Exam 3 (Final) Flashcards
1
Q
Describe a study that investigates the role of NPY in conditioning rats.
A
Training:
- 7 consecutive days of brains (ICV) injections of Saline or NPY at the same time of the day
- No food was given at time of injections
- During the training rats were fed at a particular time (at 10-2) and at a later time received injections of saline or NPY (at 4)
Test:
- Food intake (1-hour) measured after ICV injections of Saline or NPY
2
Q
What are the test groups in the NPY conditioning study?
A
- Saline/saline – control, can be stressful to receive injections
- Saline/NPY – eating a certain amount, didn’t learn about NPY, then eat more when administered NPY (acute effect)
- NPY/saline – supposed to have learned that NPY was coming at a certain time of the day, expect that if they eat more it shows that they learned to expect to eat more at that time of the day – time of the day alone is enough to induce this change in intake (learning, not actual physiological change)
• This is the group of interest - NPY/NPY – positive control
3
Q
What were the results of the NPY conditioning study?
A
Results: Tested intake during 1-hour post saline or NPY injections
- Sal/NPY, NPY/Sal, and NPY/NPY increased in a clear bar graph cascade
- Sal/sal had the lowest food intake
- The NPY/Saline group did not receive NPY prior to test but ate similar amounts to those that received NPY prior to test
4
Q
What did the NPY conditioning study indicate?
A
- This is revealing a principle that we already know in reference to salivation and insulin – they learned to eat more even when not administered the drug
- The effect in NPY/Saline group was accomplished by conditioning NPY targets in the brain
5
Q
How was Pavlovs work expanded upon in reference to feeding substrates?
A
Early work of Pavlov showed that salivation can be conditioned. Later work showed that peripheral (insulin) and central (brain;NPY) feeding substrates can be conditioned
6
Q
Describe a study involving conditioning food consumption in children.
A
STUDY: Conditioned Meal Initiation in Young Children
- Learning can influence how much children eat.
- Children played a song
- Latency is how long it took for the children to go to the table
- Learning caused the children to eat a larger amount
- Both latency and amount eaten affected by CS
- CS+ is a conditioned stimuli
- Children who learned (were able to identify cues correctly) ate more
7
Q
How does conditioned stimuli get to the feeding circuitry?
A
Human amygdala
8
Q
What are the two domains of the amygdala?
A
o Central Nucleus of the Amygdala (CEA;CN)
o Basolateral Amygdalar Area (BLA; ABL)
9
Q
What are the four cues in a Pavlovian conditioning study?
A
o US: unconditioned stimulus
o UR: unconditioned response
o CS: conditioned stimulus
o CR: conditioned response
10
Q
What do CS+ and CS- mean?
A
o CS+ the cue paired with food
o CS- the control cue, not paired with food
11
Q
What were two studies with the CEA and BLA?
A
Study 1: Tested if CEA and/or BLA are critical for cue (CS) induced feeding
Study 2: Tested if the BLA gets to the feeding circuitry via the Lateral Hypothalamus (LHA)
12
Q
Describe: Study 1: Tested if CEA and/or BLA are critical for cue (CS) induced feeding
What enzyme used?
A
- Selective neurotoxic, bilateral lesions of the Basolateral Amygdala (BLA) or Central Nucleus of the Amygdala (CEA)
- NMDA – is an agonist for glutamine and over-excites neurons until they die
- Bilateral neurotoxic lesions of the BLA lesions abolished CS-driven feeding
- Therefore need BLA to have CS-driven feeding
- Bilateral neurotoxic lesion of the Central Nucleus of the Amygdala (CEA) performed similar to sham-lesioned controls
13
Q
How are cue induced feeding studies performed?
A
Phase I – Pavlovian conditioning
- Rats are food restricted during training to motivate learning
- Food (US) – feeding behavior (UR)
- Tone (CS) – neutral in respect to feeding
- Rats move to the chamber where they can be fed when they hear a tone
Phase II – Food Consumption Tests
- Rats are satiated before tests to show that the food-cue motivates eating without hunger
- Tested in 2 tests, counterbalanced order: One test with a cue that signals food (CS; food-cue) and the other test with no cue
14
Q
Describe the following study: Study 2: Tested if the BLA gets to the feeding circuitry via the Lateral Hypothalamus (LHA)
A
- Rats with Sham, Ipsilateral or Contralateral BLA-LHA lesions tested for Food Consumption with CS+ or CS- presentations
- Disconnection of BLA-LHA system (Contralaterally) produced a similar effect as bilateral BHA lesions: abolished CS-Induced Feeding
- Sham group and ipsilateral group still experienced CS induced feeding
15
Q
How is the BLA connected with the LHA?
A
The BLA is connected with the LHA via direct (monosynaptic) and indirect (polysynaptic) pathways. These connections are ipsilateral.
16
Q
What are the different types of brain connections?
A
o Unilateral – one side
o Bilateral- two sides
o Ispilateral – stays on the same size
o Contralateral – crossing over between sides
17
Q
Describe contralateral lesion design.
A
o Unilateral lesions of the BLA and unilateral lesions of the LHA
o But on the opposite sizes of the brain
o The procedure disconnects functional BLA-LHA circuitries on both sides of the brain (in both hemispheres) because connections between these structures are ipsilateral (within the same hemisphere).
- What would happen to feeding if LHA was eliminated on both sides of the brain?
