CMM/BIO4350

Tues April 5, 2012

Diane Lagace, PhD

Assistant ProfessorDepartment of Cellular and Molecular Medicine (CMM)

Neuroscience ProgramRGH, 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 M1-

M3. The third section is based on Dr. Lagace’s material and is worth 30 marks. This includes questions L1-L17.

6 Lectures

1. Embryonic Development 101 Chapter 7: Understanding CNS structure through development (p178-201)

2. 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)3. 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

4. Chemical Controls of Brain and Behavior Chapter 15: Hypothalamus, ANS, Neurotransmitter Systems (p482-504)

5. 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/

P534-535

http://www.artemisu.net/ranthour/?p=571

Genderless – Baby Storm

June 2011

http://www.ctv.ca/CTVNews/TopStories/20110526/genderless-baby-storm-110526/

The Genetics of Sex

p535

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

http://destinationofmarvel.blogspot.ca/2011/06/human-chromosomes-and-dna.html

P297, 535http://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

P536-537

– 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

Sex Hormones

P510-511

– Sex hormones: Steroids made from cholesterol

Steroid Biosynthesis… bit more complex

http://www.gfmer.ch/Books/Reproductive_health/Steroid_hormone_metabolism_Fig2.html

p549

– Fetus has Y chromosome and SRY gene, make testosterone

– ACTUALLY is testosterone – converted to estradial by aromatase that causes masculinization – careful here p549 bottom)

Sex Hormones

P510-511

– Female concentration testosterone is ~10% of male

– Males: Testes- release androgenTestosterone – increase at puberty leads to development of secondary sex characteristics

Females: Ovaries- secrete estradiol (estrogen) and progesterone (progestin) Blood concentrations of sex hormones varyMales- levels fluctuate dailyFemales- levels fluctuate, 28-day cycle

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

p539

– Hypothalamus:

GnRH – gonadotropin-releasing hormone

– Gonadotropins:

LH and FSH– Males- LH produces testosterone; FSH

aids sperm maturation– Females- LH, FSH cause estrogen

secretion

Seasonal Variations: GnRH - Melatonin

p539

– 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;)

The light and dark regulation of the biological clock (suprachiasmatic nucleus), pineal melatonin production, and seasonal reproduction in photoperiodic mammals.

Reiter R J et al. Biol Reprod 2009;81:445-456

Feedback to the Brain

p539

Feedback to the Brain

p539

Estradiol –ER receptors

Testosterone–Can have 2 actions:Androgen ReceptorsAromatase act at ER receptors

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

p549

Indirect: They can indirectly influence gene transcription.

Direct:Steroids can directly affect transmitter synthesis, transmitter release, or postsynaptic transmitter receptors.

Hormones Act at Receptors on Extracellular Membrane

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

p538

Biosynthesis, Release, and Action of Steroid Hormones

p539

Whole story Male: Testosteronehttp://www.youtube.com/watch?v=djqqao2Uebo

Neurochemistry of Reproductive Behaviors

p544http://research.yerkes.emory.edu/Young/volegenome.html

Meadow vs Prairie Vole: Differ Reproductive Social Behaviors

P544-545Enhanced partner preference in a promiscuous species by manipulating the expression of a single geneMiranda M. Lim, Zuoxin Wang, Daniel E. Olazábal, Xianghui Ren, Ernest F. Terwilliger and Larry J. YoungNature 429, 754-757(17 June 2004)doi:10.1038/nature02539

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).

Oxytocin and Vasopressin Receptor Expression Differ

P544-545

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).

Altering Vasopressin Receptor Expression Can Modify Behavior

P544-545

Oxytocin, Vasopressin, and the Neurogenetics of SocialityScience 7 November 2008: vol. 322 no. 5903 900-90

http://www.youtube.com/watch?v=pA4w--HP7tc

HOW AND WHY male and female BRAINS DIFFER OR NOT?

Are there sexual dimorphisms?

http://fr.toonpool.com/cartoons/Male%20and%20female%20brains_11805

P 546, 547

Humans do not have large dimorphisms in gross anatomy

This is not what most people think…. because

MIT Women & Gender Studies Presentation

September 16, 200835

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.

The claim: Womens’ corpus callosum is larger than mens’ and that difference is important.

March 2006 Parents magazine, The Daily Telegraph, Ottawa Citizen,Cleveland Plain Dealer,many, many more

MIT Women & Gender Studies Presentation

September 16, 200836

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

The facts: Corpus Callosum.

Some species do have large dimorphisms in gross anatomyCan identify male or female by trained eye

Blue circles are the vocal control regions (VCR) in the male and female zebra finches

P 546, 552

Sexual dimorphisms another example - THE “SDN”

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

P 547, 549

Sexual Dimorphisms in Cognition

P 548

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.)

MIT Women & Gender Studies Presentation

September 16, 200840

d’ = 0.15

MIT Women & Gender Studies Presentation

September 16, 200841

Gender Gap - Math – Influence of Culture

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, 200842

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.

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

P555

Men: Rise in testosterone, anticipation of sex, Fall in testosterone, decreased sexual interest

Effects During NursingPlasticity in Cortical Regions that Surround Nipples

P555

Estrogen – Neurite GrowthDominique Toran-Allerand, 1980s

P555

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

Estrogen –Spine Number, Excitability in Hippocampus

P556, 557

Gould, Woolley, and McEwen Estradiol increases number of spinesMore excitatory synapsesMore NMDA glutamate receptorsReduced seizure threshold (see Fig. 17.17)

Hormone Replacement TherapyHormone 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.