1. CMM/BIO4350 Tues Aril 3, 2012 Diane Lagace, PhD Assistant ProfessorDepartment of Cellular and Molecular Medicine (CMM)Neuroscience ProgramRGH, Room 3510G, University of Ottawa,dlagace@uottawa.ca

2. Exam Info 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.

3. 6 Lectures • 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)

4. Hypothalamus and Homeostasis • Energy Balance – Long term regulation of Feeding • Set Point for Body Weight • Discovery of Leptin • Hypothalamic Lesions and Feeding Behavior • Response to Elevated or Reduced Levels of Leptin • Anorectic and Orexigenic Peptides from Arcuate Nucleus • Orexigenic Peptides from Lateral Hypothalamus (MCH and Orexin) • Short-term regulation of feeding: • Ghrelin, Gastric Distension, CCK, Insulin • Insulin and Leptin

5. Patterns of Communication in Nervous System Neuron-Neuron Point-Point 3 MORE BROAD Hypothalamus ANS Modulatory Neurotransmitter System p483

6. Hypothalamus - Homeostatsis • Regulatory process: Regulates body temperatureand blood composition • Hypothalamus commands in cold weather • Shiver, goosebumps, turn blue • Hypothalamus commands in hot weather • Turn red, sweat p484

7. Homeostatsis – Negative Feeedback http://www.mattk.com/anatomy_notes_homeostasis_negative_feedback.php In negative feedback the body responds to an extreme condition by reversing the current direction of change (thus the term negative feedback). The goal is to always keep the internal conditions within a normal range.

8. Homeostatsis Hypothalamic Regulation • Three components of how hypothamalus neurons respond to sensory signals • Humoral response: • Stimulating or inhibiting release of pituitary hormones into the blood stream • Visceromotor response: • Adjust the balance of the sympathetic and parasympathetic outputs of the ANS • Somatic motor response: • Appropriate somatic motor behavioral response P510-511

11. Anabolism During Prandial State (Latin for “Breakfast”) p512

12. Catabolism during Postabsorptive State p512

13. Catabolism during Postabsorptive State

14. p512

15. Stress Response - Short and Long-term Response p490 See danger During exams

16. Energy Balance and Eating • Long-term response: maintain body fat reserves • Short term response: regulate meal size and frequency p512

17. Maintenance of Body Weight and Set Point p513 Lipostatic Hypothesis: 1953: Brain monitors the amount of body fat

19. Coleman and Friedman and the • Discovery of Leptin http://www.youtube.com/watch?v=tyusgTI3Syo p514

20. From Mice to Men • Yet there are very few cases of this miracle cure ;( Similar on p514 http://media.hhmi.org/hl/04Lect1.html #21

21. Genetic Basis to Weight p514 Identical twins (Monozygote) have almost exactly the same genetic make-up. Non-identical twins (Dizygote), on the other hand, share about 50% of the genetic traits. It has been shown from twin studies that percentage of heritability of obesity ranges between 70 % to 80% - the only trait being higher than obesity is your height!

22. Leptin is the afferent signal in a negative feedback loop that maintains homeostatic control of adipose mass. It circulates in the blood and acts on the brain to regulate food intake. When fat mass falls, plasma leptin concentrations fall too, stimulating appetite and suppressing energy expenditure until fat mass is restored. When fat mass increases, leptin levels increase, suppressing appetite until weight is lost. This system maintains homeostatic control of adipose tissue mass. Leptin thus conveys nutritional information to specific neural populations in the brain, which in turn regulate most, and perhaps all, other physiological systems. This homeostatic system enables mammalian organisms to maintain optimal levels of stored energy (fat) under a wide range of environmental conditions. A tale of two hormones Jeffrey M Friedman Nature Medicine 16, 1100–1106 (2010) MOVIE http://media.hhmi.org/hl/04Lect1.html #21

23. http://im-09-tb.blogspot.ca/2009/03/obesity-reviving-promise-of-leptin_30.htmlhttp://im-09-tb.blogspot.ca/2009/03/obesity-reviving-promise-of-leptin_30.html

24. Hypothalamus and Feeding • Back to 1940s and lesion studies and incorrect • dual center model hypothesis Hunger center Satiety center p515

25. Three Hypothalamic Nuclei Important for Feeding p516

26. Increase Leptin Levels – Body Fat is Increased • Activation ofaMSH and CART containing arcuate neurons • aMSH: alpha melanocytestimulating hormone, • CART = cocaine- and ampethamine-regulated transcripts • CAREFUL HERE – • alpha-melanocyte stimulating hormone is a post-translational derivative of proopiomelanocortin, Pomc – THEREFORE MANY INTRO BOOKS TALK OF POMC P516-7

27. http://en.wikipedia.org/wiki/File:POMC.png http://knol.google.com/k/the-genetics-of-obesity#

