Review Article | Published:

The brain reward circuitry in mood disorders

Nature Reviews Neuroscience volume 14, pages 609625 (2013) | Download Citation

  • An Erratum to this article was published on 20 August 2013

This article has been updated


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.

Key points

  • Major depression encompasses heterogeneous disorders in humans that are associated with abnormalities in reward-related brain structures such as the nucleus accumbens, prefrontal cortex, amygdala and hippocampus. Changes in the activity and functional connectivity of these sites leads to abnormalities in the perception and interpretation of reward valence, in the motivation for rewards, and in subsequent decision-making.

  • Recent drug development efforts and other new treatment approaches such as deep brain stimulation offer the potential to more effectively treat depression. However, the field still faces major difficulties. The heterogeneity of depression symptoms suggests that its aetiology is diverse, there are still no known or accepted biomarkers to diagnose major depression — let alone its many subtypes — and promising new treatments have yet to gain approval by the US Food and Drug Administration (FDA).

  • Increasing evidence indicates that precipitating factors such as chronic stress induce changes in the functional connectivity within the brain's reward regions, and that such changes mediate reward-related depression-like behavioural symptoms in animal models, including social avoidance and anhedonia. The molecular and cellular bases of these behavioural abnormalities include changes in glutamatergic and GABAergic synaptic plasticity, dopamine neuron excitability, epigenetic and transcriptional mechanisms, and neurotrophic factors.

  • The nucleus accumbens is central in processing and responding to rewarding and aversive stimuli. It has been extensively implicated in reward-related behavioural abnormalities that characterize depression and associated syndromes. Chronic exposure to stress alters gene expression patterns in and the morphology (and ultimately the functional activity and connectivity) of nucleus accumbens neurons — neuroadaptations that contribute importantly to depression-like behaviours.

  • Advanced experimental tools, such as inducible mutations in mice, virus-mediated gene transfer and optogenetics, have made it possible for the first time to directly delineate the role of specific proteins acting within specific cell types within reward-related brain structures in mediating depression-like behavioural abnormalities in animal models. For example, medium spiny neurons (MSNs) that predominantly express D1 dopamine receptors have a very different effect on reward from MSNs that predominantly express D2 dopamine receptors.

  • It will be important for future studies to examine the molecular and cellular underpinnings of depression-like behaviours in females. Depression is twice as likely to occur in women than in men, but animal studies have mostly been conducted in males. There is evidence that females use different cognitive strategies, exhibit increased stress sensitivity and show variations in reward-related behaviours throughout the oestrus cycle that may render them more sensitive to the deleterious effects of stress.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Change history

  • 20 August 2013

    In table 2 of this article, the arrow indicating decreased susceptibility as an effect of ΔFOSB in depression models (third column) was incorrectly displayed as pointing upwards. This has been corrected in the online version.


  1. 1.

    , , , & Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62, 617–627 (2005).

  2. 2.

    Why do you need to move beyond first-line therapy for major depression? J. Clin. Psychiatry 71 (Suppl. 1), 4–9 (2010).

  3. 3.

    , , & Lifetime comorbidity of DSM-IV mood and anxiety disorders and specific drug use disorders: results from the National Epidemiologic Survey on alcohol and related conditions. J. Clin. Psychiatry 67, 247–257 (2006).

  4. 4.

    & The mesolimbic dopamine reward circuit in depression. Biol. Psychiatry 59, 1151–1159 (2006).

  5. 5.

    & Addiction and the brain antireward system. Annu. Rev. Psychol. 59, 29–53 (2008).

  6. 6.

    , , & Ventral tegmental area glutamate neurons: electrophysiological properties and projections. J. Neurosci. 32, 15076–15085 (2012). This study provides compelling evidence that a subset of VTA projection neurons use glutamate as a neurotransmitter.

  7. 7.

    , & Dopaminergic neurons inhibit striatal output through non-canonical release of GABA. Nature 490, 262–266 (2012).

  8. 8.

    & Rewarding effects of the cholinergic agents carbachol and neostigmine in the posterior ventral tegmental area. J. Neurosci. 22, 9895–9904 (2002).

  9. 9.

    Potential vulnerabilities of neuronal reward, risk, and decision mechanisms to addictive drugs. Neuron 69, 603–617 (2011). This important review summarizes the complex role of dopaminergic systems in controlling reward.

  10. 10.

    & What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res. Brain Res. Rev. 28, 309–369 (1998).

  11. 11.

