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Terms in this set (60)
-most species have 2 types of chromosomes
-autosomes (22 pairs): identical between sexes
-sex chromosomes (1 pair): determine sex based on # & identity
-in humans, a male specific chromosome is present or absent.
What determines biological sex?
-primary sex characteristics
-secondary sex characteristics
Primary sex characteristics
gonadal tissues formed by the genes on sex chromosomes that will ultimately
support male or female gametes
-ovaries, vagina, pennis, testis, (external & internal genitalia) organs that support reproduction
Secondary sex characteristics
traits such as differences in mammary
glands, distribution of body hair/fat/ muscle.
-organs that dont support reproduction
Secondary sex characteristics can be modified to match
-Both require supplementation with hormones.
primary sex characteristics can be modified
through gender reassignment surgery
-Both require supplementation with hormones.
-Typically assigned at birth based on external genitalia.
-When external genitalia are ambiguous, other indicators such as chromosomal sex are used.
-Biological sex does not necessarily define identity
-determined by chromosomes
-The attitudes, feelings, and behaviors a given culture associates with a person's biological sex.
-Changes with cultures and time.
A person's inherent sense of being male or female.
A component of identity that includes a person's sexual and emotional attraction to another person and the behavior and/or social affiliation that may result from this attraction.
-Sex determining region Y
-a gene on the Y chromosome that is responsible for masculinization in gonads.
-primary sex characteristic
SRY encodes SRY protein
-aka Testis determining factor (TDF)
-default state unless SRY is present
Ultimately what becomes the primary sex characteristics?
-a bipotential genital ridge
-sertorli cells- testis cords-semiferous tubules-(spermatogenesis) Leydig cells (produce testosterone)
SRY is regulated by 3 transcription factors
1. SF1 (Steroidogenic Factor 1)/Nr5a1
2. WT1 (Wilms tumor protein)
3. SP1 (Specificity Protein 1)
Transcriptional regulation of SRY leads to production of
what does TDF regulate?
SOX9 (a transcription factor) in sertoli cell precursors, which then upregulates genes involved in differentiation of sertoli cells.
Differentiating sertoli cells assemble into testis cords, which then stimulate
the sex-‐specific development of germ cells to form seminiferous tubules, testosterone-‐producing Leydig cells, and ultimately form the testes.
The bipotential gonad becomes male sertoli cells via
an autoregulatory feedback loop between SOX9 and FGF9.
SRY gene effects occur
6-8 weeks post-conception in humans
-10 weeks post-coitom in mice.
The testis secrete
anti-mullerian hormone (suppresses female reproductive tract) and testosterone (promotes male external genitalia)
SRY expression/sertoli cell differentiation is highly regulated
1. SRY expression starts in the middle 1/3 of the bipotential ridge and then spreads to the poles.
2. Critical window for SRY expression: delaying the expression of SRY expression results in a failure to initiate the testis development pathway.
-6 hr shift there's no development of testis.
3. Amount of SRY expression: a certain amount of SRY may be required to induce sertoli cell differentiation
4. Threshold: specific number of sertoli cells are required for testis development.
Even if 2 X chromosomes are present
-just the presence of SRY on the Y chromosome is sufficient to confer male phenotype
-ex. Klinefelter syndrome XXY: males are often sterile due to low T, hypogonadism and low sperm count.
The testis-determining activity of SRY is
so highly conserves that XX mice will undergo sex reversal w transgenic SRY from human or goat.
SRY is not believed to drive masculization of the
How does the brain become masculinized?
-testosterone (T) secreted into the bloodstream from testes and aromatized at distal sites (brain).
-Estradiol (E2) secreted by ovaries.
What is masculine behavior?
-Copulatory behavior (most studied), aggression (also studied), and physical characteristics (used in some species).
