The brain and appetite –
Reward Pathways
Zane Andrews
Learning Objectives / Summary:
Understand that • Reward provides a powerful input to
food intake in addition to homeostasis
• Possible to define neural pathways
in the brain related to reward
• Reward and Homeostatic pathways are
interrelated in the brain
Energy homeostasis
SENSATION &
INTEGRATION
Excessive
calorie intake
(overfed)
Mechanisms to
dissipate energy
Mechanisms to
conserve energy
EFFECTOR TARGET ORGANS
Limited calorie
intake
(starved)
Hedonistic vs Homeostatic eating
What really drives obesity?
Hedonic is defined as “related to pleasure”
Hedonism is defined as “devoted to pleasure”
Homeostatic feeding = need to eat
Reward pathways = desire to eat (want or like)
Where did it go wrong? Why the sudden obesity
epidemic?
• Strong attraction
to food (reward)
• Slow satiety
mechanisms (eat more)
• High metabolic
efficiency (store more)
Increase survival
when
food is scarce
Homeostasis vs Hedonism
“A changing environment (more high fat foods) and lifestyle
on the background
of evolutionary engraved or perinatally-imprinted physiological
response patterns is the foremost explanation for the current
obesity epidemic”
Food addiction?
• Addiction = Knowing the
behaviour is not good
for you but being unable
to stop.
•
Conclusions Similar patterns of neural activation
are implicated in addictive-like eating behavior
and substance dependence: elevated activation in
reward circuitry in response to food cues and
reduced activation of inhibitory regions in
response to food intake.
Food addiction?
• Addiction = Knowing the behaviour is not good for
you but being unable to stop.
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Mesolimbic reward pathways
• The main neurotransmitter
is dopamine
• Dopamine cell bodies are
located in the ventral
tegmental area (VTA)
• The classic reward
pathways involves
dopamine projections to
the nucleus accumbens
• Main site of action for
drugs of reward (cocaine)
Dopamine is required for food
intake
•
Dopamine deficient mice are
hypophagic and hypoactive
•
Mice die at 3 weeks of age unless
given L-DOPA
Dopamine is require for the
motivation to eat
•
Dopamine is generally involved
in motivation
There is a difference between liking and
wanting
In certain situations you might not want
something
However, in a different situation you may
want the previously unwanted item.
Incentive salience
You normally don’t like drinking salt water
But if you are salt depleted for a period of
time you will want to drink salt water.
Incentive salience is the motivational
“wanting” of a stimulus or goal under
certain circumstance. It is different to liking
“Liking” and “Wanting”
“Liking “ – essentially hedonic impact, the brain reaction underlying
sensory pleasure triggered by the immediate receipt of a reward such
as sweet taste
“Wanting” – is the incentive salience or the motivational incentive
attached to attaining a reward. It is the motivational value of a reward
not its hedonic impact
“Wanting” and “Liking” may have evolved as distinct from each other.
“Wanting” providing a common neural basis for the motivation to seek a
number of different rewards whether they be food, sex or, in a modern
context, drugs.
The important thing is that the neural circuits that drive “wanting” and
“liking” can be separated.
Reward, food, “wanting” and “liking”, meso-limbic pathways
There is a division amongst the core processes of reward into
- ‘liking”
Based on behavior and neural pathways
- “wanting”
“Liking”
is an objective affective reaction that is mediated for taste in the brain by
distributed neural networks extending from the brain stem to the nucleus accumbens
Examples of hedonic “liking” reactions are stereotypical and preserved across species
and exist without higher centres
Tongue protrusion
Gape
“wanting”
is an objective motivational process that is often termed incentive
salience (the importance of a motivation)
What are the transmitters involved in “wanting” and “liking”?
•Dopamine was originally thought to be the transmitter that mediated sensory
pleasure or “liking” however 6 OH DA lesions (eliminate dopamine pathways)
show otherwise ie elimination of dopamine from the nucleus accumbens and
ventral striatum (palidum) leads to aphagia (no eating) but no shift in “liking”
Mice lacking dopamine will still show a preference for sucrose
• increasing levels of dopamine in the nucleus accumbens does not change “liking”
but increases the motivational component of reward or “wanting”
Dopamine is the most likely
“wanting”
Reward, food, “wanting” and “liking”, meso-limbic pathways
What are the key brain regions and neurotransmitters involved?