18
Q
What type of neurons within the lateral hypothalamus are critical for cue induced eating?
A
Orexin/Hypocretin Neurons
19
Q
Describe how episodic memory and appetite regulation were studied in humans.
A
o Covertly manipulating the amount participants believed they ate
o Self-refilling soup bowl apparatus
o They can refill/remove the soup without the people knowing
o “Incongruous eating” – pit against their visual cues and their bodily cues
o How much they ate vs how much they saw
20
Q
Describe what was discovered in the episodic memory experiments?
A
Experiment 1:
- Given bowl of soup and asked to eat when it gets to a certain line
- At time zero the amount eaten has a more dramatic impact on hunger than the amount seen
- At 1 hour no significant effects
- After more time what matters is more what they saw than what they ate when they are rating their hunger, more significant effect of the amount of soup seen
- We are most accurate right after eat, after 2 or 3 hours episodic memory plays more of a role
Experiment 2:
- 24h after experiment 1 participants were shown a bowl containing 400ml of soup and asked to evaluate/predict how satiating they would expect it would be
- Expected satiation from a fixed portion: 400ml bowl
- If they saw a bigger bowl they expect more satiation, if they saw a smaller bowl it’s the opposite, memory/the size of the bowl they saw has a bigger impact on expected satiation than how much they ate.
21
Q
What are the two types of memory that affect feeding?
A
Associative (learning and memory) and episodic memory
22
Q
Describe how associative learning and memory is regulated in the brain.
A
- Amygdala – LHA circuit allows learned cues to override satiety and promote eating
- Tone food pairings
23
Q
Describe how episodic memory affects feeding.
A
- Hippocampus suspected
- Episodic memory and appetite regulation – really was satiety not appetite
- When things are looking visually differently it really confuses the body
24
Q
What are DZ and MZ twins?
A
DZ – dizygotic (siblings)
MZ – monozygotic (actual identical genetic code)
25
What was observed in the gut microbiota twin study?
Gut microbiota from twins discordant (different) for obesity modulate metabolism in mice
26
Describe how the twin mice study was performed.
Transplanted human microbiota to mice from obese twin and lean twin separately to obese and lean mice
- Reliable replication of human donor phenotype in (*gnotobiotic) mice
- * = all the microbiota known or not present at all
- Were able to induce adiposity in mice by changing the microbiota
27
How does the co-housing of obese and lean mice affect the mice?
- Co-housing Ob and Ln mice transforms the adiposity phenotype of cage mates (harboring the obese co-twins microbiota) to a lean state
- When the mice are put together – the obese mice’s gut microbiota changes to the lean microbiota
- Bacteria populations (bacteriodales) from Ln invaded the Ob
28
How does diet affect changes produced by cohousing obese and lean mice?
- The rescue of obese mice depended on the diet – lower fat, higher fiber most effectively led to the change in phenotype (bacteria fed on the higher fiber diet)
- Highly processed foods have been linked to a less diverse gut microbiota
- Processing kills the bacteria
- Only effective if low fat/high fiber (fruits/vegetables) diet
29
How do antibiotics affect body weight in mice?
At least one study found that mice given low doses of antibiotic developed 15% more body fat compared to control mice
30
What are the mechanisms through which bacteria impact metabolism?
- Intestinal microbiota break down and ferment dietary fibers into short chain fatty acids = these fatty acids may be enough to mediate satiety
- They will produce fatty acids but in the end will keep us lean
- The microbiota in lean mice produce larger amounts of SCFAs (Short chain fatty acids) and digest more of the plant fiber present in the mouse’s diet than the microbiota of Ob mice
- Increased weight gain in Ob mice does not result from increased energy harvest
31
Describe the role of SCFAs
Although SCFAs are a source of energy and they promote leanness by
- inhibiting fat accumulation in adipose tissue
- raising energy expenditure
- enhancing production of hormones associated with feelings of satiety
32
What are two theories for ways microbiota impact body mass?
- The microbiota might increase efficiency of energy harvested from ingested food
- It might promote low grade inflammation that can result in impaired signaling by various metabolic receptors that control satiety
33
What is the emotional eating theory?
Individuals eat to cope with stress and that could lead to Stress- Eating-Obesity Nexus
34
What is innately preferred across species?
sweet taste
35
Describe the chocolate study.
o Mood induced by watching a movie clip: A sad sequence from the champ, when harry met sally, processing and usage of copper
o Rated their mood then fed a piece of chocolate, just for the taste (control group drinking water – controls for possibility that they would be distracted)
o When fed chocolate it changed the mood for the sad film
o The palatability effects the amount of mood change
36
What were the results of the chocolate study?
- The experiments showed that eating a small amount of sweet chocolate improved an experimentally induced negative mood immediately and selectively, and that the effect was due to palatability
- The effect was more pronounced in emotional eaters
37
Describe the physiology of the stress response.
Hypothalamus (Corticotropin-releasing hormone (CRH)) –> Pituitary Gland (Adrenocorticotropin hormone) (ACTH) –> Adrenal Gland (Glucocorticoids) Cortisol (Human) Corticosterone (Rat)
38
What are glucocorticoids?
- released by the adrenal gland
- stimulate gluconeogenesis (glucose synthesis from protein and fat)
- fasting increases release of glucocorticoids, which helps maintenance of normal concentrations of glucose in blood
- stress causes energy usage
39
How was the connection between glucocorticoids and stress tested?