    & Decision-making in the adolescent brain. Nature Neurosci. 15, 1184–1191 (2012).

  12. 12.

    , & Neuroeconomics: a bridge for translational research. Biol. Psychiatry 72, 87–92 (2012).

  13. 13.

    & Cortico-basal ganglia reward network: microcircuitry. Neuropsychopharmacology 35, 27–47 (2010).

  14. 14.

    et al. Recombinase-driver rat lines: tools, techniques, and optogenetic application to dopamine-mediated reinforcement. Neuron 72, 721–733 (2011). This paper describes the use of optogenetics to show that light stimulation of VTA dopamine neurons expressing ChR2 causes mice to self-stimulate those neurons, confirming that VTA dopamine neuron activity is indeed reinforcing.

  15. 15.

    et al. GABA neurons of the VTA drive conditioned place aversion. Neuron 73, 1173–1183 (2012).

  16. 16.

    et al. Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning. Science 324, 1080–1084 (2009).

  17. 17.

    , , & Activation of VTA GABA neurons disrupts reward consumption. Neuron 73, 1184–1194 (2012).

  18. 18.

    et al. Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward. Science 330, 385–390 (2010).

  19. 19.

    , & Distinct roles for direct and indirect pathway striatal neurons in reinforcement. Nature Neurosci. 15, 816–818 (2012).

  20. 20.

    & Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nature Neurosci. 8, 1481–1489 (2005).

  21. 21.

    et al. Cholinergic interneurons control local circuit activity and cocaine conditioning. Science 330, 1677–1681 (2010).

  22. 22.

    et al. Ventral tegmental area GABA projections pause accumbal cholinergic interneurons to enhance associative learning. Nature 492, 452–456 (2012). This paper identifies a GABAergic projection from the VTA that selectively innervates cholinergic interneurons in the NAc. Despite being a relatively minor (2%) component of all VTA projections, this pathway has a robust behavioural effect.

  23. 23.

    , & Cholinergic involvement in lateral hypothalamic rewarding brain stimulation. Brain Res. 329, 19–26 (1985).

  24. 24.

    et al. Synaptic and behavioral profile of multiple glutamatergic inputs to the nucleus accumbens. Neuron 76, 790–803 (2012).

  25. 25.

    et al. Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking. Nature 496, 359–362 (2013).

  26. 26.

    , & Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behaviour. Nature 481, 71–75 (2012).

  27. 27.

    et al. Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking. Nature 475, 377–380 (2011).

  28. 28.

    & Activation of lateral habenula inputs to the ventral midbrain promotes behavioral avoidance. Nature Neurosci. 15, 1105–1107 (2012).

  29. 29.

    , , & Projection-specific modulation of dopamine neuron synapses by aversive and rewarding stimuli. Neuron 70, 855–862 (2012).

  30. 30.

    et al. Input-specific control of reward and aversion in the ventral tegmental area. Nature 491, 212–217 (2012).

  31. 31.

    et al. Phospholipase Cγ in distinct regions of the ventral tegmental area differentially modulates mood-related behaviors. J. Neurosci. 23, 7569–7576 (2003).

  32. 32.

    et al. Regulation of drug reward by cAMP response element-binding protein: evidence for two functionally distinct subregions of the ventral tegmental area. J. Neurosci. 25, 5553–5562 (2005).

  33. 33.

    & Bipolar and major depressive disorder: neuroimaging the developmental-degenerative divide. Neurosci. Biobehav. Rev. 33, 699–771 (2009).

  34. 34.

    et al. Hippocampal volume reduction in major depression. Am. J. Psychiatry 157, 115–118 (2000).

  35. 35.

    et al. White matter lesion volumes and caudate volumes in late-life depression. Int. J. Geriatr. Psychiatry 21, 1193–1198 (2006).

  36. 36.

    et al. A magnetic resonance imaging study of putamen nuclei in major depression. Psychiatry Res. 40, 95–99 (1991).

  37. 37.

    et al. Magnetic resonance imaging of the caudate nuclei in depression. Preliminary observations. Arch. Gen. Psychiatry 49, 553–557 (1992).

  38. 38.

    et al. A functional anatomical study of unipolar depression. J. Neurosci. 12, 3628–3641 (1992).

  39. 39.

    et al. Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol. Psychiatry 48, 830–843 (2000).

  40. 40.

    et al. Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression. Nature Med. 19, 337–344 (2013). This paper identifies an epigenetic mechanism in the NAc of depressed humans that reduces the expression of the small GTPase RAC1. It further shows that stress reduces Rac1 expression through a similar mechanism in mice and is necessary and sufficient to induce depression-like changes in behaviour and excitatory synaptic plasticity.

