The brain reward circuitry in mood disorders
Open accessAbstract
Mood disorders are common and debilitating conditions characterized in part by profound deficits in reward-related behavioural domains. A recent literature has identified important structural and functional alterations within the brain's reward circuitry--particularly in the ventral tegmental area-nucleus accumbens pathway--that are associated with symptoms such as anhedonia and aberrant reward-associated perception and memory. This Review synthesizes recent data from human and rodent studies from which emerges a circuit-level framework for understanding reward deficits in depression. We also discuss some of the molecular and cellular underpinnings of this framework, ranging from adaptations in glutamatergic synapses and neurotrophic factors to transcriptional and epigenetic mechanisms.
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Dopaminergic projections from the VTA to NAc, PFC, amygdala and hippocampus that regulate reward and aversion are dysregulated in MDD and in rodent chronic stress models.
“For example, dopaminergic projections from the VTA to the nucleus accumbens (NAc), prefrontal cortex (PFC), amygdala and hippocampus that regulate responses to rewarding or aversive stimuli are reportedly dysregulated in people with MDD as well as in rodent models of chronic stress39–42.”
From Central regulation of stress-evoked peripheral immune responses (2023) · cites this paper as [40]
“The brain’s reward circuitry” describes VTA dopamine projections to the NAc, PFC, amygdala and hippocampus and their roles in reward and aversion. “Functional studies of monosynaptic reward circuits” reports altered VTA–NAc and VTA–PFC activity in chronically stressed mice, but does not establish such changes for the amygdala or hippocampus projections. The human-imaging discussion says the VTA had not yet been characterized functionally or structurally in human depression, so the claim about these dopaminergic projections in people with MDD is not supported. Page numbers were unavailable in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredSeveral brain regions that innervate bone marrow have been linked to stress responses, reward processing and the pathogenesis of depression and anxiety disorders.
“Notably, several of these bone marrow-innervating brain regions have been implicated in stress responses, reward processing and the pathogenesis of depression and anxiety disorders.”
From Central regulation of stress-evoked peripheral immune responses (2023) · cites this paper as [40]
The NAc plays a crucial role in stress responses and mood disorders including MDD.
“The NAc plays a crucial role in stress responses and mood disorders including MDD28.”
From Social stress induces neurovascular pathology promoting depression (2017) · cites this paper as [28]
Susceptible and resilient mice show distinct cellular and circuit alterations between the NAcc and other brain regions within the reward circuitry.
“Susceptible and resilient mice show distinct cellular and circuit alterations between the NAcc and other brain regions within the reward circuitry”
From Social functioning in major depressive disorder (2016) · cites this paper as Russo and Nestler, 2013
Plasticity in the NAcc reward circuit has a causal role in mediating social anhedonia in a mouse model of depression.
“demonstrating a causal role for plasticity in this circuit in mediating social anhedonia in a mouse model of depression”
From Social functioning in major depressive disorder (2016) · cites this paper as Russo and Nestler, 2013
Prefrontal cortex and hippocampus decode stimulus and environmental features to guide adaptive reward responses, while lateral hypothalamus-lateral habenula circuits encode negative valence; both are integrated in nucleus accumbens and ventral tegmental area to regulate dopamine.
“A grossly oversimplified overview of these circuits is that the prefrontal cortices and hippocampus are devoted to detecting and decoding specific features of stimuli and the environment, including the social environment, to guide decision-making and ensure adaptive, flexible, and predictive responses to rewarding stimuli, whereas the lateral hypothalamus-lateral habenula circuits predominantly En”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [51]
Prairie voles show strong OXTR expression in MLR regions, a conserved reward-processing network implicated in depression, addiction, and schizophrenia.
“Prairie voles strongly express OXTR in regions of the MLR, a conserved neural network (75) involved in reward processing and implicated in numerous human psychiatric disorders including depression (76), addiction (77), and schizophrenia (78).”
From Variation in the Oxytocin Receptor Gene Predicts Brain Region–Specific Expression and Social Attachment (2016) · cites this paper as [75]
Depressive behavior is mediated in part by increased NAc BDNF signaling.