• “Liking” is mediated by mu opioid receptors in the nucleus accumbens
(ie local injection of morphine or the mu opioid receptor agonist DAMGO leads to
appetite for highly palatable, highfat, sweet foods)
• selective mu opioid receptor antagonists (block opioid receptors) reduce the “liking”
of previously favoured sweet solutions
• Endocannabinoids are also distributed in this region and may also increase appetite
for highly palatable foods
“Liking”
Cognitive incentive
processing
Reward Pathways – Pleasure Electrodes?
The basis of hedonistic feeding
Electrical self stimulation.
Rats will repeatedly simulate
electrodes that are placed in
the nucleus accumbens.
Excitation of dopaminergic
neurons arising from the
ventral tegmental area and
projecting to the basal
forebrain (nucleus accumbens).
Lever pressing as a measure of motivation
Dopamine in reward
Dopamine is the reward “skeleton”
primarily driving wanting and motivation,
upon which other neural systems act to
drive hedonistic behaviours or “liking”
The opioid and endocannabinoid system
interact with the mesolimbic dopamine
system.
What other information could affect the
motivational dopamine system???????
Energy homeostasis
SENSATION &
INTEGRATION
• Under negative energy balance you “want” food more.
• Even brussel sprouts taste good if you’re really hunger
Limited calorie
intake
(starved)
Schematic showing the flow of information amongst distributed neural networks
controlling food intake, energy expenditure and energy homeostasis
Orbital frontal cortex is intimately
connected with other related
areas of cortex including the prefrontal, anterior cingulate and
insula cortex together with the
amygdala and hippocampus form
the “paralimbic cortex”
Stored experiences with food
Zheng H and Berthoud H-R
Current opinions in Pharmacology (2007)
Energy homeostasis
SENSATION &
INTEGRATION
Excessive
calorie intake
(overfed)
Mechanisms to
dissipate energy
Mechanisms to
conserve energy
EFFECTOR TARGET ORGANS
Limited calorie
intake
(starved)
Impact on brain reward systems
Signals that reduce
wanting
High glucose
High Insulin
High Leptin
High GLP1
Signals that promote
“Wanting”
Low glucose
High ghrelin
Low leptin
Low insulin
SENSATION &
INTEGRATION
Engage food intake
And food seeking
Excessive
calorie intake
(overfed)
Suppress food intake
And food seeking
REGULATION & MODULATION
Limited calorie
intake
(starved)
Ghrelin
20
Food intake (kJ)
• Ghrelin interacts with
dopamine neurons in the
VTA (ghrelin receptors are
on dopamine neurons)
• Ghrelin injection into the
VTA or nucleus accumbens
increases food intake
****
15
10
5
0
aCSF
Ghrelin
(chow)
VTA injection (d
Ghrelin enhances reward value
of food
Ghrelin enhances reward value
of food
BOLD = blood oxygen level dependent
increased BOLD = increased neuronal activation
Ghrelin
• Effect of VTA ghrelin on food intake depends on peripheral
glucose.
• This represents an important interaction between
homeostatic signals and motivation.
• Ie if brain perceives high glucose, ghrelin affect to increase
food intake “not required”. Low motivation or “low wanting”.
• If brain perceives low glucose (2DG) feeding response to
ghrelin is higher. High motivation or “high wanting”
Intra-VTA
aC SF
Intra-VTA
G h re lin
0 .8
**
#
0 .4
0 .0
S a lin e
G lu c o s e
***
##
1.2
F o o d In ta k e ( g )
F o o d In ta k e (g )
1 .2
%%
a C SF
Ghrelin
0.8
*
**
0.4
0.0
S aline
2 DG
Ghrelin
• Ghrelin stimulates lever pressing for sucrose rewards
• Ghrelin stimulates a conditioned place preference
• CPP is a behavioural task based on the association of an
internal reward state established by an exogenous treatment
(i.e. ghrelin in our experiments) and a context. The ability of
an animal to form a conditioned place preference to drugs of
reward such as cocaine, amphetamine, morphine, alcohol and
heroin requires a functional
• mesolimbic dopamine system
Ghrelin
• Ability of ghrelin to increase a place preference depends on
diet
• No place preference to ghrelin in mice on HFD.