  41. 41.

    et al. Serotonin transporter gene status predicts caudate nucleus but not amygdala or hippocampal volumes in older persons with major depression. J. Affect Disord. 98, 137–142 (2007).

  42. 42.

    , , & A volumetric study of hippocampus and amygdala in depressed patients with subjective memory problems. J. Neuropsychiatry Clin. Neurosci. 12, 493–498 (2000).

  43. 43.

    et al. Hippocampal and amygdala changes in patients with major depressive disorder and healthy controls during a 1-year follow-up. J. Clin. Psychiatry 65, 492–499 (2004).

  44. 44.

    , & Amygdala core nuclei volumes are decreased in recurrent major depression. Neuroreport 9, 2023–2028 (1998).

  45. 45.

    Stress and hippocampal plasticity. Annu. Rev. Neurosci. 22, 105–122 (1999).

  46. 46.

    et al. Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study. Biol. Psychiatry 50, 651–658 (2001).

  47. 47.

    et al. Attenuation of the neural response to sad faces in major depression by antidepressant treatment: a prospective, event-related functional magnetic resonance imaging study. Arch. Gen. Psychiatry 61, 877–889 (2004).

  48. 48.

    , , , & Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: related and independent features. Biol. Psychiatry 61, 198–209 (2007).

  49. 49.

    , & Recovery after chronic stress fails to reverse amygdaloid neuronal hypertrophy and enhanced anxiety-like behavior. Neuroscience 128, 667–673 (2004).

  50. 50.

    et al. Smaller cingulate volumes in unipolar depressed patients. Biol. Psychiatry 59, 702–706 (2006).

  51. 51.

    et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature 386, 824–827 (1997).

  52. 52.

    , , , & Reduction of orbital frontal cortex volume in geriatric depression. Biol. Psychiatry 48, 971–975 (2000).

  53. 53.

    , , & Left orbital frontal cortex volume and performance on the Benton Visual Retention Test in older depressives and controls. Neuropsychopharmacology 28, 2179–2183 (2003).

  54. 54.

    et al. Neural basis of abnormal response to negative feedback in unmedicated mood disorders. Neuroimage 42, 1118–1126 (2008).

  55. 55.

    Targeted electrode-based modulation of neural circuits for depression. J. Clin. Invest. 119, 717–725 (2009).

  56. 56.

    Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol. Psychiatry 48, 766–777 (2000).

  57. 57.

    , , & Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: a study from the Stanley Neuropathology Consortium. Schizophr Res. 67, 269–275 (2004).

  58. 58.

    et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nature Med. 18, 1413–1417 (2012). This study uses microarray analysis to demonstrate downregulation of numerous synapse-related genes in the dorsolateral PFC of depressed humans.

  59. 59.

    & The role of the hippocampus in the pathophysiology of major depression. J. Psychiatry Neurosci. 29, 417–426 (2004).

  60. 60.

    , , & Lower hippocampal volume in patients suffering from depression: a meta-analysis. Am. J. Psychiatry 161, 598–607 (2004).

  61. 61.

    & What causes the hippocampal volume decrease in depression? Are neurogenesis, glial changes and apoptosis implicated? Eur. Arch. Psychiatry Clin. Neurosci. 257, 250–260 (2007).

  62. 62.

    et al. Functional magnetic resonance imaging correlates of emotional word encoding and recognition in depression and anxiety disorders. Biol. Psychiatry 71, 593–602 (2012).

  63. 63.

    The effects of stressful life events on depression. Annu. Rev. Psychol. 48, 191–214 (1997).

  64. 64.

    & Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors. Neuroscience 69, 89–98 (1995).

  65. 65.

    et al. Chronic restraint stress induces changes in synapse morphology in stratum lacunosum-moleculare CA1 rat hippocampus: a stereological and three-dimensional ultrastructural study. Neuroscience 140, 597–606 (2006).

  66. 66.

    et al. Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol. Psychiatry 71, 996–1005 (2011).

  67. 67.

    , , , & Stress-induced dendritic remodeling in the prefrontal cortex is circuit specific. Cereb. Cortex 19, 2479–2484 (2009).

  68. 68.

    et al. Anatomical connectivity of the subgenual cingulate region targeted with deep brain stimulation for treatment-resistant depression. Cereb. Cortex 18, 1374–1383 (2008).

  69. 69.

