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

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.

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. Hypothalamus and Homeostasis

2. Energy Balance – Long term regulation of Feeding

3. Set Point for Body Weight

4. Discovery of Leptin

5. Hypothalamic Lesions and Feeding Behavior

6. Response to Elevated or Reduced Levels of Leptin

7. Anorectic and Orexigenic Peptides from Arcuate Nucleus

8. Orexigenic Peptides from Lateral Hypothalamus (MCH and Orexin)

9. Short-term regulation of feeding:

• Ghrelin, Gastric Distension, CCK, Insulin

10. Insulin and Leptin

Patterns of Communication in Nervous System

Neuron-NeuronPoint-Point

3 MORE BROAD

Hypothalamus

ANS

Modulatory Neurotransmitter System

p483

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

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.

http://www.mattk.com/anatomy_notes_homeostasis_negative_feedback.php

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

Anabolism During Prandial State (Latin for “Breakfast”)

p512

Catabolism during Postabsorptive State

p512

Catabolism during Postabsorptive State

p512

Stress Response - Short and Long-term Response

See danger During exams

p490

Energy Balance and Eating

Long-term response: maintain body fat reserves

Short term response: regulate meal size and frequency

p512

p513

Maintenance of Body Weight and Set Point

Lipostatic Hypothesis: 1953: Brain monitors the amount of body fat

http://www.youtube.com/watch?v=tyusgTI3Syo

Coleman and Friedman and the Discovery of Leptin

p514

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

p514

Genetic Basis to Weight

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!

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 hormonesJeffrey M Friedman Nature Medicine 16, 1100–1106 (2010)MOVIE http://media.hhmi.org/hl/04Lect1.html #21

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

Hypothalamus and FeedingBack to 1940s and lesion studies and incorrect

dual center model hypothesis Hunger center

Satiety center

p515

Three Hypothalamic Nuclei Important for Feeding

p516

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

http://knol.google.com/k/the-genetics-of-obesity#

http://en.wikipedia.org/wiki/File:POMC.png

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

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

Hormones Released by Anterior Pituitary Gland

Last lecture p488

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

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

What would happen if you inject

aMSH or CART into the brain?

P516-7

p519

Decrease Leptin Levels

– Stimulation of the NPY and AgRP expressing arcuate neurons

– Humoral response: inhibit secretion of TSH and ACTH

P516-7

p519

p518

Competition for MC4 receptor

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

p519

2 more Orexigenic Peptides That Control Feeding from Lateral Hypothalamus

Orexin and MCH both rise when leptin levels are reduced

http://archives.focus.hms.harvard.edu/1999/Sept17_1999/research_briefs.html

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://en.wikipedia.org/wiki/Orexin

http://www.yourdiscovery.com/video/is-it-possible-narcoleptic-dog/

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

http://www.thetech.org/genetics/ask.php?id=419

More then just LEPTIN…..

m-09-tb.blogspot.ca/2009/03/obesity-reviving-promise-of-leptin_30.html

CCKCCK is present in some cells in the intestines and released as a satiety peptide.

Short-term regulation of Feeding Behavior

p520

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

Blood concentrations of ghrelin are lowest shortly after consumption of a meal, then rise during the fast just prior to the next meal

Ghrelin was discovered in 1999Hunger is not just the absence of satiety

p520

p520

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

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

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

Synergistic Action of Gastric Distension and CCK on Feeding

http://goanimate.com/videos/0oL8bpkMa_HY

Last one is insulin

m-09-tb.blogspot.ca/2009/03/obesity-reviving-promise-of-leptin_30.html

CCKCCK is present in some cells in the intestines and released as a satiety peptide.

Insulin

Celphalic PhaseAnticipating the food

Parasympathetic innervations stimulates Bcells to release insulinSmall reduction in glucose in bloodActivation of NPY neurons in arcuate

P522

Insulin

Gastric PhaseFood enters the stomach

Bcells to release insulin even more, increase by release of CCKSmall reduction in glucose in blood

P522

Insulin

Substrate PhaseFood absorbed into intestines

Max amount of insulin releasePrimary stimulus for insulin release increase in blood glucose

P522

Insulin and Leptin

P522

http://www.medbio.info/Horn/Time%205/Metabolic%20syndrom%20and%20diabetes%20type%202.htm

Insulin and Leptin

P530

1. Hypothalamus and Homeostasis

2. Energy Balance – Long term regulation of Feeding

3. Set Point for Body Weight

4. Discovery of Leptin

5. Hypothalamic Lesions and Feeding Behavior

6. Response to Elevated or Reduced Levels of Leptin

7. Anorectic and Orexigenic Peptides from Arcuate Nucleus

8. Orexigenic Peptides from Lateral Hypothalamus (MCH and Orexin)

9. Short-term regulation of feeding:

• Ghrelin, Gastric Distension, CCK, Insulin

• Insulin and Leptin

Example QuestionDuring 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. 4 MARKS

Example QuestionDuring 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. 4 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.