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Behavioral Development:
The Influence of Sex I
Robert Meisel
April 16, 2015
Dispensing with Nature vs. Nurture
Prenatal
In Amnion
Ex Amnion
Postnatal
Dating from the Nobel Laureate Konrad Lorenz, the
idea was that anything occurring prior to birth and
within the individual was the product of nature (e.g.,
genes), whereas anything after birth and outside the
skin was environmental
How Sex Develops
Defining Sex
1.
2.
3.
4.
5.
6.
7.
8.
Chromosomal
Gonadal
Internal Reproductive Morphology
External Reproductive Morphology
Hormonal Sex
Gender Identity
Partner Preference
Sexual Behavior
Distributions of Sex Differences
Of course sex differences are not dichotomous, but
have overlapping distributions that depend on the
dependent measure.
Origins of Behavioral Sex Differences:
Pre-1959
• Chromosomes
• Adult Hormonal Patterns
Reproductive System Development
If the embryo is female (XX), no
testosterone is made, the Wolffian
ducts atrophy, and the Mullerian
ducts develop into the internal
female reproductive organs.
If the embryo is male (XY),
testosterone stimulates the
development of the Wolffian ducts
to develop into male internal
reproductive organs and the
Mullerian ducts atrophy.
From Kobayashi and Behringer Nat Rev Genetics 4:969, 2003
Note that masculinization and feminization are separate
processes.
Organizational Hypothesis of
Sexual Behavior Development
Endocrinology 65:369, 1959
Organizational Hypothesis of
Sexual Behavior Development
Phoenix et al. (1959) experiment:
Pregnant guinea pigs were injected daily from days
10-68 of gestation (69 day gestation period) with 1 of
2 doses of testosterone. In adulthood the females
had their ovaries removed and were given hormone
treatments appropriate for stimulating male or female
sexual behavior.
Organizational Hypothesis of
Sexual Behavior Development
Phoenix et al. findings:
• “Hermaphrodites” showed male
mounting behavior, but little female
sexual behavior.
• “Unmodified” females also showed
mounting and little female sexual
behavior.
• Organization of the brain is more
sensitive to hormones than is peripheral
morphology.
Organizational Hypothesis of
Sexual Behavior Development
M McCarthy Physiol Rev 88:91, 2008
There is a period in early
development (the timing
of which differs among
species) during which
the brain is programmed
to respond in a male or
female direction when
stimulated by hormones
(activation) in adulthood.
Organizational Hypothesis of
Sexual Behavior Development
The twist here is that
regardless of the animal’s
genetic sex, manipulating
hormonal exposure in the
appropriate direction
produces female or male
behavioral and neural
phenotypes.
Fetal Testosterone Levels
Weisz and Ward Endocrinology 106:306, 1980
So here’s the rub…Both fetal male and female rats have
appreciable levels of testosterone, so why aren’t
females masculinized?
Male Fetuses Masculinize
Female Littermates In Utero
But they are (to a degree):
Rats
Guinea Pigs
Gerbils
Ferrets
Humans (?)
Meisel and Ward Science 213:239, 1981
Mice
Voles
Pigs
Rabbits
Hormonal Organization of the Brain
A small sampling of
regions omitting sex
differences in fiber
pathways.
From Wilson and Davis Reproduction 133:331, 2007
Sexually Dimorphic Nucleus of
the Preoptic Area (SDN-POA)
Roger Gorski, UCLA
Sexually Dimorphic Nucleus of
the Preoptic Area (SDN-POA)
SDN-POA in the mouse
labeled for androgen
receptor expression.
Oddly, though the most
famous sex difference, a
function for the SDNPOA has never been
clearly established.
Shah et al. Neuron 43:319, 2004
Interstitial Nucleus of the Anterior
Hypothalamus in Humans
Male
Female
Garcia-Falgueras and Swaab Brain 131:3132, 2008
Hormonal Organization of the Brain
Ingalhalikar et al. PNAS 111:823, 2014
Diffusion tensor imaging showing
pre-teen sex differences in interhemispheric connections. Red:
F>M; Blue: M>F
Estrogen Regulates Expression
of Apoptotic Proteins
Neonatal estradiol
injection decreases the
pro-apoptotic protein
Bax, while increasing
levels of Bcl-2.
Tsukahara et al Neurosci Lett 432:58, 2008
Regional Sex Differences are
Produced by Neuronal Death
Bax knockout (which inhibits
apoptosis) results in an
increased number of neurons
in the posterior bed nucleus
of the stria terminalis
(pBNST), eliminating the sex
difference in neruonal
number in this region.
Forger et al. PNAS 101:13666, 2004
GABA as a Bipotential Switch
During embryonic development the reversal potential for Cl- in
GABA neurons is positive relative to the membrane, meaning
that opening the ionotropic GABA receptor depolarizes the cells.
Bipotential Regulation of GABA
1. The chloride co-transporter, NKCC1, is highly expressed
perinatally. This transporter maintains high intracellular Clconcentrations, which along with the positive reversal potential
maintains GABA neurons as excitatory.
2. Over time this excitation will trigger the expression of the KCC2
transporter which pumps Cl- out of the cell, producing the
conventional hypopolarizing responses of GABA neurons.
3. Estrogen helps maintain GABA neurons in their depolarization
state, which through CREB-mediated signaling promotes cell
survival and plasticity.
4. It is thought this is part of the mechanism that protects brain
regions in males from apoptotic events.
Prostaglandins Mediate the
Masculinizing Effects of Estrogen
on Brain and Behavior
Neonatal Prostaglandins Masculinize
Adult Sexual Behavior
Amateau and McCarthy Nat Neurosci 7:649, 2004
Cox-2 is expressed in lower
levels in neonatal females
than in males. Neonatal
estrogen treatment reaises
Cox-2 levels to that of
males. Because COX-2 is
involved in the synthesis of
prostaglandins the idea was
that prostaglandins mediate
masculinization.
Neonatal Prostaglandins Masculinize
Adult Sexual Behavior
Estradiol appears to increase
spinophilin immunoreactivity
in the preoptic area of
neonatal rats. This effect is
mediated by prostaglandin
PGE2 signaling through
AMPA receptors.
Neonatal Prostaglandins Masculinize
Adult Sexual Behavior
The increase in spinophilin
neonatally is reflected in a
sex difference in the density
of dendritic spines on medial
preoptic area neurons in
adulthood. This sex
difference is eliminated by
giving female rats estradiol
neonatally or manipulating
PGE2.
Neonatal Prostaglandins Masculinize
Adult Sexual Behavior
The biochemical and structural
effects of the neonatal
manipulations were mirrored in
the levels of male copulation in
adulthood. Male rats treated
neonatally with a prostaglandin
inhibitor showed less
mounting, whereas females
treated with prostaglandin
mounted more as adults.
Prostaglandins and Sexual Behavior:
Translational Impact?
Aspirin inactivates COX-2, so it
is perhaps not surprising that
treating male rats neonatally
with aspirin reduces mounting
by the males in adulthood.
To be continued…