    , & Dissociable roles of prelimbic and infralimbic cortices, ventral hippocampus, and basolateral amygdala in the expression and extinction of conditioned fear. Neuropsychopharmacology 36, 529–538 (2011).

  70. 70.

    , , & Neural mechanisms of the cognitive model of depression. Nature Rev. Neurosci. 12, 467–477 (2011).

  71. 71.

    & Stress, anxiety, and dendritic spines: what are the connections? Neuroscience (2012).

  72. 72.

    , , , & Stress duration modulates the spatiotemporal patterns of spine formation in the basolateral amygdala. Proc. Natl Acad. Sci. USA 102, 9371–9376 (2005).

  73. 73.

    et al. IκB kinase regulates social defeat stress-induced synaptic and behavioral plasticity. J. Neurosci. 31, 314–321 (2011).

  74. 74.

    , & Stress during development alters dendritic morphology in the nucleus accumbens and prefrontal cortex. Neuroscience 216, 103–109 (2012).

  75. 75.

    , & Stress-induced changes in nucleus accumbens glutamate synaptic plasticity. J. Neurophysiol. 101, 3192–3198 (2009).

  76. 76.

    et al. Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology 33, 368–377 (2008). This study shows the potential for deep brain stimulation of reward structures, such as the NAc, in depression treatment.

  77. 77.

    et al. Inhibitory synaptic control of depression-like behavior in a nucleus accumbens microcircuit. Soc. Neurosci. Abstr. 605.20 (2012).

  78. 78.

    & Differential effects of acute and repeated stress on hippocampus and amygdala inputs to the nucleus accumbens shell. Int. J Neuropsychopharmacol. (2013).

  79. 79.

    , & Role of the prefrontal cortex in altered hippocampal-accumbens synaptic plasticity in a developmental animal model of Schizophrenia. Cereb. Cortex (2012).

  80. 80.

    et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007).

  81. 81.

    et al. Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action. J. Neurosci. 30, 16453–16458 (2010).

  82. 82.

    et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 493, 532–536 (2013). This study uses circuit-specific optogenetics to confirm that increased phasic firing of VTA dopamine neurons projecting to the NAc has a role in in mediating stress susceptibility.

  83. 83.

    , , & Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli. Proc. Natl Acad. Sci. USA 106, 4894–4899 (2009).

  84. 84.

    , & Different stressors produce excitation or inhibition of mesolimbic dopamine neuron activity: response alteration by stress pre-exposure. Eur. J. Neurosci. 35, 1312–1321 (2012).

  85. 85.

    et al. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 493, 537–541 (2013). Along with reference 82, this paper highlights the complexity of understanding reward function in depression. Although chronic social defeat stress induces dopamine firing to promote depression-like behaviour (reference 82), these authors find that chronic mild stress decreases dopamine firing to promote depression-like behaviour.

  86. 86.

    The glutamate homeostasis hypothesis of addiction. Nature Rev. Neurosci. 10, 561–572 (2009).

  87. 87.

    et al. Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J. Neurosci. 30, 16082–16090 (2011).

  88. 88.

    et al. Glutamatergic microcircuits regulate stress-induced alterations in social behavior. Soc. Neurosci. Abstr. 605.21 (2012).

  89. 89.

    et al. Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior. Proc. Natl Acad. Sci. USA 109, 11360–11365 (2012).

  90. 90.

    , & Human biomarkers of rapid antidepressant effects. Biol. Psychiatry 73, 1142–1155 (2013).

  91. 91.

    et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311, 864–868 (2006).

  92. 92.

    et al. Brain-derived neurotrophic factor in the ventral midbrain–nucleus accumbens pathway: a role in depression. Biol. Psychiatry 54, 994–1005 (2003).

  93. 93.

    et al. Extracellular signal-regulated kinase-2 within the ventral tegmental area regulates responses to stress. J. Neurosci. 30, 7652–7663 (2010).

  94. 94.

    et al. Juvenile administration of concomitant methylphenidate and fluoxetine alters behavioral reactivity to reward- and mood-related stimuli and disrupts ventral tegmental area gene expression in adulthood. J. Neurosci. 31, 10347–10358 (2011).

  95. 95.

    et al. AKT signaling within the ventral tegmental area regulates cellular and behavioral responses to stressful stimuli. Biol. Psychiatry 64, 691–700 (2008).

  96. 96.

    & A neurotrophic model for stress-related mood disorders. Biol. Psychiatry 59, 1116–1127 (2006).