(in women)
- First 3 sessions: Exposure to 45 minutes of stress
- Fourth session: Rest session (sat quietly, reading and listening to music)
- After the stressor (or after rest on the last session) participants given a basket of snacks and left for 30 min while leisurely reading
- Salivary cortisol samples collected before, during, and after test:
o Baseline (15 min; 30 min)
o Before stress (45min)
o During stress (60 min; 70 min)
40
What was the stress in the cortisol/eating behavior study?
Modified version of Trier social stress test
• Subject asked to perform 3 challenging tasks designed to be stressful by giving unrealistic time constraints to perform the expected goals
• 1) visual spatial puzzle
• 2) serial subtraction of a prime number from a high number
• 3) deliver a videotaped presentation they were told would be evaluated from behind a one way mirror
41
What were the snacks in the cortisol/eating behavior study?
* To account for individual food preferences for sweet versus salty and high versus low fat snacks four snacks were provided
* High fat: chocolate granola bar, potato chips
* Low fat: sweetened rice cake, salty pretzels
42
What were the results of the cortisol/eating behavior study?
- Results: High cortisol reactors consumed more calories on stress days and preferred sweet/high fat foods compared to low reactors
- Dieting was not related to consumption after stress, but was significantly lower on the control day
43
Describe the major players in stress response.
```
Hypothalamus
• Paraventricular nucleus (PVH/PVN)
• Nucleus right above the arcuate nucleus
• Has CRH neurons
Pituitary gland
Adrenal Gland
```
44
What is the PVH/PVN connected to?
(Plays a role in stress response)
Also the PVH/PVN is connected with the feeding circuitry and it receives inputs from NPY/AgRP and CART/aMSH neurons, like the LHA
45
How were the effects of chronic stress on energy intake studied?
Experiments Design:
- 2x2 Stress or no stress x comfort or no comfort food
- Stress: Restraint stress (3hr daily for 5 days)
- What they chose to eat and how much they ate was measured
46
What were the experimental groups in the chronic stress, energy intake study?
Group (-) chow only and no stress
Group (+) chow, lard and sucrose but no stress
Group R (-) received restraint stress but chow only
Group R(+) restraint stress, chow, and lard and sucrose
47
What were the results of chronic stress?
- If animals are expecting something stressful they don’t eat
- Caloric efficiency calculated as a ratio of body weight change divided by calorie intake
- If you don’t change your diet and you’re under constant stress you start losing weight
- Immediately after stress they would start eating more if the food is available
- The stress group that has access/ate comfort food had a blunted corticosterone response to a new stress
- How content/rewarding your life is right before something stressful happens matters
48
What were the general conclusions from the chronic stress study?
- Chronic stress increased consumption (appetitive drive) of palatable food
- Consumption of palatable food blunted next stress response
49
How could stress induce appetite drive for palatable foods? Where does this act?
o Corticotropin- releasing Hormone/Factor (CRH/CRF)
- In the HPA axis CRH/CRH acts as a hormone (endocrine system)
- Central Action (non-HPA axis) CRH/CRF acts as a neurotransmitter (brain)
o CRH/CFH forebrain systems can be activated in response to Aversive (stressful) and appetitive (positive) events/stimuli
50
Where does central CRF (non-HPA) act within the forebrain?
• Nucleus Accumbens (ACB/NACC)
- Part of the ventral striatum
- The ACB has
- CRF-fibers
- CRF-receptors
- Local neurons expressing CRF
51
How were the effects of CRF within the nucleus accumbens studied?
- Testing subjects for the motivation to obtain reward: sucrose pellets (by level pressing) while being primed by a sound that reminds them of the pellets
-Rats trained using Pavlovian Instrumental Transfer, prior to testing rats received micro injections of
• Vehicle
• CRF
• Amphetamine (positive control)
52
What is PIT and what was it used to study?
- Pavlovian-Instrumental Transfer (PIT)
- Testing subjects for the motivation to obtain reward: sucrose pellets (by level pressing) while being primed by a sound that reminds them of the pellets
- Used to study effects of CFR in the nucleus accumbens on incentive motivation of sucrose reward cues
53
How was Pavlovian instrumental transfer trained?
Phase 1: Instrumental Learning
• Rats place in a chamber with two levers: active and inactive, responding on the active lever delivers sucrose (reward) while responding on the inactive level has no consequence
Phase 2: Pavlovian Conditioning
• Rats are presented with two cues (auditory)
• One cue is immediately followed by sucrose CS+ while the other cue is paired with no outcome (CS-)
• Rats have no control of sucrose delivery, however they learn the association between the cue (CS+) and sucrose delivery. They approach the place (food-cup) where the sucrose is delivered, during presentation of the CS+, but not during CS-
Phase 3: Test (of Pavlovian-to-instrumental transfer)
• Rats in operant chambers with both levers present and the CS+ and CS- (tones) are presented to the rats and lever responding is assessed
• No sucrose rewards given
• Evidence of PIT is that the rats increase responding to the active lever during the CS+ compared to the CS-
54
What were the results of the CRF study in mice?
