CMM/BIO4350
Tues April 5, 2012
Diane Lagace, PhD
Assistant Professor
Department of Cellular and Molecular Medicine (CMM)
Neuroscience Program
RGH, Room 3510G, University of Ottawa,
dlagace@uottawa.ca
Exam Info
QUESTIONS ALL IN ENGLISH
CAN ANSWER IN FRENCH OR ENGLISH
INSTRUCTIONS
This is a closed-book exam. No supplemental materials are allowed.
Read each question carefully and answer ALL questions.
The exam will be graded out of a total of 50 marks.
The first section is based on Dr. Beique’s material and is worth 10 marks. This includes questions B1-B3.
The second section is based on Dr. Maler’s material and is worth 10 marks. This includes questions M1M3.
The third section is based on Dr. Lagace’s material and is worth 30 marks. This includes questions L1L17.
6 Lectures
1.
2.
3.
4.
5.
Embryonic Development 101
Chapter 7: Understanding CNS structure through development (p178-201)
Gross Neuroantaomy
Chapter 7: Gross Organization of Mammalian Nervous System (p168-176)
Chapter 23 Genesis of Neuron, Connections and Elimination of Cells and Synapses
(p690-707
Chapter 7 Appendix: Illustrated Guide to Human Neuroanatomy (p206-248)
The Genesis of the Neuron (Neurogenesis) and Neuronal Connections and Regeneration of Nervous
System
Chapter 23: Connections and Elimination of Cells and Synapses (p690-707)
From lecture notes only; not in text book
Chemical Controls of Brain and Behavior
Chapter 15: Hypothalamus, ANS, Neurotransmitter Systems (p482-504)
Motivation and Homeostasis
Chapter 16: Feeding Regulation Short and Long-Term and Why We Eat (p510-527)
6. Sex and the Brain
Chapter 17 (p534-561)
1.
Sex versus gender
2.
The Genetics of Sex: XY or XX, SRY gene
3.
Sex Development and Differentiation
4.
Steroid Hormones: Biosynthesis, Release, Action in Brain (LH, FSH, GnRH)
5.
Neurochemistry of Reproductive Behavior: Prairie Vole, Oxytocin, Vasopressin
6.
Sexual Dimorphisms : Varies Across Species
7.
Sexual Dimorphisms in Cognition in Humans
8.
Activation Effects of Sex Hormones
•
Testosterone Sexual Activity
•
Brain Plasticity and Maternal Behavior
•
Estrogen Effects: Neurite growth, seizure threshold
http://www.loyarburok.com/2011/04/10/sex-and-gender-%E2%80%93-born-with-it-or-perceived-to-be-it/
http://www.artemisu.net/ranthour/?p=571
P534-535
Genderless – Baby Storm
June 2011
http://www.ctv.ca/CTVNews/TopStories/20110526/genderless-baby-storm-110526/
The Genetics of Sex
Genotype- Male: XY, Female: XX
• X chromosome larger than Y
• X contains 1500 and Y contains 50 genes
• In humans Dad contributes X or Y to make male or female
• X-linked diseases: Occur more often in men than women
p535
http://destinationofmarvel.blogspot.ca/2011/06/human-chromosomes-and-dna.html
P297, 535
http://en.wikipedia.org/wiki/X-linked_recessive_inheritance
Sex-Determining Region of Y Chromosome (SRY)
–
Location of SRY on Y chromosome
–
Encodes testis-determining factor
–
Causes development of testes and
testicular hormones
–
Makes fetus develop as male
–
Default pathway, female
p535
Sexual Development
–
First 6 weeks sexually undifferentiated
–
Uncommitted gonads: 2 ducts
–
Fetus has Y chromosome and SRY gene,
make testosterone then:
–
–
Wolffian duct develops into male
internal organs
–
Inhibition of Mullerian duct
development by hormone called
Mullerian-inhibiting factor
Hermaphroditism: genitals intermediate
between male/female
P536-537
Sex Hormones
–
Sex hormones: Steroids made from cholesterol
P510-511
Steroid Biosynthesis… bit more complex
http://www.gfmer.ch/Books/Reproductive_health/Steroid_hormone_metabolism_Fig2.html
–
Fetus has Y chromosome and SRY gene, make testosterone
–
ACTUALLY is testosterone – converted to estradial by aromatase that
causes masculinization – careful here p549 bottom)
p549
Sex Hormones
–
Female concentration testosterone is ~10% of male
–
Males: Testes- release androgen
Testosterone – increase at puberty leads to
development of secondary sex characteristics
Females: Ovaries- secrete estradiol (estrogen) and
progesterone (progestin)
Blood concentrations of sex hormones vary
Males- levels fluctuate daily
Females- levels fluctuate, 28-day cycle
P510-511
What regulates the Secretion of Steroid Hormones from
Gonads
Once AGAIN – we look at…….
