radioactive DNA with
cell’s nucleus
can identify “birthdate” of
neurons by exposing brain
sections to X-ray film or by
dipping sections in a
photographic emulsion
Developing
Brain
Ventricular
Zone
day 17 day 18 day 19
Gestation
[3H]-thymidine
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radioactivity will expose the photographic
emulsion
can learn: how many neurons are born
on a given day, where they migrate, and
if they survive into adulthood
Hormones--Target-Derived Neurotrophic Function:
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Ex. Spinal Nucleus of the Bulbocavernosus (SNB) (in rats)
SNB is present in males and absent in females
SNB neurons are motoneurons that innervate muscles attached to the penis
(perineal muscles)
early in development: androgens increase survival of muscles which leads to
survival of motoneurons innervating the muscles
Perineal
muscles
secrete a
“retrograde factor”
that leads to
survival
of neurons
•
•
SNB
during
critical period
of development,
muscles can bind
androgens while the
motoneurons
cannot
later in development: androgens act subsequently to increase size of neurons
(larger); ARs are expressed in SNB motoneurons at later time than ARs
expressed in muscle
administration of estrogen cannot masculinize SNB motoneurons (aromatization
is not important); thus, androgens act directly at ARs to masculinize SNB system
Example Question:
What structures within the nervous system would be masculinized or feminized
in a male rat with testicular feminization mutation?
SDN-POA
normal
male
male with
TFM
masculinized
(large)
SNB
masculinized
(large)
Sexual Differentiation of the Human Nervous System:
Sexually dimorphic nuclei have been described within preoptic area of humans:
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INAH-1 (intermediate nucleus of the anterior hypothalamus--cell group #1)
– nucleus is larger in males than in females
– sex difference develops postnatally (not present at birth)
– after 4 years of age, the number of neurons in nucleus die in females, but remain
the same in males; androgens are believed important for survival of these neurons
– function is not currently known
•
INAH-3 (interstitial nucleus of the anterior hypothalamus--cell group #3)
– nucleus is larger in males than in females
– not clear how hormones affect its development
– nucleus is also larger in heterosexual men than homosexual men; suggested that
this nucleus might be important for sexual orientation
– sexual orientation can be viewed as a sexually dimorphic response: masculine
preference is for female partners, and feminine preference is for male partners
– smaller INAH-3 in homosexual men=feminine preference for male partners
– elevated androgens in utero may act to masculinize sexual orientation
– evidence that 37% women with CAH rate themselves as bisexual or homosexual
while only 7% women without the disorder rate themselves similarly
– cautionary note: sex behavior in humans can be affected by many factors
Sexual Differentiation of the Human Nervous System:
Onuf’s nucleus is also sexually dimorphic in humans:
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Onuf’s nucleus is the homologue to the rat SNB
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motoneurons within Onuf’s nucleus innervate roughly the same group of
muscles within the perineum: the bulbocavernosus (BC) and ischiocavernosus
(IC) muscles; humans (and other higher mammals) lack levator ani muscle
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men have larger BC and IC muscles and more neurons within Onuf’s nucleus
than females
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subtle effect: sex difference between men and women is smaller than the
difference reported between male and female rats; in female rats, these
muscles are lost and so are the motoneurons
Sexual Differentiation of the Human Nervous System:
Sex differences have also been reported in cognitive function:
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men are lateralized in auditory function: most men can hear better with their
right ear than with their left
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in contrast, women tend to be less lateralized in auditory processing, hearing
equally well with right and left ears
Women exposed to a synthetic estrogen in utero show higher levels of
lateralization in auditory function:
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in 1950s and 1960s, diethylstilbestrol (DES--synthetic estrogen) was given to
pregnant women to prevent miscarriages
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women exposed to DES in utero were more lateralized in word detection than
their sisters that were not exposed to the drug
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in females, exposure to exogenous estrogen can masculinize auditory function
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in males, testosterone is most likely aromatized to estrogen which leads to
lateralization of auditory function