Mammalian sexual differentiation simple model

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Mammalian sexual differentiation (simple model)
Genetic Sex
Gonad (primary sex organ) Sex
Phenotypic Sex

• Key developmental neuroendocrine concept
• Organization versus activational effects of
  hormones

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Male Female Sexual Development

• Lack of SRY results in formation of ovaries.
• No MIS allows Mullerian ducts to develop.
• No Testosterone results in Wolfian duct
  regression.
• Feminization and demasculinization Default or
  Pre-Programmed Pathways

• SRY determines testis formation
• Sertoli cells in developing testis produce
  Mullerian-inhibiting hormone (aka MIS).
• Leydig cells in developing testis produce
  testosterone.
• MIS results in defeminization of accessory sex
  organs.
• Testosterone/DHT results in masculinization of
  genitalia.

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Summary of Mechanisms Underlying Sexual
Dimorophisms in the Nervous System.

• Spinal nucleus of bulbocavernosous (SBN) produced
  indirectly by masculinization of genitalia
  (requires androgen receptor stimulation) during
  perinatal development.
• Sexually-dimorphic nucleus of the preoptic area
  (SDN-POA) produced by estrogen-receptor
  mediated reduction of apoptosis during perinatal
  development.
• Medial amygdala posterior dorsal (MeApd)
  produce by estrogen-receptor stimulation that
  must be maintained throughout life.

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Classifications of Behaviors

• Consummatory behavior behaviors exhibited
  during completion of a motivated behavior.
  Consummatory sexual behaviors copulation.
• Appetitive behavior all behaviors an organism
  exhibits when attempting to gain access to a
  positive reinforcer (or avoiding a negative
  reinforcer). Appetitive sexual behaviors
  behaviors exhibited in order to gain access to an
  sexual partner.

Appetitive behaviors facilitate or arouse
consummatory behaviors
Temporal-Relational Model
Appetitive behavior
Consummatory behavior
Consummatory behaviors tend to diminish
appetitive behaviors
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The Hypothalamus-Pituitary-Gonadal Axis

• The brain is the overall controller of
  circulating gonadal steriods.
• Gonatopropin Releasing Hormone (GnRH) release by
  hypothalamus to stimulate anterior pituitary.
• Gonadotroph cells in anterior pituitary release
  Luteinizing hormone (LH) follicle stimulatin
  hormoner (FSH).
• LH stimulates Leydig cells in testis to release
  testosterone.
• FSH stimulates sertoli cells to produce sperm.
• Testosterone feedbacks to influence brain
  function, particularly those relating to
  reproduction.

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Hormonal Control of Male Sexual Behavior Summary

• Sexual behavior in both rodent and primate males
  is regulated by steriod hormones.
• Males have relatively constant levels of steroids
  and behavior.
• Both male sexual behavior is influenced by both
  androgen receptor (erection) and estrogen
  receptor (brain) stimulation.

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mPOA, DA, T in Male Copulation

• Glutamate is increased by sexual stimulation.
• Glutamate stimulates NMDA receptors which
  activates NOS.
• Increased NO stimulates DA release and/or reduces
  reuptake.

mPOA serves complex role in regulating sexual
behavior -integration of environmental stimuli
genital stimulation to trigger arousal/excitement
ejaculaiton.

• Roles of DA receptors in the mPOA during
  copulation.
• low threshold D2R respond to sensory stimuli
  (e.g. chemosensory) to facilitate erection.
• D1R respond to senory and genital (copulation)
  stimulation to maintain erection.
• High threshold D2R initiate ejaculation.

ER stimulation increases NOS making mPOA more
responsive to glutamate during sexual
stimulation-gt-gtinc DA release
Glutamate comes from MEA (chemosensory)
brainstem (genital)
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Endocrine Function in Rat Estrus Cycle
Diestus Low E P, releases LH FSH from
negative feedback and LH FSH rise producing
growth of follicle which increases E. Proestrus
Hypothalamic GnRH control of LH FSH regulated
by E in positive feedback (unknown mechanism)
resulting in LH surge that causes ovulation.
Estrus Hypothalmus returns to negative feedback
by E P. Corpus luteum grows giving rise to
increases in progresterone.
Notes Estrous (behavior) proestrus (endocrine)
phase Similar (perhaps identical) hormonal
regulation in menstrual and estrus cycles
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The Ovary during Menstrual Cycle
P
FSH
LH Surge
Graffian Follicle
E