P re fe re n c e s c o re (% )
• Motivation and homeostasis are closely entwined
80
B e fo re
***
60
**
40
20
0
Chow
H FD
H FD
G h re lin
G h re lin
C o c a in e
A fte r
Neural pathways of food reward – interaction with peptides
sensing energy availability
• Microinjections of leptin and insulin into the ventral tegmental nucleus abolish conditioned
place preference in rats
Leptin receptors are present on dopamine containing neurons in the VTA (these neurons
control motivated behavior, “wanting”, addiction and reward)
• Local injection of leptin into the VTA causes a reduction in firing rate and food intake
• Knock down of the leptin receptor leads to an increase in food intake especially of highly
palatable food
Leptin impinges not only on homeostatic but can
also change the attractiveness of food or the
degree to which it is “wanted”
Leptin’s impact on meso-limbic circuits and eating behavior in the human
• Subject 1 – 14 year old boy leptin deficiency studied before and after 7 days of leptin treatment
Subject 2 – 19 year old girl
• test meal, substantial reduction in caloric intake after treatment
• fMRI response to food and non food images before and after leptin treatment
• How much do you like the images, leptin and leptin deficient, fed and fasted
Farooqi etal Science
2007
These data are consistent with the notion that leptin acts on neural circuits governing food
intake to diminish the perception of food reward while enhancing the response to satiety
signals during food consumption
Interaction between hypothalamic “homeostatic”
and mesolimbic “reward” pathways -AgRP
Cortex
Cb
BNST PVN
VTA
PBN
Arc
NAc
NPY/AgRP
(GABA)
POMC/CART
See commentary by Richard
Palmiter, Nature Neuroscience,
15.1060.1061
Clear that there is an interplay between “homeostatic” and “reward” pathways
in the control of food appetite and food intake
AgRP/NPY/GABA neurons
• Activation of AgRP neurons increase the
motivation to obtain food when not present
– DREADD pharmacogenetic technology
Krashes et al 2011 Journal of Clinical Investiation
AgRP/NPY/GABA neurons
• Activation of AgRP neurons drives a
condition place preference when animals
conditioned with food
• Activation of AgRP neurons drives a
condition place aversion when animals
conditioned without food
Hanger
Metabolic and Hedonic controls of food
intake
Metabolic consequences of food are regulated by homeostatic functions and
Hedonic consequences by reward functions
Hedonic and Metabolic aspects of food intake are interrelated ie
- hedonic value of food affects food intake (1) and
- metabolic status has an impact on hedonic processing (2)
Not clear at the moment whether Obesity is a cause (1) or consequence (3) of
altered reward functions
Berthoud etal (2011) Am J
Physiol 300: R1266-R1277
Metabolic and Hedonic controls of food
intake
Metabolic consequences of food are regulated by homeostatic functions and
Hedonic consequences by reward functions
Hedonic and Metabolic aspects of food intake are interrelated ie
- hedonic value of food affects food intake (1) and
- metabolic status has an impact on hedonic processing (2)
Not clear at the moment whether Obesity is a cause (1) or consequence (3) of
altered reward functions
Berthoud etal (2011) Am J
Physiol 300: R1266-R1277
Metabolic and Hedonic controls of food
intake
Metabolic consequences of food are regulated by homeostatic functions and
Hedonic consequences by reward functions
Hedonic and Metabolic aspects of food intake are interrelated ie
- hedonic value of food affects food intake (1) and
- metabolic status has an impact on hedonic processing (2)
Not clear at the moment whether Obesity is a cause (1) or consequence (3) of
altered reward functions
Berthoud etal (2011) Am J
Physiol 300: R1266-R1277
Summary
• Reward behaviour is influenced by motivation “wanting” and
hedonic behaviour “liking”
• Dopamine primarily regulates motivation whereas opioid and
endocannabinoid interact with dopaminergic pathways to influence
liking
• Homeostatic and motivational pathways are closely linked and
interact together
• Metabolic signals of energy surfeit (leptin, insulin, GLP1) and energy
deficit (ghrelin) attenuate and potentiate motivational pathways
respectively.
• Regulation of energy homeostasis depends on both homeostatic
(hypothalamic mechanisms) and motivation (dopaminergic
systems)
Honours Projects 2020
• How does “Hanger” effect the brain?
http://www.huffingtonpost.com.au/2016/08/03/tur
ns-out-being-hangry-is-actually-a-scientific-thing/
• What are the hormone signals to the brain
that increase food-reward during hunger?
• Why is our memory enhanced during hunger?