- After AMPH given rats enhance pressing on sucrose lever selectively during CS+
• No change on control lever or pressing during pre-CSs or CS-
- After CRF given rats enhanced pressing on sucrose lever selectively during CS+
• No change on control lever or pressing during pre-CSs or CS-
o Conclusions: CRF enhanced appetitive motivation for reward, similar to the effects of AMPH
55
How was self control choice and stress studied?
o Experience stress (ice water) then, while in fMRI, choose food items from pictures to eat after the testing, bold brain activation patterns measured
o Was found that stress increased the influence of immediately rewarding taste attributes on choice and reduced self-control
56
What is self-control failure?
o Self-control failure is defined as choosing a more tasty less healthy item in the subset of trials where health and taste attributes were in conflict because the healthier item was less tasty
57
What activity was observed in the brain in the stress, self-control choice study?
o Increased functional activity across brain areas related to:
Associative learning: amygdala
Reward: nucleus accumbens (ACB)
Decision-making: prefrontal cortex (PFC), ventromedial (vmPFC) and dorsolateral (dlPF)
58
What was found to be critical for emotional decision making in the stress, self-control choice study?
o Ventromedial Prefrontal Cortex (vmPFC) critical for Emotional Decision Making
o Greater connectivity between the vmPFC and AMY and ACB when choosing tastier but less healthy food under stress and reduced connectivity between the vmPFC and a region linked to self-control success (dorsolateral prefrontal cortex)
o vmPFC connectivity with amygdala and vSTr(ACB) increased with stress and during tastier choices was associated with cortisol but not PSL
o The opposite was found for vmPFC-dlPF connectivity: decreased connectivity with stress correlated with PSL but not cortisol
59
How were orexin and reward studied?
o Conditioned Place Preference (CPP)
60
What is conditioned place preference?
During training rats are exposed to two chambers (contexts). One chamber becomes associated with drug or food reward through repeated pairings, whereas the other chamber is associated with no reward.
Test: No reward is given during the test. Preference for reward is measured by the amount of time animals spend in the reward associated chamber minus the time it spends in the non-rewarded chamber when given free access to both chambers after conditioning
61
What are place preference scores?
Expressed as the time spend in the reward-paired chamber minus the time spend in the non-rewarded chamber on the test day
62
What is extinction?
In conditioned place preference: o Extinction – after repeated exposures to the chambers with no rewards, there is no preference for the reward associated chamber
Extinction does not erase prior memory, but rather it is a new learning
Spontaneous recovery of responding (after extinction)
63
What is recovery after extinction? And how is it induced?
Renewal (reinstatement) of responding (after extinction) can be induced with:
• Brief exposure to the reward (US)
• Cue for the reward
• Stress
64
How was the relationship between orexin and reward studied (specific)?
o Behavioral evidence for the role or ORX in processing reward by using conditioned-place preference paradigm
o Place preference scores for: Morphine, cocaine, and food (lucky charms) paired environments
65
Are Orexin neurons activated during CCP/reward seeking?
Examined whether the environment (contextual cues) previously conditioned with food or drug reward activates Orexin neurons
• Activity of orexin neurons was measured with the immediate early gene c-fos protein (Fos) induction
• Fos-induction of ORX neurons positively correlated with preference score
• Orexin neurons in the LHA are critical for reward processing for food and drugs
• ORX neurons are activated by reward cues
66
Could stimulation of ORX neurons drive relapse (renewal) of drug seeking behavior? Could NPY Y4 receptor activation in the LHA (where ORX neurons are located) reinstate extinguished CPP?
- Stimulation of LHA area where ORX neurons located via NPY-Y4R by rPP (a pancreatic polypeptide) micro infusion reinstated an extinguished CPP for morphine
- A caveat: NPY-Y4 receptors are not only located on ORX in the LHA, but also on other neurons, which could have been stimulated by rPP via NPY-Y4 receptors
67
Describe the structure of ORX neurons.
ORX Neurons: cell bodies located in LHA and receive axonal projections (input) from NPY neurons
68
Is the effect of reinstatement induced by Y4 stimulation blocked by systemic ORX-R antagonism?
Systemic administration of ORX-R1 antagonist blocked rPP-induced reinstatement of CPP
69
What is rPP?
(a pancreatic polypeptide)
70
What is CPP?
conditioned place preference
71
Where is Orexin released to produce reinstatement of reward (morphine) seeking (CPP)?
- Hypothesize that ORX action is in VTA
- Ventral Tegmental Area – contains neurons that make dopamine
- Orexin administration into the VTA reinstated an extinguished CPP for morphine
(There is a group of dopamine neurons in the VTA)
72
What are the four questions asked about Orexin and reward?
Are Orexin neurons activated during CCP/reward seeking?
Could stimulation of ORX neurons drive relapse (renewal) of drug seeking behavior?
Is the effect of reinstatement induced by Y4 stimulation blocked by systemic ORX-R antagonism?
Where is Orexin released to produce reinstatement of reward (morphine) seeking (CPP)?
73
What is dopamine? What is it important for and what reinforces it?
A neurotransmitter
Important for reinforcing and rewarding properties of natural rewards and drugs
Natural reinforcers (food, water, sex) cause dopamine release in the brain (Nucleus Accumbens) and drugs (cocaine. Amphetamine) act on these systems to elevate dopamine levels in the brain
74
What are the two groups of dopamine systems?
Two groups of dopamine neurons in the midbrain
- Ventral tegmental area (VTA) and the substantia nigra (SN)
- Dopamine neurons send axons to the striatum in a topographical manner (VTA) to the ventral striatum (nucleus accumbens), and SN to the dorsal striatum
75
Give a summary of orexin and reward.