  97. 97.

    , & BDNF-dependent synaptic sensitization in midbrain dopamine neurons after cocaine withdrawal. Nature Neurosci. 9, 605–607 (2006).

  98. 98.

    Neuroendocrine and immune system interactions in stress and depression. Psychiatr. Clin. North Am. 21, 443–463 (1998).

  99. 99.

    & Inflammatory factors contribute to depression and its comorbid conditions. Sci. Signal 5, pe45 (2012).

  100. 100.

    et al. Treatment with interferon-alpha (IFNα) of hepatitis C patients induces lower serum dipeptidyl peptidase IV activity, which is related to IFNα-induced depressive and anxiety symptoms and immune activation. Mol. Psychiatry 6, 475–480 (2001).

  101. 101.

    , & Central administration of murine interferon-α induces depressive-like behavioral, brain cytokine and neurochemical alterations in mice: a mini-review and original experiments. Brain Behav. Immun. 31, 115–127 (2013).

  102. 102.

    et al. A meta-analysis of cytokines in major depression. Biol. Psychiatry 67, 446–457 (2010).

  103. 103.

    & IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc. Natl Acad. Sci. USA 105, 751–756 (2008).

  104. 104.

    et al. Innate peripheral immune responses predispose mice to susceptibility to repeated social defeat stress. Soc. Neurosci. Abstr. 12.10 (2012).

  105. 105.

    , , , & Nuclear factor-κB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proc. Natl Acad. Sci. USA 107, 2669–2674 (2010).

  106. 106.

    et al. Effects of inhibitor of κB kinase activity in the nucleus accumbens on emotional behavior. Neuropsychopharmacology 37, 2615–2623 (2012).

  107. 107.

    et al. Nuclear factor κB signaling regulates neuronal morphology and cocaine reward. J. Neurosci. 29, 3529–3537 (2009).

  108. 108.

    et al. Rac1 is essential in cocaine-induced structural plasticity of nucleus accumbens neurons. Nature Neurosci. 15, 891–896 (2012).

  109. 109.

    , & Metabolic hormones, dopamine circuits, and feeding. Front. Neuroendocrinol. 31, 104–112 (2010).

  110. 110.

    et al. A β3-adrenergic–leptin–melanocortin circuit regulates behavioral and metabolic changes induced by chronic stress. Biol. Psychiatry 67, 1075–1082 (2011).

  111. 111.

    , , , & Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens. Nature 487, 183–189 (2012). This study provides evidence for a model in which chronic stress-induced increases in melanocortin signalling to the NAc, acting via melanocortin 4 receptors, selectively attenuate the strength of glutamatergic synapses on D1-type MSNs.

  112. 112.

    et al. Orexin signaling mediates the antidepressant-like effect of calorie restriction. J. Neurosci. 28, 3071–3075 (2008).

  113. 113.

    et al. The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress. Nature Neurosci. 11, 752–753 (2008).

  114. 114.

    et al. Forebrain glutamatergic neurons mediate leptin action on depression-like behaviors and synaptic depression. Transl. Psychiatry 2, e83 (2012).

  115. 115.

    et al. Role of nuclear factor κB in ovarian hormone-mediated stress hypersensitivity in female mice. Biol. Psychiatry 65, 874–880 (2009).

  116. 116.

    et al. Imipramine treatment and resiliency exhibit similar chromatin regulation in the mouse nucleus accumbens in depression models. J. Neurosci. 29, 7820–7832 (2009).

  117. 117.

    & Balancing histone methylation activities in psychiatric disorders. Trends Mol. Med. 17, 372–379 (2011).

  118. 118.

    , & Epigenetics of the depressed brain: role of histone acetylation and methylation. Neuropsychopharmacology 38, 124–137 (2012).

  119. 119.

    & Epigenetics and the environmental regulation of the genome and its function. Annu. Rev. Psychol. 61, 439–466 (2010).

  120. 120.

    , & The many faces of CREB. Trends Neurosci. 28, 436–445 (2005).

  121. 121.

    The role of CREB in depression and antidepressant treatment. Biol. Psychiatry 59, 1144–1150 (2006).

  122. 122.

    et al. A role for repressive histone methylation in cocaine-induced vulnerability to stress. Neuron 71, 656–670 (2011). One of the first studies to establish an epigenetic-based mechanism for stress susceptibility versus resilience in the NAc. The authors show that chronic social defeat stress downregulates the HMTs G9a (also known as EHMT2) and GLP (also known as EHMT1) in the NAc, which promotes susceptibility via induction of BDNF–CREB signalling in this brain region.