28. Increase Leptin Levels – Body Fat is Increased • Activation of aMSH and CART containing arcuate neurons • INDUCES: • Humoral response: increase activity of paravenctricular nucleus to increase secretion of TSH and ACTH from anterior pituitary P516-7

29. Neurosecretory cells of the hypothalamus Parvocellularneurosecretory cells secrete hypophysiotropic hormone into hypo-pituitary portal circulation Hormones act in anterior lobe of pituitary where they trigger release or inhibitions of pituitary hormone release. Last lecture p489

30. Hormones Released by Anterior Pituitary Gland Last lecture p488

31. Increase Leptin Levels • Activation of aMSH and CART containing arcuate neurons • INDUCES: • Humoral response: increase activity of paravenctricular nucleus to increase secretion of TSH and ACTH from anterior pituitary • Visceromotor response: increase tone of sympathetic division of ANS through axons that project from either paravenctricular or arcuate P516-7

32. Increase Leptin Levels • Activation of aMSH and CART containing arcuate neurons • INDUCES: • Humoral response: increase activity of paravenctricular nucleus to increase secretion of TSH and ACTH from anterior pituuitary • Visceromotor response: increase tone of sympathetic division of ANS • Somatic motor response: decrease feeding behavior P516-7

33. What would happen if you inject • aMSH or CART into the brain? P516-7

34. p519

35. Decrease Leptin Levels • Stimulation of the NPY and AgRP expressingarcuate neurons • Humoral response: inhibit secretion of TSH and ACTH P516-7

36. p519

37. Competition for MC4 receptor p518

38. Decrease Leptin Levels • Stimulation of the NPY and AgRP expressingarcuate neurons • INDUCES: • Humoral response: inhibit secretion of TSH and ACTH • Visceromotore response: increase tone of parasympathetic division of ANS (not shown;() • Somatic motor response: stimulate feeding behavior P516-7

39. 2 more Orexigenic Peptides • That Control Feeding from Lateral Hypothalamus p519

40. Orexin and MCH both rise when leptin levels are reduced http://archives.focus.hms.harvard.edu/1999/Sept17_1999/research_briefs.html

41. Orexin Orexin was discovered almost simultaneously by two independent groups of rat-brain researchers.[4][5] One group named it orexin, from orexis, meaning "appetite" in Greek; the other group named it hypocretin, because it is produced in the hypothalamus and bears a weak resemblance to secretin, a hormone found in the gut.[2] narcolepsy http://www.yourdiscovery.com/video/is-it-possible-narcoleptic-dog/ http://en.wikipedia.org/wiki/Orexin

42. Orexin - Hypocretin When it is time to be awake, there are certain neurons in your brain that release hypocretin. This hypocretin tells the brain to be awake.When it is time to go to sleep, brain cells make less hypocretin. Now you get sleepy and fall asleep.It makes perfect sense that people with narcolepsy have problems with their hypocretin. A sudden drop in this key brain chemical and you'd go right to sleep.In fact, doctors can now test to see if a person has low levels of hypocretin by taking a sample of some spinal fluid. This can help them figure out if a person has narcolepsy. But they can't use hypocretin as a curesincehypocretin will not pass blood brain barrier and enter into brain http://www.thetech.org/genetics/ask.php?id=419

43. More then just LEPTIN….. CCK is present in some cells in the intestines and released as a satiety peptide. CCK m-09-tb.blogspot.ca/2009/03/obesity-reviving-promise-of-leptin_30.html

44. Short-term regulation of Feeding Behavior p520

45. http://7bigspoons.com/stress/stress-feel-hungry-nice/attachment/ghrelin/http://7bigspoons.com/stress/stress-feel-hungry-nice/attachment/ghrelin/

46. Ghrelin was discovered in 1999 • Hunger is not just the absence of satiety Blood concentrations of ghrelin are lowest shortly after consumption of a meal, then rise during the fast just prior to the next meal p520

47. p520 http://www.diabesity.eu/ghrelin.htm

48. Receptors for ghrelin have been found on NPY/AgRP neurons in the hypothalamic arcuate nucleus.  The NPY neurons are potent stimulators of appetite and upon activation by ghrelin they inhibit the POMC neurons by releasing the inhibitory neurotransmitter GABA which inhibits the release of aMSH, an inhibitor of appetite.  Ghrelin also activates the release of AgRP which is an antagonist of the alpha MSH receptors MC3 and MC4, blocking alpha MSH from activating its receptor and inhibiting appetite.  p520 http://www.diabesity.eu/ghrelin.htm

49. Synergistic Action of Gastric Distension and CCK on Feeding Both gastric distension and CCK signals converge on axons in vagus nerveResult in reduce meal frequency and sizeCCK release in response to certain type of food (especially fatty ones) http://goanimate.com/videos/0oL8bpkMa_HY p520,521

50. Last one is insulin CCK is present in some cells in the intestines and released as a satiety peptide. CCK m-09-tb.blogspot.ca/2009/03/obesity-reviving-promise-of-leptin_30.html