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Behavioral Development:
The Influence of Sex II
Robert Meisel
April 21, 2015
Interim Summary
1. For all vertebrates there is a period during
early development when the nervous system is
organized in a male or female direction.
2. Among mammals, generally the production of
conversion of estrogen in the brain is the
trigger for the development of a male-like
nervous system.
3. Mechanistically, estrogen can promote the
immature conductance of Cl- in GABA neurons
hyperpolarizing the neurons and offering
protection against apoptosis.
Interim Summary
4. Another mechanism through which the
nervous system is sculpted in early
development is through the estradiol induction
of COX-2 and PGE2 synthesis, promoting
dendritic plasticity through AMPA-mediated
glutamatergic signaling.
5. All of these developmental events predispose
hormonal secretion in adulthood to activate
male or female patterns of behavioral
expression.
Epigenetic Regulation
of Sexual Differentiation
DNA methylation promotes feminization of the brain
whereas estradiol induced demethylation is involved
in masculinization.
Sex Differences in DNA
Methylation in the Preoptic Area
Nugent et al. Nat Neurosci e-pub, 2015
There are higher levels of complete methylation in the
preoptic area of female rats, with estradiol treatment
producing a male-like methylation pattern in females.
DNA Methylation Inhibitors
Masculinize Female Rats
Neonatal treatment with DNA methylation inhibitors
masculinized dendritic spine density in the preoptic
area and mounting behavior in adulthood.
DNA Methylation Inhibitors
Masculinize Female Rats
Demethylation can
masculinize outside
the developmental
window of estrogen
effectiveness.
Conditional Knockout of DNMT3a
Masculinizes Female Mice
Dnmt3aloxP/loxP mice
injected with AAV2-Cre in
the preoptic area are
masculinized as adults.
Dnmt3a is regulated by
neuronal activity and
therefore induces de
novo methylation, rather
than replication induced
methylation.
Sex Differences in Gene Methylation
Methylation of genes were
screened comparing males,
females and females who were
masculinized following
treatment with a DNA
methylation inhibitor. The
primary findings were that the
gene for the aromatase enzyme
(converts androgens to
estrogens) and 2 genes related
Cyp19a1: Aromatase to dendritic spine formation
Ppp1r9b: Neurabin II were demethylated.
Dbn1: Drebrin I
Rat Sex Video
Coincident Development of
Copulation and Genital Responses
Copulatory Behaviors
Genital Reflexes
Sachs and Meisel Psychoneuroendocrinology 4:287, 1979
The development of mounting, intromissions (mounts
with insertion) and ejaculation is coincident with the
associated genital reflexes.
Coincident Development of
Copulation and Genital Responses
Genital Reflexes in Rodents
Ischiocavernosus (IC)
Bulbospongiosus (BC)
Levator Ani (LA)
Levator Ani Development
Tobin and Joubert Develop Biol 146:131, 1991
The size of the levator ani
muscle diverges between
sexes prior to birth and to a
greater extreme postnatally.
This size difference in the
muscle is regulated by
androgens.
Spinal Motor Nucleus
of the Bulbocavernosus (SNB)
S Marc Breedlove
Michigan State
Art Arnold
UCLA
Sexually Dimorphic Nucleus
of the Bulbospongiosus (SNB)
Breedlove and Arnold Science 210:564, 1980
The SNB is essentially
absent in female rats,
mirroring the sex
difference in the dorsal
(levator ani) and ventral
bulbospongiosus muscles.
In other species (e.g.,
Onuf’s nucleus in humans)
the sex difference is not as
extreme.
Birth of the SNB
Thymidine labeling
showed that for both
males and females
the final cell division
for SDN neurons was
prenatal day 12.
Breedlove et al. Dev Brain Res 9:39, 1983
Developmental Control of SNB and LA
Breedlove and Arnold J Neurosci 3:424, 1983
Treating rats prenatally with an androgen receptor
antagonist (flutamide) reduced the size of the levator
ani and neuron number in the SNB.
Sculpting the SNB
Not surprisingly, the SNB
is present in both males
and females prenatally,
with cell death occurring
in female SNB neurons
without the trophic
actions of androgens.
Nordeen et al. Science 229:671, 1985
Is SNB Survival Activity Independent?
Unilateral treatment of SNB
neurons with TTX over a
period of 10 days has no
effect on SNB survival (graph
and image A). In contrast,
unilateral treatment with an
inhibitor of retrograde
transport decreases SNB
number, which can be
rescued by BDNF.
Al-Shamma and Arnold PNAS 94:1521, 1997
Target Tissue Regulation of the SNB
Removal of the target muscles
the day after birth produced
an elimination of SNB
neurons to the level seen in
normal female rats.
Kurz et al. Develop Brain Res 70:181, 1992
Target Tissue Regulation of the SNB
Araki et al. J Neurosci 11:3025, 1991
SNB neurons had their
axons cut and regeneration
then directed at either the
cognate targets (LA and BC
muscles, C) or an atypical
muscle target (S). The
trophic hormonal response
of SBN neurons depended
on their reinnervation to
the LA/BC muscles.
SNB Regulation of Target Tissue
Androgens have less
of a trophic effect on
denervated LA and BC
muscles.
Lubischer and Arnold J Neurobiol 26:225, 1995
Maternal Care and SNB Development
Female rats lick the genitals
of male pups more than they
do female pups. Male rat
pups with less than normal
levels of stimulation had
fewer SNB motor neurons
than males that were licked
more.
Moore et al. Brain Res 572:52, 1992
General Conclusions
• Estrogens acting on the medial preoptic
area in males maintain neurons
necessary for the development of overt
copulatory behaviors.
• Androgens maintain the motor neuron
muscle integrity needed for genital
reflexes critical to reproductive
success.