  123. 123.

    & Regulation of gene expression and cocaine reward by CREB and ΔFosB. Nature Neurosci. 6, 1208–1215 (2003).

  124. 124.

    et al. CREB regulation of nucleus accumbens excitability mediates social isolation-induced behavioral deficits. Nature Neurosci. 12, 200–209 (2009).

  125. 125.

    , & The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res. 1314, 44–55 (2010).

  126. 126.

    et al. Desipramine reduces stress-activated dynorphin expression and CREB phosphorylation in NAc tissue. Mol. Pharmacol. 75, 704–712 (2009).

  127. 127.

    et al. CREB modulates excitability of nucleus accumbens neurons. Nature Neurosci. 9, 475–477 (2006).

  128. 128.

    et al. A silent synapse-based mechanism for cocaine-induced locomotor sensitization. J. Neurosci. 31, 8163–8174 (2011).

  129. 129.

    et al. Serum response factor promotes resilience to chronic social stress through the induction of ΔFosB. J. Neurosci. 30, 14585–14592 (2010).

  130. 130.

    et al. ΔFosB in brain reward circuits mediates resilience to stress and antidepressant responses. Nature Neurosci. 13, 745–752 (2010).

  131. 131.

    et al. A novel role of the WNT–dishevelled–GSK3β signaling cascade in the mouse nucleus accumbens in a social defeat model of depression. J. Neurosci. 31, 9084–9092 (2011).

  132. 132.

    , , & Decoding the epigenetic language of neuronal plasticity. Neuron 60, 961–974 (2008).

  133. 133.

    et al. Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens. Nature Neurosci. 13, 1137–1143 (2009).

  134. 134.

    et al. Histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli. Neuron 56, 517–529 (2007).

  135. 135.

    et al. Epigenetic status of Gdnf in the ventral striatum determines susceptibility and adaptation to daily stressful events. Neuron 69, 359–372 (2011).

  136. 136.

    , , & The forced swimming-induced behavioural immobility response involves histone H3 phospho-acetylation and c-Fos induction in dentate gyrus granule neurons via activation of the N-methyl-D-aspartate/extracellular signal-regulated kinase/mitogen- and stress-activated kinase signalling pathway. Eur. J. Neurosci. 27, 2701–2713 (2008).

  137. 137.

    , , , & Hippocampal-dependent antidepressant-like activity of histone deacetylase inhibition. Neurosci. Lett. 493, 122–126 (2011).

  138. 138.

    , , , & Regulation of hippocampal H3 histone methylation by acute and chronic stress. Proc. Natl Acad. Sci. USA 106, 20912–20917 (2009).

  139. 139.

    et al. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nature Neurosci. 9, 519–525 (2006).

  140. 140.

    et al. Setdb1 histone methyltransferase regulates mood-related behaviors and expression of the NMDA receptor subunit NR2B. J. Neurosci. 30, 7152–7167 (2010).

  141. 141.

    et al. Antidepressant actions of histone deacetylase inhibitors. J. Neurosci. 29, 11451–11460 (2009).

  142. 142.

    et al. Identification of the cortical neurons that mediate antidepressant responses. Cell 149, 1152–1163 (2012). The authors demonstrate that p11, a protein that promotes the activity of certain serotonin and several other G protein-coupled receptors, is required for antidepressant-like responses. This action is mediated not only by p11 action in the PFC but also in the NAc, as the authors demonstrated previously.

  143. 143.

    , , , & MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell 151, 1417–1430 (2012).

  144. 144.

    , , & From menarche to menopause: exploring the underlying biology of depression in women experiencing hormonal changes. Psychoneuroendocrinology 33, 3–17 (2008).

  145. 145.

    , & The roles of sex and serotonin transporter levels in age- and stress-related emotionality in mice. Brain Res. 1286, 84–93 (2009).

  146. 146.

    Women's mental health research: the emergence of a biomedical field. Annu. Rev. Clin. Psychol. 2, 135–160 (2006).

  147. 147.

    & Sex, trauma, stress hormones and depression. Mol. Psychiatry 15, 23–28 (2010).

  148. 148.

    , , , & The effects of gonadal steroids on brain stimulation reward in female rats. Behav. Brain Res. 82, 235–244 (1997).

  149. 149.

    , , & A standardized protocol for repeated social defeat stress in mice. Nature Protoc. 6, 1183–1191 (2011).