1) Orexin neurons in the LHA are activated during CpP
2) NPY Y4 receptor activation in the LHA can reinstate and extinguished CPP
3) This effect (reinstatement induced by Y4 stimulation) can be blocked by systemic ORX antagonism
4) Orexin administered in the VTA can reinstate an extinguished CPP/reward (morphine)
76
How was leptin and reward studied in rats?
Evidence from brain self-stimulation study
77
What is BSR?
- Brain Stimulation Reward (BSR) – self administration of electrical current into the brain (“self-stimulation”)
- In 1950s Olds and Milner discovered that rats would work (perform operant response such as lever pressing) to obtain electrical stimulation of some brain areas
- The highest rate of responding was in the lateral hypothalamus
78
What is BSR affected by?
- The effectiveness of stimulation in the Lateral Hypothalamus is sensitive to physiological hunger state
- Chronic food restriction enhances the effectiveness of stimulation in the Lateral Hypothalamus (area around the fornix)
79
What was the goal of the Leptin BSR study?
assess changes in rewarding effect of LHA stimulation after leptin administration in food deprived animals`
80
Describe the procedure of the leptin, BSR study.
o Methods: Subjects and Testing Procedure:
Stimulation Procedure
• Chronic stimulating electrodes in LHA
• Self-administration of current via lever press (LP)
• Stimulation frequency varied across trials
Leptin Administration
• Intracerebroventricular (ICV) cannula
Measured BSR under chronic food deprivation and 1 hour after ICV injection of leptin
81
Describe how the BSR graphs could be interpreted?
Rewards/min: # LPs/min (increased motivation)
Log base 10 frequency – increased amount of stimulation
Shift to the left – enhanced BSR
Shift to the right – reduced BSR
82
What were the results of the leptin BSR study?
Effect of Chronic Food Deprivation:
Results: Rats press more (work harder) to get brain reward when food deprived/restricted (under heightened motivated state)
Leftward shift in S-curve = enhancement of BSR
Effect of Leptin administration during food deprivation
Rightward shift in S-curve = reduction in BSR
Rats give up sooner when given leptin (low motivated state)
83
What were the conclusions from the BSR/Leptin study?
Leptin acts antagonistically to food deprivation to change the motivational state of the animal via LHA neurons (that are sensitive to food-deprivation)
84
Other than the BSR study, how was leptin and reward studied?
Evidence from leptin-deficient patients
85
Describe ob/ob mice
Low metabolism
Overeating
Morbid obesity
Type II diabetes
86
What does leptin administration in ob mice produce?
Reduces food intake
Increases activity and metabolism
Reduces body weight
87
Describe the methods of studying Leptin and reward in leptin deficient patients.
```
Subjects born with leptin deficiency:
- Subject 1: 14yo boy
- Subject 2: 19yo girl
Methods: training procedure
-Leptin-deficient subjects treated with leptin for 1 week, tested subjects before and after treatment
Fasted vs Fed
- fMRI: food vs Non-food images
- Ratings: hunger, satiety, “liking”
```
88
What were the effects of leptin treatment in leptin deficient patients?
Results: Leptin treatment was effective in regulating food intake and hunger/satiety
- Leptin treatment significantly decreased food intake (ad libitum energy intake at a test meal)
- Fasted state: Leptin treatment reduced hunger rating
- Sated state: Leptin treatment increased satiety rating
Results: Effect of Leptin Treatment on Ratings of Images
- (“How much they like images”; tested in fasted and fed states)
- Leptin-deficient not treated: High ratings to food images in fed and fasted states
- Leptin-deficient after treated: High ratings in fasted state, Reduced liking ratings in fed state (~30%)
89
Where was the interaction of Liking, fasting, and leptin in the brain?
The nucleus accumbens (ACB) is a site of interaction between “liking”, fasting and leptin
- In the leptin-deficient (-) state ACB activation correlated positively with liking ratings in fasted and fed states
- In the leptin-treated (+) state ACB activation correlated positively with liking ratings in only the fasted states
90
What is the overall relationship between leptin and reward?
Leptin reduces feeding behavior by changing a subject’s motivational state and/or their subjective (perceived) reward-value of food-related stimuli.
91
What is Berridges model for reward processing?
```
Kent C Berridges model for reward processing wanting and liking
o Motivation – dopamine system (wanting)
o Hedonic (pleasure) – opioid system (liking)
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92
Describe the endogenous opioid system.
o Opioid system/opiates produce powerful positive affective state.
o Animals will work to obtain intravenous opiates.
o Opiates enhance feeding.
o They mediate palatability (hedonic evaluation) of food.
o Support from studies with opioid antagonists (naloxone; naltrexone).
93
How was the effect of endogenous opioids studied?
Administration of opioid-antagonists
In Humans:
*Subjects report less pleasantness with the food eaten
*Reduces favorable ratings of taste without changing hunger
In Humans & Animals:
*Reduces preference for -sweet foods -high-fat foods -salty foods
o Opioids increase food palatability (& intake) through changes in pleasure derived from tastes rather than changes in taste per se.
94
What are the types of opioid receptors?
There are at least three different types of opioid receptors: μ (mu), δ (delta), κ (kappa)
94
What are the types of opioid receptors?