“Depressive behavior is mediated in part by increased NAc BDNF signaling (reviewed in ref. [66]).”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [66]
The mesolimbic dopamine system, composed of dopamine neurons of the VTA and their projections to the NAc, is most often associated with the rewarding effects of food and sex.
“The mesolimbic dopamine system, composed of dopamine neurons of the ventral tegmental area (VTA) and their projections to the nucleus accumbens (NAc), is most often associated with the rewarding effects of food and sex and plays an essential role in stress-induced anhedonia and other depression-related behavioral abnormalities [87, 88].”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [88]
The mesolimbic dopamine system plays an essential role in stress-induced anhedonia and other depression-related behavioral abnormalities.
“The mesolimbic dopamine system, composed of dopamine neurons of the ventral tegmental area (VTA) and their projections to the nucleus accumbens (NAc), is most often associated with the rewarding effects of food and sex and plays an essential role in stress-induced anhedonia and other depression-related behavioral abnormalities [87, 88].”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [88]
One source of dopamine in the hippocampus derives from dopaminergic neurons in the VTA.
“One of the sources of DA in the hippocampus derives from DAergic neurons in the VTA17.”
From Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer’s disease (2017) · cites this paper as [17]
VTA dopaminergic neurons target the nucleus accumbens and cerebral cortex, mediating control of incentive motivation and reward processing.
“VTA DAergic neurons also target the nucleus accumbens (NAc) and cerebral cortex, mediating the control of incentive motivation and reward processing17.”
From Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer’s disease (2017) · cites this paper as [17]
Frontostriatal circuits subserving reward processes are modulated by dopamine.
“Frontostriatal circuits subserving reward processes are modulated by the neurotransmitter dopamine (DA) The primary reward circuit includes dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens, which release dopamine in response to reward-related stimuli (Russo and Nestler, 2013).”
From Dopaminergic reward sensitivity can promote adolescent health: a new perspective on the mechanism of ventral striatum activation (2016) · cites this paper as Russo and Nestler, 2013
Molecular changes within specific cell types of the brain's reward regions shape the ways in which adolescents respond to changes in the environment, determining either resilience or susceptibility.
“Molecular changes within specific cell types of the brain's reward regions shape the ways in which adolescents respond to changes in the environment, determining either resilience or susceptibility (Russo and Nestler, 2013).”
From Dopaminergic reward sensitivity can promote adolescent health: a new perspective on the mechanism of ventral striatum activation (2016) · cites this paper as Russo and Nestler, 2013
Vulnerability for depression, risk taking, or other psychopathologies may be determined by molecular changes in cells that occur following stressors.
“Vulnerability for depression, risk taking, or other psychopathologies may be determined by molecular changes in cells that occur following stressors (see Russo and Nestler, 2013).”
From Dopaminergic reward sensitivity can promote adolescent health: a new perspective on the mechanism of ventral striatum activation (2016) · cites this paper as Russo and Nestler, 2013
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- Authors
- Russo, S. J., & Nestler, E. J.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Russo, Scott J.
- Venue
- Nature Reviews Neuroscience
- Published
- 2013-08-14
- Volume
- 14
- Issue
- 9
- Pages
- 609-625
- ISSN
- 1471-003X (ISSN-L)
- 1471-0048
- PMC
- PMC3867253
- OpenAlex
- W2071815275
- Cited by
- 1,870
- References
- 164
- Citations by year
- 2026: 129 · 2025: 144 · 2024: 169 · 2023: 156 · 2022: 143 · 2021: 175 · 2020: 160 · 2019: 147 · 2018: 147 · 2017: 159 · 2016: 140 · 2015: 122 · 2014: 74 · 2013: 4
- FWCI
- 11.54
- Type
- journal article
- Language
- en
- Update notices
- erratum (2013-08-20)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature reviews. Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH090264, P50MH096890, R01 MH-51399, R01MH051399, P50-MH96890)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- brain reward system, mood disorders, depression, anhedonia, ventral tegmental area, nucleus accumbens, glutamatergic synapses, neurotrophic factors, epigenetic mechanisms, transcriptional regulation, animal models of depression
- MeSH terms
- Animals, Brain, Humans, Neural Pathways, Reward, Mood Disorders
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