Tues April 5, 2012 Diane Lagace, PhD CMM/BIO4350 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 M1-M3. The third section is based on Dr. Lagace’s material and is worth 30 marks. This includes questions L1-L17.

6 Lectures Sex and the Brain Chapter 17 (p534-561) 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) Sex and the Brain Chapter 17 (p534-561)

Sex versus gender The Genetics of Sex: XY or XX, SRY gene Sex Development and Differentiation Steroid Hormones: Biosynthesis, Release, Action in Brain (LH, FSH, GnRH) Neurochemistry of Reproductive Behavior: Prairie Vole, Oxytocin, Vasopressin Sexual Dimorphisms : Varies Across Species Sexual Dimorphisms in Cognition in Humans Activation Effects of Sex Hormones Testosterone Sexual Activity Brain Plasticity and Maternal Behavior Estrogen Effects: Neurite growth, seizure threshold

http://www. loyarburok 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/

Genotype- Male: XY, Female: XX X chromosome larger than Y 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: 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

Female concentration testosterone is ~10% of male 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

Once AGAIN – we look at……. 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;) The light and dark regulation of the biological clock (suprachiasmatic nucleus), pineal melatonin production, and seasonal reproduction in photoperiodic mammals. Specialized photoreceptive cells in the retinas (melanopsin-containing ganglion cells) mediate the effects of light (450–490 nm) on the biological clock and melatonin production. The circuitous neural connections between the eyes and the pineal gland (pinealocyte) are shown. At night, the postganglionic sympathetic neurons ending in the pineal gland release norepinephrine, which activates primarily β-adrenergic receptors to stimulate a cascade of molecular events that culminate in melatonin production and release. Seasonally changing photoperiods alter the duration of elevated nocturnal melatonin production, a signal that provides mammals with the time-of-year information. This message determines the breeding season of both long-day and short-day breeders. In both cases, the young are characteristically delivered in the spring or early summer. ASMT, acetylserotonin O-methyltransferase; HIOMT, hydroxyindole O-methyltransferase; NAT, alkylamine N-acetyltransferase. Reiter R J et al. Biol Reprod 2009;81:445-456 p539

Feedback to the Brain p539

Aromatase act at ER receptors 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

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 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 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). P544-545 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

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 P544-545 http://www.youtube.com/watch?v=pA4w--HP7tc

OR NOT? Are there sexual dimorphisms? 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. 4/15/2017 6:56 PM 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. According to Michael Gurian: March 2006 Parents magazine, The Daily Telegraph, Ottawa Citizen, Cleveland Plain Dealer, many, many more MIT Women & Gender Studies Presentation September 16, 2008

The facts: Corpus Callosum. 4/15/2017 6:56 PM 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

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” 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

4/15/2017 6:56 PM d’ = 0.15 Although the overall gender difference in math was trivial, there were measurable gender differences for complex-problem solving beginning in high school. The effect size was .29, favoring males. This difference, it was argued, could forecast the under-representation of women in science, technology, engineering, and mathematics careers. 254 studies, 3,175,188 students MIT Women & Gender Studies Presentation September 16, 2008

Gender Gap - Math – Influence of Culture There was similar variation in the proportion of girls and boys who scored above 95% or 99% of the country-level distribution. GGI = Gender Gap Index 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

4/15/2017 6:56 PM 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

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 P555 http://www.cumc.columbia.edu/dept/gsas/anatomy/Faculty/ToranAllerand/index.html

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

Sex versus gender The Genetics of Sex: XY or XX, SRY gene Sex Development and Differentiation Steroid Hormones: Biosynthesis, Release, Action in Brain (LH, FSH, GnRH) Neurochemistry of Reproductive Behavior: Praire Vole, Oxytoxin, Vasopressin Sexual Dimorphisms : Varies Across Species Sexual Dimorphisms in Cognition in Humans 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.