There are at least three different types of opioid receptors: μ (mu), δ (delta), κ (kappa)
95
What is an obese adult?
An obese adult is classified as having a body mass index equal to or greater than 30
96
Increasing number of _____ around the world
obese children
97
What are some health risks of obesity?
```
Type 2 diabetes
Cardiovascular disease
Some types of cancers
Stroke
Arthritis
Depression
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98
What is BMI?
a person's weight in kilograms divided by the square of their height in meters (kg/m2)
99
What are the ranges of BMI?
- Normal range: 18.5-25 kg/m2
- Overweight: > 25 kg/m2
- Obese: > 30 kg/m2
100
What is a cause of obesity (in a small percentage of obese people)?
Single gene mutations
o Single gene mutations (known to cause obesity)
Leptin (ob/ob) - can undergo leptin treatment
MC4 receptor - difficult to treat, harder to add receptors where they are missing
101
Other than genes, what is producing obesity?
Environments
102
What change is predicted to be able to prevent obesity? Why is this not effective in our society?
- Affecting energy balance by 100 kilocalories per day could prevent weight gain in most of the population
- Equivalent to 15 minutes per day of walking or eating a few less bites of each meal
- Now people put more pressure on time so this is not always permitted in our lifestyle
- We have issues with things that take a long time
103
What is the environment that predisposes individuals to obesity called?
obesogenic environment
104
What does the obesogenic environment involve?
the social and physical environment
105
How does the environment affect predisposition to obesity?
energy intake: increase availability of Food and Food cues (in developed society), changes in attitudes
expenditure: sedentary lifestyles
106
How does the environment impact energy intake/what are some recent changes that influence energy intake?
* Increase in the intake of carbs
* Increased consumption of sweetened drinks
* Consumer price index – fresh fruits and vegetables are very expensive, much more economical to eat sweets and soft drinks – economic aspect is impacting culturally how we think about food
* Meat is relatively cheap compared to fruits and vegetables
107
How do sweet drinks impact obesity?
- If you drink something sweet without calories then you become desensitized to the sugar
- Beverages that contain sugar are handled differently by the body than when sugar or HFCS are incorporated in solid foods
- Humans may lack a physiological basis for processing carbohydrate or alcoholic calories in beverage
- Sweet, non-caloric drinks “diet” are not a good replacement because they produce a counterintuitive effect of inducing metabolic derangements
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How does drinking water impact health?
- Drinking water is associated with weight loss in overweight dieting women independent of diet and activity
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How do food cues produce obesity?
- Increased availability of food cues
| - Eating is driven more by our outside world than the physiology
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Describe americans food attitudes.
- Attitudes to food and the role of food in life in the USA, Japan, and Flemish Belgium and France
- Ask what comes to mine upon hearing the phrase “chocolate cake”
• Americans say guilt
• French people say celebration
- Ask what comes to mine upon hearing heavy cream
• Americans say unhealthy
• French say whipped
- Americans associated food with health the most and with pleasure the least
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How does food function differently in American society?
Americans worry more about food and derive less pleasure from eating than people in any other nation they surveyed
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What are two examples of gene environment interactions?
1) Polygenetic genotypes – genetic predisposition is due to multiple genes and their interactions
2) Gene-Environment Interactions – genetic and environmental contributions can be interdependent
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What is the thrifty genes theory?
* Thrifty phenotype: efficient metabolism – slow metabolism, can live on less
* Spendthrift phenotype: inefficient metabolism “fast metabolism” expend a lot of energy
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If you have a fast metabolism you are always______
warm
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When is a thrifty phenotype useful?
Adaptive in times of famine but maladaptive in times of plenty
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Describe a study that examined gene-environment interactions
• Pima people
o Due to their migration patterns they are an examples of how genes interact with different environments
o Began in Mexico and then a large population moved to Arizona
o 700-1000 years ago separated into two groups
o Same genetic background, different environments
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What genes do Pima people have?
o Pima people therefore have what people call “thrifty genes”
Was helpful for long periods of famine
Not adapted for Obesogenic environment
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How did Pima people respond to their different environments?
o In Mexico: similar lifestyle to ancestors: subsistence farming, limited access to high calorie foods Average weight 141lbs
o In USA: contemporary lifestyle/environment: less physical activity, food availability, average weight 198lbs higher cholesterol, 5x higher rate of diabetes
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What is a genetic difference observed in Pima people?
- One example is a protein that determines a rate at which energy is metabolized
- UCP: Uncoupling Protein (in mitochondria)
- Majority of Pima people have low levels of UCP (thrifty genotype)
- Some Pima people have high levels of UCP (spendthrift genotype)
- Those who have high UCP levels and likely other aspects of spendthrift metabolism are resistant to obesity in the USA
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What is UCP correlated with?
* Negatively correlated with BMI
| * Positively correlated with metabolic rate
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How does Leptin interact with UCP?
Leptin increases the expression of UCP
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What are individual differences in metabolism called?
NEAT (Non Exercise Activity Thermogenesis)
o Non-exercise energy expenditure – fidgeting
o When non-obese adults were over-fed the amount they gained was inversely related to NEAT
o NEAT and overall activity of individuals is believed to be genetically programmed
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What are some similarities between food and drug addiction?
o Behavior Food and Drugs are Rewarding and Reinforcing
o Learning – learned habits and preferences for food and drugs are formed by repeated exposure to reinforcing properties of rewards
o Overeating and drug addiction are strongly linked with exposure to reinforcers
o role of stress important in both
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What is an important difference between food and drug addiction?
