1. Tues Aril 3, 2012 Diane Lagace, PhD CMM/BIO4350
Assistant Professor Department of Cellular and Molecular Medicine (CMM) Neuroscience Program RGH, Room 3510G, University of Ottawa,

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 Motivation and Homeostasis
Embryonic Development 101
Chapter 7: Understanding CNS structure through development (p )
Gross Neuroantaomy
Chapter 7: Gross Organization of Mammalian Nervous System (p )
Chapter 23 Genesis of Neuron, Connections and Elimination of Cells and Synapses (p
Chapter 7 Appendix: Illustrated Guide to Human Neuroanatomy (p )
The Genesis of the Neuron (Neurogenesis) and Neuronal Connections and Regeneration of Nervous System
Chapter 23: Connections and Elimination of Cells and Synapses (p )
From lecture notes only; not in text book
Chemical Controls of Brain and Behavior
Chapter 15: Hypothalamus, ANS, Neurotransmitter Systems (p )
Motivation and Homeostasis
Chapter 16: Feeding Regulation Short and Long-Term and Why We Eat (p )
Sex and the Brain
Chapter 17 (p )

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 temperature and blood composition
Hypothalamus commands in cold weather
Shiver, goosebumps, turn blue
Hypothalamus commands in hot weather
Turn red, sweat
p484

7. Homeostatsis – Negative Feeedback
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. Hypothalamic Regulation
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 P

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

12. Catabolism during Postabsorptive State

13. Catabolism during Postabsorptive State

14. p512

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

16. Long-term response: maintain body fat reserves
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
Lipostatic Hypothesis: 1953: Brain monitors the amount of body fat

19. Coleman and Friedman and the
Discovery of Leptin
p514

20. Yet there are very few cases of this miracle cure ;(
From Mice to Men
Yet there are very few cases of this miracle cure ;(
Similar on
p514
#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 #21

23. http://im-09-tb. blogspot

24. Back to 1940s and lesion studies and incorrect
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

26. Increase Leptin Levels – Body Fat is Increased
Activation of aMSH and CART containing arcuate neurons
aMSH: alpha melanocyte stimulating 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

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
Parvocellular neurosecretory 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?

34. p519

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

36. p519

37. Competition for MC4 receptor

38. Decrease Leptin Levels
Stimulation of the NPY and AgRP expressing arcuate 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. That Control Feeding from Lateral Hypothalamus
2 more Orexigenic Peptides
That Control Feeding from Lateral Hypothalamus
p519

40. Orexin and MCH both rise when leptin levels are reduced

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

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 curesince hypocretin will not pass blood brain barrier and enter into brain

43. More then just LEPTIN….. CCK
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

46. Hunger is not just the absence of satiety
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

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

49. Synergistic Action of Gastric Distension and CCK on Feeding
Both gastric distension and CCK signals converge on axons in vagus nerve Result in reduce meal frequency and size CCK release in response to certain type of food (especially fatty ones)
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

51. Insulin
Celphalic Phase
Anticipating the food
Parasympathetic innervations stimulates Bcells to release insulin
Small reduction in glucose in blood
Activation of NPY neurons in arcuate
P522

52. Insulin
Gastric Phase
Food enters the stomach
Bcells to release insulin even more, increase by release of CCK
Small reduction in glucose in blood
P522

53. Insulin
Substrate Phase
Food absorbed into intestines
Max amount of insulin release
Primary stimulus for insulin release increase in blood glucose
P522

54. Insulin and Leptin
P522

55. Insulin and Leptin
P530

56. 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

57. Example Question
During the winter months you have been eating a lot more food.
Using the following words (anterior pituitary, arcuate neurons, leptin, ACTH, TSH, sympathetic activity, CART, somatic motor) describe regulation of feeding in 2-6 sentences.
You can use a diagram as part of your answer MARKS

58. Example Question
During the winter months you have been eating a lot more food.
Using the following words (anterior pituitary, arcuate neurons, leptin, ACTH, TSH, sympathetic activity, CART, somatic motor) describe regulation of feeding in 2-6 sentences.
You can use a diagram as part of your answer MARKS
When you have been eating more for sustained periods of time you will have more fat and this will increase the amount of leptin released from the fat storage.
Leptin will activate the CART and aMSH neurons in the arcuate neurons.
This will induce a humoral response which involves increased secretion of TSH and ACTH from anterior pituitary.
There is also increase in tone of the sympathetic activity which rises metabolic rate.
Lastly, there is somatic motor response that decreases feeding behavior.