NEURAL CIRCUITS OF REWARD - FABRICIO H. DO MONTE, DVM, PHD ASSISTANT PROFESSOR DEPT. NEUROBIOLOGY & ANATOMY
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Neural circuits of reward
GS14 1024 – Systems Neuroscience
April 29th, 2021
Fabricio H. Do Monte, DVM, PhD
Assistant Professor
Dept. Neurobiology & Anatomy
Important definitions
Reward: any stimulus that elicits appetitive behaviors (e.g.,
consummatory or approaching responses); or the positive
value ascribed to an object, act or internal state.
Reinforcement: the consequence of a behavioral response
that increases its likelihood of occurring again in the future.
• Positive – delivery of a rewarding stimulus after
a specific behavior.
• Negative – removal of an aversive stimulus or a
state of need after a specific behavior.
The brain reward system
J Comp. Phys. Psychol. 1954 Dec; 47(6):419‐27.
First demonstration of
intra-cranial self-
stimulation in rats
The brain reward system
Controversial and unethical studies using DBS in
septal/ventral striatum in humans
Dr. Robert G. Heath
1915-1999
Which brain regions and neural circuits are
part of the reward system?
The dopamine reward system
Substantia
nigra
Ventral tegmental
area (VTA)
VTA neurons respond initially to reward
No prediction Reward
Reward occurs responses
Before teaching the
monkey that light
predicts reward
Schultz et al., 1997
For a review see: Berridge, 2018.
After reward conditioning, VTA neurons
respond to reward predictors
Reward predicted
Reward occurs Lack of reward
responses
After teaching the
monkey that light
predicts reward
Schultz et al., 1997
For a review see: Berridge, 2018.
During omission of expected rewards,
VTA neurons are inhibited
Reward predicted Prediction error signal
No reward occurs
Inhibitory
responses
After teaching the
monkey that light
predicts reward, but
omitting the reward
Schultz et al., 1997
For a review see: Berridge, 2018.
The VTA sends dense dopaminergic projections to
the striatum, including the nucleus accumbens
The NAc regulates incentive salience (i.e., “wanting”)
and liking (i.e., pleasure);
The NAc is mainly composed of GABAergic MSNs
(95%, expressing dopamine receptors D1, D2 or both);
The NAc is important for reward associations (e.g.,
classical reward conditioning);
Exposure to either natural rewards (e.g., food, water,
sex) or drugs (e.g., cocaine, amphetamine, alcohol,
nicotine) increases dopamine levels in the NAc.
For a review see Castro and Bruchas, 2019 Hnasko et al., 2012VTA self-stimulation elicits dopamine release in the NAc
Fiorino et al., 1993
Patriarchi et al., 2018Dopamine in the NAc is necessary for reward self-stimulation
Intra-NAc infusion of dopamine antagonists blocks MFB or VTA self-stimulation,
whereas drugs that increase dopamine release (e.g., cocaine, amphetamine)
facilitate it.
Animals learn to self-administer drugs that increase dopamine levels in the NAc
or even dopamine agonists directly into this region.
In contrast to dopamine, activation of glutamatergic inputs to the NAc can
either reduce or increase food-seeking motivation (Britt et al., 2012; Stuber
et al., 2011; Do Monte et al, 2017; Reed et al 2018), most likely due to
distinct cell targets (e.g., ChAT, D1, D2).
For a review see Wise, 2005Contradictions about the hedonic role of dopamine in the NAc
Intra‐NAc infusion of opioids
Both liking and disgust reactions persist after depleting 99% of dopamine inputs to NAc
For a review Berridge and Kringelbach, 2015The NAc in the modulation of motivated behaviors
Interface between limbic and motor regions
Reward and reinforcement
Nucleus accumbens
Goal-oriented behavior
Incentivized learning
Impulsivity
Feeding
Social interaction
Sexual drive
For a review see Salgado and Kaplitt, 2015The NAc is implicated in motivated behaviors in humans
Humans Humans
Heller et al., 2009
Reduced fronto-striatal connectivity DBS of NAc as a therapy for substance
in patients with depression. use disorders and eating disorders.Striosomal and matrix compartments of the NAc
µ‐opioid receptors
Striosome: high levels of µ-opioid receptors, substance P, dopamine-1-
receptor (D1R), met-enkephalin, calretinin, Nr4a1, pro-dynorphin, GAD-2.
Matrix: high levels of calbindin, somatostatin (SST), enkephalin, dopamine-
2-receptor (D2R), and cholinergic markers.
For a review see Brimblecombe and Cragg, 2017Local microcircuits in the NAc
For a review see Russo and Nestler, 2013How does the NAc communicate with other brain regions to regulate reward-seeking responses?
Inputs and outputs of the NAc
Paraventricular
Hippocampus thalamic nucleus
Substantia nigra, lateral
hypothalamus, septum, Prefrontal
BNST, PAG.
cortex
Glutamatergic
GABAergic NUCLEUS D1R
ACCUMBENS D2R
Dopaminergic
Amygdala
Ventral
Tegmental
Sensorimotor cortex, amygdala, habenula, Area
Ventral pallidum
midline thalamus, hypothalamus, midbrain.For a review on NAc peptidergic modulation see:
VTA inputs from lateral habenula or laterodorsal tegmentum
mediate aversion or reward
Lammel et al, 2012Distinct glutamatergic inputs to NAc mediate reward and aversion
Photoactivation of BLA-NAc projections Photoactivation of PVT-NAc projections suppresses
promotes self-stimulation reward seeking and induces aversion
Stuber et al, 2012 Do Monte et al, 2017VTA-NAc projections regulate social interaction
VTADA neurons respond to VTADA neurons respond to
sucrose reward social contact
VTADA terminals in the NAc respond to social contact Photoactivation of VTADA-NAc neurons
increases social interaction
Gunaydin et al., 2014Serotonin (5HT) in reward and aversion
Mood regulation
Pain
Sleep
Food‐intake regulation
Raphe
nuclei Social behaviorEvidence for serotonin’s role on reward While many studies have attributed an antagonist role of 5HT in reward function (for a review see Boureau and Dayan 2011), more recent studies have suggested a positive role of 5HT in reward processing (for a review see Hu, 2015); A large fraction of 5-HT neurons change their baseline tonic activity on the basis of reward value, showing greater activity in blocks of reward than in blocks of punishment (Cohen et al., 2015; Seymour et al. 2012); Local GABAergic neurons in VTA are inhibited during reward seeking and activated during aversive stimuli (Li et al, 2016); In humans, depression is commonly treated with selective serotonin reuptake inhibitors, which elevate synaptic levels of 5-HT (for a review see Hirschfeld 2000).
Recommended review on the topic
Potential role of 5HT in
regulating hedonic
responses (liking)A glutamatergic reward input from raphe to VTA
Dorsal raphe makes synapses with VTADA–NAc neurons
Qi et al., 2014Functionally distinct role of dorsal raphe projections to
orbitofrontal cortex and central amygdala
Ren et al., 2018Q U E S T I O N S
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