Cholesterol converted to 17B estradiol
1. aromatise to 17B estradiol (major)
2. 5a reductase to dihydrotestosterone (active metabolite)
Sexual Differentiation in the Brain:Cell-‐to-‐cell signaling:
2. Paracrine (neurotransmission and hormones) produced in brain
3. Endocrine (traditional view of hormone signaling) into bloodstream
Arnold Berthold, 1849: sexual differentiation
*Removed the testis from the rooster
and they became less aggressive, lost interest in hens, and did not develop like other males.
• "The testis acts on the blood, and the blood acts on the whole organism"
• Substance in testis, traveling through the blood, was responsible for regulating neural circuits and behavior.
1959, William C. Young: The Organizational/ Activational Hypothesis
- Prenatal treatment with hormones in female guinea pigs alters sexual behavior in adulthood (prenatal androgens reduce lordosis in adulthood in females)
- Sex steroid hormones during development "program" the nervous system for subsequent sex-‐specific behaviors.
~1959-‐1992: Sex differences in behavior are largely observable in mating/ copulatory behavior and parenting.
1. SDN-‐POA (sexually dimorphic nucleus of the preoptic area):
• Part of the MPOA
• 1st discovered (late 1970)
• most extensively studied, most obvious volumetric sex difference
• rodents, humans, ferrets, sheep, primates
• Contains GABAergic cells
2. AVPV (anteroventral periventricular nucleus):
• Part of the POA
• Second most obvious volumetric sex difference
• Contains GABAergic and dopaminergic cells
• ~1992-‐present: Sex steroid hormones regulate synaptic plasticity
1. Sexually Dimorphic Nucleus of the Preoptic Area (SDN-‐POA):
• Size and neuron number M>F (3-‐5x)
• T aromatized to E2 prevents apoptosis of neurons in males.
- Males have higher levels of the anti-‐apoptotic protein Bcl-‐2
- Females have higher levels of the pro-‐apoptotic protein Bax and higher levels of
caspase-‐3 to cause cell death of the SDN-‐POA.
• Exogenous E2 to females reverses these differences, suggesting that females have low levels of E2 or T converted to E2 during this time.
• Not yet understood how E2 regulates these proteins in the SDN-‐POA
In the SDN-‐POA (in rodents):
- Neurogenesis is E14-‐E18
- The sensitive period is E18-‐P4
- Sex differences are apparent after P4
Functional differences in SDN-‐POA between sexes
- Males: Can either block all copulatory behavior or diminish the frequency of mounting depending on extent of lesion.
- Females: Causes them to avoid male partners; will not display copulatory behavior.
• Neuronal activity:
- Males: Specifically increases firing before sexual activity, but declines soon
after contact with the female.
- Females: Increases firing during intromission, during preparatory phase of
mounting, and during ejaculation by the male.
-ex. rhesus monkeys used to demonstrate
2. Anteroventral periventricular nucleus (AVPV):
• F> M
• Absence of T in females prevents cell death of AVPV and promotes ovulation
• Presence of T in males promotes AVPV cell death.
• Projects directly to GnRH neurons that control the release of LH.
- In males, there is a pulsatile pattern
responsible for regulating levels of T.
- In females, there is a cyclic pattern
followed by a large surge -this causes ovulation.
• Also important for oxytocin regulation
and parental care
AVPV and parenting role and aggression
• TH+ neurons in AVPV controls oxytocin, maternal care (not paternal), and male- male aggression
• Overall, AVPV has more TH+ (dopamine) cells in F>M.
• Being a parent increases expression of TH+ cells in females, not males.
• Dopaminergic neurons of the AVPV can facilitate parental behavior in both virgin females postpartum females.
• No difference in maternal behavior is observed between the two groups following increased DA modulation except for in maternal duration.
-Male parental behavior was not significantly affected by manipulation
of TH+ cells in the AVPV.
-In males, TH+ cells in the AVPV do not affect aggression towards the pups, but they do regulate aggression towards other adult males.
Sex steroids hormones are potent regulators of synaptic plasticity
Sex differences exist outside of the hypothalamus as well and are of significant (and growing) interest in the last 30 years: implications for disease and the
processing of emotions, cognition, and memory.