Last lecture
P488, 539
All of them together – from what we have learned so far
Bidirectional Interaction Between Brain and Gonads
–
Hypothalamus:
GnRH – gonadotropin-releasing hormone
–
Gonadotropins:
LH and FSH
–
Males- LH produces testosterone; FSH
aids sperm maturation
–
Females- LH, FSH cause estrogen
secretion
p539
Seasonal Variations: GnRH - Melatonin
The light and dark regulation of the biological clock (suprachiasmatic nucleus),
pineal melatonin production, and seasonal reproduction in photoperiodic mammals.
–
Nonhuman species
–
Light inhibits melatonin from pineal gland
–
GnRH inhibited by melatonin
–
Seasonal change in elevation of melatonin
function of calendar
–
Season of breeding, Adjust gestations lenght
–
How you get season of breeding: spring;)
Reiter R J et al. Biol Reprod 2009;81:445-456
p539
Feedback to the Brain
p539
Feedback to the Brain
Estradiol –
ER receptors
Testosterone–
Can have 2 actions:
Androgen Receptors
Aromatase act at ER receptors
p539
http://www.sinauer.com/levay3e/webtopic0504.html
Distribution of Estradial Receptors in Rat Brain
p538
Steroid Hormones Get Inside and Act Within Cells:
Indirect Effect
Steroid hormones and thyroid hormones, because of their lipid solubility, bind directly to their receptors in the
cytoplasm of target cells. Once bound to its receptor, the steroid hormone-receptor complex travels to the
nucleus, where the steroid hormone-receptor binds to promoters of genes, either stimulating or repressing
transcription.
http://163.16.28.248/bio/activelearner/47/ch47c1.html
P538, 549
Steroid Hormones Indirect Effect vs Direct Effect on
Neurons
Indirect:
They can indirectly influence
gene transcription.
Direct:
Steroids can directly affect
transmitter synthesis,
transmitter release, or
postsynaptic transmitter
receptors.
p549
Hormones Act at Receptors on Extracellular Membrane
p538
Hormones act only on cells that are able to bind to the hormone, based on the presence or absence of receptors
for the hormone on the cell membrane.
http://163.16.28.248/bio/activelearner/47/ch47summary.html
Biosynthesis, Release, and Action of Steroid Hormones
Whole story
Male: Testosterone
http://www.youtube.com/watch?v=djqqao2Uebo
p539
Neurochemistry of Reproductive Behaviors
http://research.yerkes.emory.edu/Young/volegenome.html
p544
Meadow vs Prairie Vole:
Differ Reproductive Social Behaviors
Although prairie voles and meadow
voles are similar in physical appearance,
prairie voles are highly affiliative as
depicted here in 'huddling' side by side
(a), whereas meadow voles are solitary
(b). c, d, Partner preference test. After
mating and cohabitating with a female, a
male prairie vole tended to spend
significantly more time in contact with
the partner (filled columns) than the
stranger (open columns) (P < 0.05,
Student's t-test) (c), whereas meadow
voles do not form partner preferences
and spent relatively little time huddling
with either female (d).
Enhanced partner preference in a promiscuous species by manipulating the expression of a single gene
Miranda M. Lim, Zuoxin Wang, Daniel E. Olazábal, Xianghui Ren, Ernest F. Terwilliger and Larry J. Young
Nature 429, 754-757(17 June 2004)
doi:10.1038/nature02539
P544-545
Oxytocin and Vasopressin Receptor Expression Differ
Figure 2. Contrasting Distribution of Oxytocin and Vasopressin V1a Receptors to Prairie (Monogamous) and Meadow (Promiscuous) VolesReceptors are labeled with
iodinated ligands by in vitro receptor autoradiography. Levels matched across species with arrows pointing to homologous structures. Prairie voles show higher
binding in nucleus accumbens for oxytocin and ventral pallidum for vasopressin. Meadow voles show higher binding for vasopressin in lateral septum. Not shown are
differences in other regions, including posterior cingulate-retrosplenial cortex (high for vasopressin V1a receptor in prairie vole) and ventral thalamus and amygdala
(high for oxytocin receptor in meadow vole). PFC, prefrontal cortex; CP, caudate putamen; NAcc, nucleus accumbens; LS, lateral septum; VP, ventral pallidum. Figure
adapted with permission from Hammock and Young (2006).
P544-545
Altering Vasopressin Receptor Expression
Can Modify Behavior
Oxytocin, Vasopressin, and the Neurogenetics of Sociality
Science 7 November 2008:
vol. 322 no. 5903 900-90
http://www.youtube.com/watch?v=pA4w--HP7tc
P544-545
HOW AND WHY male and female BRAINS DIFFER
OR NOT?
Are there sexual dimorphisms?
P 546, 547
http://fr.toonpool.com/cartoons/Male%20and%20female%20brains_11805
Humans do not have large dimorphisms in gross anatomy
This is not what most people think…. because
The claim: Womens’ corpus callosum is larger than mens’
and that difference is important.