One important difference is that food is necessary for survival – abstinence is not an option
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What are critical factors common to drug abuse and overeating?
1) availability of reinforcers
2) Learning
3) Stress
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What brain systems do food and drugs both activate?
- Palatable food activates brain reward circuitry through
- Fast/initial sensory inputs (taste)
- Slower/later, post ingestive mechanisms
- Drugs can activate the same reward systems that are activated by the natural rewards via direct pharmacological effects
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Describe a neurobiological adaptation in drug/food addicted?
- D2 receptor availability
- Lose a lot of available receptors
- When you stimulate a system with a drug the homeostatic response is to downregulate the receptors
- Less D2 receptors binding (fewer receptors available) in obese
- Genetic predisposition and/or neurobiological adaptation
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Describe a study examining D2 receptors.
o Tested whether overconsumption of high-fat/high calorie diet would decrease D2 in the striatum and change rats responses to reward (BSR)
o Fed rats “cafeteria style diet”
o Johnson & Kenny 2010
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What were the results of the D2 rats study?
Compared to controls, rats that had extended access to cafeteria diet
- ate more and gained a lot more weight
- increased reward threshold in BRS: they need more current
- Increased threshold=Decreased sensitivity of the brain reward system
- Had fewer D2 receptors
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What do fewer D2 receptors represent?
- An example of neuroadaptation: a response to overconsumption of palatable foods was downregulation of D2 receptor
- Having fewer D2 in turn causes or perpetuates addiction-related behaviors
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How did Johnson and Kenny examine correlation vs causation in reference to D2 receptors and obesity?
Eliminated D2 receptors (with a viral vector knock-down methods)
And as a result rats developed addiction-like behaviors faster
132
What are 4 obesity treatments/cures?
o Drug treatment
o Bariatric Surgery
o Exercise
o Change in lifestyle
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What are ways in which drugs could help people lose weight?
1) reduce appetite/the amount of food they eat
2) prevent some of the food they eat from being digested
3) increased their metabolic rate (provide them with a “spendthrift phenotype”)
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What are some attempted weight-loss drugs +risks?
- Some serotonergic antagonists suppress eating: (fenfluramine and sibutramine)
Have hazardous side effects (increased incidence of heart attacks and strokes)
- CB1 cannabinoid receptor antagonist (rimonabant)
Blocks appetite, but increased depressive mood disorder, anxiety, and increased suicide risk
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What is bariatric surgery, what is it aimed at and what does it disrupt? What is the most successful type?
o Designed to reduce the amount of food that can be eaten during a meal or interfere with absorption of calories from the intestines
o Bariatric surgery has been aimed at the stomach, the small intestine, or both
o RYBG procedure is the most successful because it disrupts the secretion of ghrelin, which makes you less hungry
o Some weight loss surgeries can diminish cravings for sweets through impacting dopamine
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What are eating disorders?
Persistent behaviors intended to control body weight that significantly impair physical health
137
Is obesity an eating disorder?
•Obesity is not defined as an eating disorder but binge eating is
If obesity had an addiction component then it would be an eating disorder
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What is anorexia?
o 0.5-2%
o Anorexia Nervosa
o Anorexia (“loss of appetite”) – lack of eating
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What are anorexia symptoms?
1) Restricted eating to the point of starvation (below 85% normal body weight)
2) Fear of gaining weight/becoming obese
3) Body image distortion
4) Obsessions w food
5) Obsessive exercising
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What is bulimia?
```
o 1-3%
o Means “ox hunger”
o Episodes of binge eating
o Compensatory behavior to present gaining weight that follows binge eating
o Vomiting, misuse of laxatives,
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What are the symptoms of bulimia?
1) Loss of control/lack of control over food/eating
2) Binges, followed by compensatory behavior, typically purging
3) Excessive self-evaluation/preoccupation with body shape/weight
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What are the health consequences of anorexia?
Long-term damage to bones (osteoporosis)
Serious reproductive problems
Cardiovascular risks
10-20% fatal
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What are the health consequences of bulimia?
- Frequent vomiting erodes tooth enamel, deplete body of vital salts, disrupting muscle, heart, and kidney function
- Laxatives destroy bowel muscles and drain away salts and water
- Bingeing/purging cycle related to irregular menstrual periods, disturbed bowel habits, cardiovascular risks
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What causes anorexia/bulimia?
o Environment: Culture, society, media, family, stress, learned behaviors
o Genetics: Heredity, personality traits
145
Describe the ED affected population.
More prevalent in western than in non-western societies
More prevalent in women (m/f 1:20 in AN; 1:10 BN)
Often triggered by dieting
146
Describe the genetic influence on eating disorders
- Higher lifetime risk among female relatives (7-20x that of the general population)
- Twin studies have confirmed that there is a genetic predisposition
- Higher concordance in mono- vs dizygotic
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Describe the role of physical activity in anorexia.
o A lot of patients were physically active prior to the onset of anorexia
o Over-activity is not only a secondary symptom but also a contributing factor
o For a number of anorexic women excessive exercise is central
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Describe how activity and food restriction interact in rats?