  150. 150.

    et al. Neurobiological sequelae of witnessing stressful events in adult mice. Biol. Psychiatry 73, 7–14 (2012).

  151. 151.

    , , , & Neurobiology of chronic mild stress: parallels to major depression. Neurosci. Biobehav. Rev. 36, 2085–2117 (2012).

  152. 152.

    et al. Sex differences in social interaction behavior following social defeat stress in the monogamous California mouse (Peromyscus californicus). PLoS ONE 6, e17405 (2012). This important study establishes the utility of the chronic social defeat stress paradigm in female mice, using a different mouse species. Interestingly, the authors show some similar molecular abnormalities in the female NAc (increased CREB activity) as shown by other groups in males.

  153. 153.

    & Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor. Neurosci. Biobehav. Rev. 29, 829–841 (2005).

  154. 154.

    & The neurobiology of anhedonia and other reward-related deficits. Trends Neurosci. 35, 68–77 (2012).

  155. 155.

    , , & Sex differences in animal models of depression and antidepressant response. Basic Clin. Pharmacol. Toxicol. 106, 226–233 (2010).

  156. 156.

    Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology 52, 90–110 (2005).

  157. 157.

    & Intracranial self-stimulation (ICSS) in rodents to study the neurobiology of motivation. Nature Protoc. 2, 2987–2995 (2007).

  158. 158.

    et al. Blockade of kappa opioid receptors attenuates the development of depressive-like behaviors induced by cocaine withdrawal in rats. Neuropharmacology 62, 167–176 (2012).

  159. 159.

    et al. Corticostriatal functional connectivity predicts transition to chronic back pain. Nature Neurosci. 15, 1117–1119 (2012).

  160. 160.

    et al. Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch. Gen. Psychiatry 65, 220–231 (2008).

  161. 161.

    , , , & Neuropathic and chronic pain stimuli downregulate central μ-opioid and dopaminergic transmission. Trends Pharmacol. Sci. 31, 299–305 (2010).

  162. 162.

    et al. An essential role for ΔFosB in the nucleus accumbens in morphine action. Nature Neurosci. 9, 205–211 (2006).

  163. 163.

    et al. Brain region specific actions of regulator of G protein signaling 4 oppose morphine reward and dependence but promote analgesia. Biol. Psychiatry 67, 761–769 (2010).

  164. 164.

    et al. Regulator of G protein signaling is a crucial modulator of antidepressant drug action in depression and neuropathic pain models. Proc. Natl Acad. Sci. USA 110, 8254–8259 (2013). This study demonstrates that the G protein regulatory protein RGS4, acting in the NAc, promotes therapeutic-like responses to standard monoamine-dependent antidepressants. By contrast, RGS4 opposes the antidepressant-like actions of non-monoamine-based drugs such as ketamine.

  165. 165.

    et al. Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation. Nature Neurosci. 16, 434–440 (2013).

Download references


Preparation of this review was supported by grants from the US National Institute of Mental Health: R01 MH090264 (S.J.R.); and R01 MH51399 and P50 MH96890 (E.J.N.).

Author information


  1. Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

    • Scott J. Russo
    •  & Eric J. Nestler


  1. Search for Scott J. Russo in:

  2. Search for Eric J. Nestler in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Scott J. Russo.



A positive emotional stimulus. In psychological terms, a reward is reinforcing — it promotes repeated responding to obtain the same stimulus.


Loss of the ability to experience pleasure from normally rewarding stimuli, such as food, sex and social interactions.

Ventral tegmental area

(VTA). A ventral midbrain site containing dopaminergic neurons that are an essential component of the brain's reward circuitry.

Nucleus accumbens

(NAc). A portion of the ventral striatum, this forebrain nucleus has a crucial role in coordinating responses to rewarding and aversive stimuli.

Medium spiny neurons

(MSNs). Principal GABAergic projection neurons of the NAc and dorsal striatum, comprising >95% of neurons in these regions.


A series of recently developed tools that make use of light-activated proteins. Most frequently, light-sensitive ion channels and pumps are used to control the firing rate of neurons, but increasingly other types of proteins are placed under similar light control.

Channelrhodopsin 2

(ChR2). Member of a family of retinylidene proteins (rhodopsins), which are light-gated ion channels that can be expressed in neurons to allow for optogenetic control of electrical excitability with exquisite temporal specificity.