Women use both sides of their brain
more symmetrically than men. The larger
corpus callosum in women explains
female intuition and the ability to
“multitask” and tune in to emotions.
March 2006 Parents magazine,
The Daily Telegraph,
Ottawa Citizen,
Cleveland Plain Dealer,
many, many more
MIT Women & Gender
Studies Presentation
September 16, 2008
35
The facts: Corpus Callosum.
Neuroscience and Biobehavioral Review, 1997:
•
No statistically significant differences in the
corpus callosum area between sexes.
•
Recent studies using MRIs, taking into account
such things as differences in brain sizes, do not
support any such difference in men and women.
•
A meta-analysis of 49 studies found no significant
sex differences in the size or shape of the corpus
callosum.
v
MIT Women & Gender
Studies Presentation
September 16, 2008
36
Some species do have large dimorphisms in gross anatomy
Can identify male or female by trained eye
P 546, 552
Blue circles are the vocal control regions (VCR) in the male and female zebra finches
Sexual dimorphisms another example - THE “SDN”
P 547, 549
The sexually dimorphic nucleus (SDN) in hypothalamus of males (left) is larger then females (right)
Lesion SDN disrupt estrous cycle in females, reduce frequency of copulation in males
Newborn rat given estrogen, will have larger SDN, develop masculine behaviors
Sexual Dimorphisms in Cognition
Cognitive tasks that may favor women or men. (a) Women may outperform men in
listing words beginning with the same letter. (b) Men appear to be somewhat better
at spatial rotation tasks, such as deciding whether two three-dimensional objects
are the same. (Source: Adapted from Kimura, 1992, p. 120.)
P 548
d’ = 0.15
MIT Women & Gender
Studies Presentation
September 16, 2008
40
Test score differences between girls and boys
Gender Gap - Math – Influence of Culture
10
5
0
-5
-10
-15
-20
-25
TUR
KOR ITA
USA
PRT
FRA
POL
NOR
SWE ISL
Guiso, L., Monte, F., Sapienza, P., & Zingales, L. (2008). Culture, gender and math. Science, 320(5880), 1164-1165.
MIT Women & Gender
Studies Presentation
September 16, 2008
41
To examine the cultural inputs to these differences, the
researchers classified the ten countries by four, highly
correlated, measures of gender equity.
These measures assess the economic and political
opportunities, education and well-being of women.
The gender gap in mathematics correlates with country
measures of gender status within the culture.
More gender-equal cultures are associated with reducing the
negative gap in math
These results suggest that the sexual dimorphisms in math
ability disappears in more gender-equal societies.
MIT Women & Gender
Studies Presentation
September 16, 2008
42
Organizational vs Activation Effects of Steroid Hormones
– Organizational effect of hormones
• Organizes perinatal tissue
• Tend to be irreversible
• Allow for development of distinct genitals and behaviors later in
life
– Activational effect of hormones
• Effects occur after early development
• Tend to be temporary
• 4 examples: testosterone role in sexual behavior, effect
lactation on sensory representation in cortex, estrogen on
neurite growth, fluctuations of hormone and seizure threshold
P550,551
Testosterone
Men:
Rise in testosterone, anticipation of sex,
Fall in testosterone, decreased sexual interest
P555
Effects During Nursing
Plasticity in Cortical Regions that Surround Nipples
P555
Estrogen – Neurite Growth
Dominique Toran-Allerand, 1980s
Estradiol treatment of tissue taken from hypothalamus of newborn
mice induces extensive outgrowth
http://www.cumc.columbia.edu/dept/gsas/anatomy/Faculty/ToranAllerand/index.html
P555
Estrogen –Spine Number, Excitability in Hippocampus
Gould, Woolley, and McEwen
Estradiol increases number of spines
More excitatory synapses
More NMDA glutamate receptors
Reduced seizure threshold (see Fig. 17.17)
P556, 557
Hormone Replacement Therapy
Hormone Effects
1.
Sex versus gender
2.
The Genetics of Sex: XY or XX, SRY gene
3.
Sex Development and Differentiation
4.
Steroid Hormones: Biosynthesis, Release, Action in Brain (LH, FSH, GnRH)
5.
Neurochemistry of Reproductive Behavior: Praire Vole, Oxytoxin, Vasopressin
6.
Sexual Dimorphisms : Varies Across Species
7.
Sexual Dimorphisms in Cognition in Humans
8.
Activation Effects of Sex Hormones
•
Brain Plasticity and Maternal Behavior
•
Estrogen Effects: neurite growth, seizure threshold
Example Question
Describe what happened to pair-bonding when vasopressin receptor was
expressed into the meadow vole. You can use a graph to help explain your
answer if you wish.
2 MARKS
By injecting a virus that allowed increased vasopressin receptor expression into
the meadow voles, the meadow vole then preferred to be reproductive with a
partner compared to a stranger, like the prairie vole. This suggests that
vasopressin receptor expression is important for vole pair-bonding.