-study by McCarthy
Sexual Dimorphism: Rapid effects
• Ovulation coincides with the LH surge in humans
• The rodent female estrous cycle is approximately 4 days
- Estropause is at approximately ~17-‐18 months of age
• The human female menstrual cycle is approximately 28 days
- Menopause occurs at ~age 50
• Oral contraceptive pills (OCPs) prevent the LH surge/ovulation.
- Maintains low E2 and P4 levels
• IUDs do not prevent ovulation.
Catherine Woolley and Bruce McEwen made a seminal finding in 1992:
circulating hormone levels influence dendritic spine density in the hippocampus of females.
-proestrus: more spines
-estrus: less spines
-remove hormones can have early menapause
ERα is located at
nuclear (largely GABAergic) and extranuclear site
• E2 increases slope of EPSP and the response induced by HFS is greater than aCSF.
Hormonal signaling in the brain
1. Classical signaling (slow - hours to days): Lipophilic steroid hormone (S) passes through the membrane and binds to a hormone receptor (HR) to regulate transcription/ translation.
2. Non-‐classical signaling (rapid - minutes): Hormone (S) binds to a receptor and activates second messenger systems to ultimately regulate gene transcription/ translation.
- Membrane-‐localized cells are believed to mediate the rapid effects.
Estrogen Receptor mechanisms
• Receptors: ERα, ERβ, GPER
• Intracellular ERs can form homodimers
• Hormones conjugated to BSA can test the effects of membrane-‐bound versus intracellular location of receptor
Progesterone Receptor mechanisms
• Receptors: mPRα-‐ε, PGRMC 1/2, PRA, PRB,
• BSA (only extracellular effect) conjugation can also be used for P4
• Enzyme inhibitors can be used to test the specificity of P4 versus ALLO.
• Testosterone can be converted to the active metabolite dihydro-‐testosterone by the enzyme 5alpha-‐reductase.
• Activates androgen receptors (AR) through a classical mechanism or indirectly through cell signaling pathways. -Not membrane-‐ bound like ERs and PRs.
Receptor expression of ERs and PRs change across the estrous cycle and differ between sexes
GPER = males and females about the same, but females had more with elevated E2 levels (similar to PR levels above presumably)
Hormones are synthesized locally in the brain (neurosteroids)
-derived from cholesterol
-converted in the mitochondrial membrane to pregnenolone then converted to neurosteroid in the ER
-then T gets aromatized to 17B estradiol
Hippocampus is a key area
• Identified using mass spec
• E2 conc. in hippocampus > plasma.
• E2 conc. in males > females in hippocampus (2x).
• P4 conc. highest during D1 in females.
• T conc. 8x higher in males than females, no cyclic change in females
• Local changes in neurosteroid levels could regulate dendritic spine density.
-progesterone increases spine density
Sex Differences in Behavior and Disease: Catamenial Epilepsey
• Cyclic fluctuations in seizures that are
related to hormonal fluctuations in the menstrual cycle (3 subtypes of catamenial epilepsy depending on when seizures occur within the cycle).
• Occurs in 10-‐70% of females with epilepsy.
• E2 = proconvulsant
• P4 = antiseizure
• Due to the decline in progesterone at the
time of menstruation.
Catamenial Epilepsey: E2 increases brain-‐ derived neurotrophic factor (BDNF)
-facilitates mossy fiber (MF) transmission
-(MF pathway connects the MF of the dentate gyrus to the CA3)
(causing epilepsy) males dont have changes in BDNF)
-P4 withdrawal decreases ALLO, synaptic
and extrasynaptic GABAA mediated inhibition is deregulated, net excitation increases.
Sex differences in behavior and disease: Addiction
• Path to abuse:
- Men are more likely to take drugs because for the positive reinforcing effects (thrill, enhance behavior).
- Women are more likely to take drugs for negative reinforcing effects (depression, anxiety, PTSD).
- This is not mutually exclusive.
• In cocaine abuse, women are more likely to transition from use to dependence, relapse, crave cocaine in response to stress, and attempt suicide.