• Under control of LH FSH, a follicle develops
  and is released at ovulation LH FSH are
  peptides that bind to cell-suface receptors on
  granulosa and theca cells and activate
  steroidogenic enzymes.
• Follicular Phase FSH induces follicular to grow
  and estrogen is produced by granulosa cells of
  the follicle as follicle grows more E is
  released.
• Periovulatory Period LH surge causes Graffian
  Follicle to rupture releasing ova. LH surge
  produced by E acting to stimulate HPG (positive
  feedback)
• Luteal Phase Progesterone is produced by Corpus
  luteum.

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Estrous versus Menustral Cycle
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Neural Control of Sexual Behavior
MPOA and VMH mutually inhibit each other to
control dynamics of lordosis and active
components of female sexual behavior.
MPOA
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The Sexual Brain
NAc
LH
VTA

• The medial preoptic area (MPOA) is critical for
  (active) copulatory behavior it receives direct
  and indirect input from brain areas that are
  important for the assimilation of sexually
  relevant information.
• Pheromonal stimulation is received by the
  olfactory bulbs (OB), the OB project to the
  medial amygdala (MeA), which relays information
  to the bed nucleus of stria terminalis (BST) and
  the MPOA.
• Additionally, the MPOA and MeA receive
  somatosensory input (from genitals) via the
  central tegmental field (CTF).
• In turn, the MPOA projects to the ventral
  tegmental area (VTA) and the brain stem (BS)
  which project to cortico-limbic structures.
• Nucleus accumbens (NAc), basolateral amygdala,
  and cortical structures are critical for
  motivational processes particularly for
  sexually-conditioned stimuli.
• Lateral hypothalamus involved in inhibiting mPOA
  and NAc.

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Types of Information Storage aka Learning/Memory

• Info storage system(s) in the brain acquires,
  stores (consolidation), and retrieves information
  to organize future behavior.
• There are multiple types of memory which seem to
  have somewhat independent neural substrates.

(Learning)
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Stress Memory
Acute mild to moderate stress (i.e. not
traumatic) has a bi-modal influence of the
storage of information.

• Epinephrine bimodally influence consildation
  (post-event encoding of information).
• Epi -gt Glucose -gt insulin -gt brain(?)
• -gt peripheral Rec - gt feedback to brain (?)

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Sex differences in human brain

• There are sex differences in neurotransmitter
  levels between men and women
• 5HT lower in women
• DA higher in women
• Also regionalization of neuropeptides e.g.
  vasopressin.
• Differences in receptor expression are also
  reported and important for transmission.

• Male brain gt female brain.
• These differences are corrected for overall size

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Sex Difference in Neurotransmitters

• There are sex differences in neurotransmitter
  levels between men and women
• 5HT lower in women
• DA higher in women
• Also regionalization of neuropeptides e.g.
  vasopressin.
• Differences in receptor expression are also
  reported and important for transmission.

Nishizawa and colleagues used positron emission
tomography (PET) to assess serotonin synthesis
rates in healthy men and women. a Images show
PET scans taken from a representative male and
female subject. Images are shown before and after
depletion of plasma tryptophan. The mean rate of
synthesis was found to be 52 higher in males
than in females. b Magnetic resonance images
for reference taken from the same level as the
PET images. The results may help to explain why
some disorders (such as unipolar depression) that
involve serotonin dysfunction do not equally
affect men and women.
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Sex Difference Cognition

• Sex difference have been recognized in a variety
  of behaviors, including cognition, reflect
  combined organizational and activational effects
  of steroids and experience on the nervous system.
• Organizing effects occur perinatally, puberty,
  and adult (e.g. chronic stress later)

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Sex Difference in Stress Cognition

• ACUTE STRESS
• Males and females show opposite effects to acute
  stress.
• Acute stress increases male dendritic trees but
  decrease those of females.
• Males also perform better on stress related
  learning (e.g. larger improvements in
  consolidation effects).
• CHRONIC STRESS
• affects male hippocampus much more than females
  (not affected by typical 2-3 week protocols).
• Effects on spatial memory match these
  morphological changes.
• Only limited stress paradigms have been examined
  (i.e. could be increased resistance not
  immunity).

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