```
o “Activity Anorexia” = even if they have a running wheel they wont lose weight
o Anorexia (in animals) induced by a combination of food restriction and exercise
o Food restriction alone is not sufficient to produce anorexia: Animals maintain body weight by increasing meal size
o When food restriction is combined with a running wheel the rats increase physical activity to the point of starvation
```
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What can be concluded from the rat/anorexia/workout study?
o Increased activity of rats on a semi-starvation diet likely reflects an innate tendency to increase seeking food when it becomes scarce
o Anorexia in animals is induced by a combination of food restriction and exercise
o Hypothesized:
Exercise is more reinforcing to semi-starved individuals
Exercise contributes to reinforcing value of food avoidance
Starvation-induced hyperactivity has features of addiction
150
Describe observations about stress and eating disorders.
Eating disorders in teens skyrocketing during the pandemic
Eating disorders are increasing among children and teens
Eating disorders are also beginning younger: below the age of 12
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What are personal traits correlated w AN?
* Ahedonia- inability to experience pleasure
* Asceticism – abstinence from pleasure
* High constraint of affect
* Rigidity – reduced spontaneity or emotional expressiveness
* Over control in eating affect and impulse
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What are personal traits correlated w BN?
* High imupulsivity
* Extremes of intense affect
* Sensation/novelty seeking
* Substance abuse
* Switching between over control or under control (losing control)
153
What disorder may predispose you to an ed?
anxiety and depressive disorders
154
What is the serotonin hypothesis?
Restricting food intake might provide a temporary break from dysphoric moods (due to serotonin transmission) and that might be reinforcing
155
Why is it hard to study serotonin?
• Hard to study: Difficult to separate cause from consequence and serotonin levels does not equal serotonin transmission
• Compensation:
o Decreased synthesis (due to low TRP) could originally lead to decreased serotonin transmission but low transmission could result in compensatory 5-HT receptors adaptation
156
What AA is related to serotonin?
Tryptophan – essential amino acid and a precursor of serotonin
TRP levels are correlated to brain serotonin synthesis and release
People with serotonin deficiencies are trying to get the right amount – tryptophan
157
What is current anorexia treatment?
- Currently there is no drug that is effective in treatment of Anorexia Nervosa
- Behavioral treatment: teaching patients to eat faster
- Food plate is placed on a scale attached to a computer that provides real time feedback (actual and ideal intake time curse)
- After a meal the patients are kept in a warm room which reduces their anxiety and activity levels
158
Describe hunger signalling in anorexia
- In anorexia levels of NPY are really high
- NPY is increased during starvation and normalizes after recovery
- Suggests intact hunger signals
- Circulating Ghrelin is also increased and normalize after recovery
- In anorexia patients hunger signals are high, as expected and decrease after recovery, as expected
159
How might hunger signals produce unexpected effects in anorexia?
- NPY might play a role in development of food-related behavior other than eating
- Mouse Study: Increased food intake by neuropeptide y
- Brain (ICV) infusions of NPY increase time spent running in food restricted rats in activity induced animal model
160
Describe satiety signals in anorexia
- Leptin increases quickly when a very little bit of weight is gained
- Increases before full recovery which could be preventing additional weight gain
161
Describe ghrelin in bulimia.
- Ghrelin is dampened, episodes are not necessarily physiologically driven
- Post-meal ghrelin decrease is blunted in Bulimia, nearly flat curve
- Blunted post-meal ghrelin response linked to dysregulation of post-ingestive satiety that could underlie binge eating
162
Describe leptin in bulimia
o Decreased serum leptin in bulimia nervosa – lower leptin, could explain the binge part
o Lower leptin in BN likely contributes to abnormal eating patterns via impaired post-ingestive satiety
o Lower leptin in recovered-Bn suggest biological/genetic trait/susceptibility
163
Describe fMRI study in ED patients
o Eating disorder patients and healthy control subjects were shown pictures of food or non-food items
o You will be shown pictures of food and other objects. Look at each picture and think how hungry it makes you feel.
o Eating disorders patients found food pictures threatening and disgusting
o No difference in ratings of the non-food pictures between patients and control subjects
o Greater medial prefrontal cortex activation in response to food items in eating disorder patients compared to controls
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Describe body image distortion study
Used digital images of subjects bodies (anorexia patients and control subjects) that were individually distorted for symptom provocation
- Fear/perception of their own image
Results: greater amygdala activation in response to target images in AN compared to control
- Amygdala is a critical node of brain fear network
- The first study to show amygdala activation in anorexia patients when they are confronted with their own distorted body shape
165
What is important for brain fear network?
amygdala
166
What was a study performed to isolate fear associated w body comparisons?
• Study: Examined brain responses (fMRI) to images of slim-idealized bodies and interior designs of homes
• Instructions: Compare your home/yourself to the home/body image
o Asked to rate their anxiety and neural activation during provocation with body shape images
o Positive correlation between subjective anxiety ratings and neural activation during provocation
167
What were the results of the body image/house comparison study?
Individuals with body shape self-comparison selectivity: Demonstrated activation of Amygdala and prefrontal cortex “fear/emotion network” in “non-eating disordered” women in response to slim body shapes
The activities in these areas were correlated with anxiety ratings induced by the images
168
Where is associative learning controlled?
Human amygdala (BLA)
169
Where is reward controlled?
Nucleus accumbens (ACB)
170
Where is decision-making controlled?
prefrontal cortex (PFC), (ventromedial (vmPFC), and dorsolateral (dlPFC))