• E2 decreases dopamine reuptake (tested in females).
• 30-‐41% of individuals with a lifetime
drug use problem have comorbid mood or anxiety disorder, which is a greater problem in females compared to males.
• This is not to say that males are protected or safe from illicit drug use or
abuse (secondary effects).
Sex more likely to become addicted to cocaine?
• AcquisiNon: 10 or more infusions on an FR1 schedule in a 6h period (one self admin session/day).
• Females learn to self-‐ admin cocaine and heroin more rapidly than males.
• Cocaine Self admin occurred in F >M
• Tamoxifen (TAM): produces a metabolite that is a potent ER antagonist
• Estradiol benzoate (EB): type of estradiol
• E2 is responsible for the increased reinforcing effects of cocaine in females.
-if u take away ovaries, didnt learn to self adm cocaine. Means Estradiol is responsible for increased reinforcement effects of cocaine in females.
Lack of E2 response in males may be due to organizational effects, whereas the E2 response in females is due to activational effects.
-Castration has no effect on cocaine self-‐administration behavior in males.
-Giving E2 to adult females can induce cocaine self-‐administration behavior irrespective of gonadal state.
Sex Differences in Behavior and Disease: PTSD/Anxiety
• Fear-‐based disorders are defined by exaggerated fear response and avoidance of cues.
• Lifetime prevalence for any anxiety disorder is 30.2% in females versus 19.2% in males.
• Females v Males: Panic disorder (5.0% v 2.0%), agoraphobia (7% v 3.5%), specific phobia (15.7% v 6.7%), social anxiety disorder (15.5% v 11.1%), generalized anxiety disorder (6.6% v 3.6%), PTSD (10.4% v. 5%) (McLean et al., 2011).
-females are more susceptible
Fear conditioning in humans
-measured by SCR (skin conductance response)
-Men had higher conditioned responses during the conditioning phase.
-No diff between men or female during extinction recall bc women are collapsed between high and low E2 conditions.
-higher extinction retention= less fear
-Women w high levels of E2 & males had better extinction learning vs females w low levels of E2.
points from the Hwang et al. (2015), study:
1. In most cases, women with high levels of E2 had greater brain activation in cingulate, amygdala, hippocampus, and hypothalamus. This was largely evident during both days of testing, so high E2 women had greater brain activation in conditioning, late extinction, and early recall.
2. High E2 women had greater brain activation than men, even though the previous study demonstrated that men exhibited greater conditioning than females. The current study was examining brain activation only and did not examine SCR as the previous study.
3. Women with low E2 and taking OCPs had similar brain activation patterns yet their estradiol levels differ. Low E2 women have temporarily low levels of E2 whereas women taking OCPs have chronically low levels of E2. This suggest that the cyclicity of hormones (E2) may be contributing to brain activation patterns and potential
physiological/behavioral effects in females. Also, synthetic estrogens found in OCPs may affect neural circuitry/overall physiology in ways that natural E2 does not.
4. Limitation: this study was conducted over two days. Although promising, this does not translate into the real world or the clinical setting very readily.
The greater SCR response in humans is representative of a greater fear response.
-Because women with low E2 express a greater fear response on recall compared
to those with high E2, it suggests that E2 facilitates consolidation of extinction on day 1.
-This is also supported in rats. High E2 rats not only learn extinction better, but E2 facilitates consolidation because high E2 results in less freezing behavior on recall.
Estradiol is necessary for extinction in males
• Increased freezing is indicative of memory for the conditioned event.
• Fadrozole prevents testosterone aromatization into E2. So if E2 is necessary for extinction consolidation, blocking E2 prevents memory of extinction training and rats will freeze on extinction recall.
• Males rats given pre-‐ or post-‐ extinction
injections of fadrozole showed impaired extinction recall (elevated freezing). -Fadrozole was ineffective when injected 4h later, because E2 was synthesized during the consolidation period (4 hours after training).
• Note that the FAD-‐Pre, FAD-‐Post group looks just like the Low E2 group in females on Day 3.
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