Intracranial self-stimulation

A behavioural paradigm in which animals work (for example, roll a cylinder with their paws) to stimulate a targeted brain region with electrical current. The current at which animals first self-stimulate, termed the brain stimulation reward threshold, is used as a measure of an animal's affective state, with higher thresholds reflecting diminished reward and anhedonia.

D1-type MSNs

(D1-type medium spiny neurons). One of two major subtypes of GABAergic projection neurons located in the nucleus accumbens and dorsal striatum, which are defined by their predominant expression of D1 dopamine receptors. D1-type neurons largely coincide with those of the direct projection pathway.

D2-type MSNs

(D2-type medium spiny neurons). One of two major subtypes of GABAergic projection neurons located in the nucleus accumbens and dorsal striatum, which are defined by their predominant expression of D2 dopamine receptors. D2 type-neurons largely coincide with those of the indirect projection pathway.

Excitatory synapses

Synapses at which the release of glutamate from presynaptic nerve terminals activates glutamate receptors located on dendritic spines on postsynaptic neurons, which increases the probability of an action potential in that postsynaptic neuron.

Dendritic spines

Small protrusions from a dendrite that are typically associated with synaptic input from glutamatergic axon terminals at the spine's head, but which may receive other inputs along their sides or necks.

Postsynaptic density

A specialization on excitatory dendritic spines, originally identified by electron-microscopy, which contains glutamate receptors and many associated scaffolding and trafficking proteins that are crucial for excitatory synaptic transmission.

Glutamate receptors

Receptors for the major excitatory neurotransmitter in the brain, comprised of ionotropic and metabotropic (G protein-coupled) classes. Ionotropic glutamate receptors are named for specific agonists, AMPA,NMDA and kainate.

Deep brain stimulation

A method that involves implantation of an electrode for stimulation of specific brain areas to treat symptoms of neurological and psychiatric diseases. It is used in the treatment of Parkinson's disease, tremor, dystonia, obsessive-compulsive disorder and depression.


A mechanism of a stable change in gene expression that does not involve changes in DNA sequence. A small subset of epigenetic changes can be transmitted to subsequent generations.


The ability to maintain normal physiological and behavioural function in the face of severe stress.


The vulnerability to succumb to the deleterious effects of stress.

Brain-derived neurotrophic factor

(BDNF). The major neurotrophin (nerve growth factor) expressed in the brain.


A tyrosine kinase receptor, located at the plasma membrane, which mediates the actions of brain-derived neurotrophic factor.

Cyclic AMP-responsive element-binding protein

(CREB). A transcription factor that can be activated by cyclic AMP, Ca2+ and brain-derived neurotrophic factor–TRKB-induced signalling cascades.


A group of cytokines that were first known for their role in immune and inflammatory responses but more recently have been found to regulate neural function.

Nuclear factor-κB

(NF-κB). A transcription factor first characterized for its regulation of immune and inflammatory responses but more recently has been implicated in controlling neural function.


A small G protein (GTPase) that, in the nervous system, plays a critical part in regulating dendritic spine outgrowth.


First characterized for its regulation of melanocytes, melanocortin is also a peptide neurotransmitter secreted by hypothalamic neurons, where it exerts potent anorexogenic effects. In addition, it is implicated in the regulation of mood via actions on the brain's reward circuitry.


Also known as hypocretin, this peptide neurotransmitter is secreted by neurons in the lateral hypothalamus to promote wakefulness and attention. It also promotes reward by direct projections to ventral tegmental area dopamine neurons.


A peptide hormone secreted by adipocytes. One of the major anorexigenic peptides known, leptin suppresses feeding behaviour through actions on hypothalamus. It has also been implicated in regulation of mood.


An orexigenic peptide hormone secreted by the stomach epithelium after periods of fasting, which acts in hypothalamus and perhaps other brain regions to stimulate appetite. It has been implicated in mood regulation as well.


A high-throughput method to sequence whole-genome cDNA in order to obtain quantitative measures of all expressed RNAs in a tissue.


The mixture of DNA and proteins that comprise the cell nucleus.

Chromatin immunoprecipitation

(ChIP). A method that enables the identification of histone modifications or transcriptional regulatory proteins at a given gene promoter. DNA is crosslinked to nearby proteins by light fixation, the material is sheared, then immunoprecipitated with an antibody to a particular protein of interest, and genes in the final immunoprecipitate are quantified by the polymerase chain reaction.


(Chromatin immunoprecipitation followed by promoter chips). A method that enables a global analysis of genes associated with a particular histone modification or transcriptional regulatory protein. Immunoprecipitated chromatin is analysed on a microarray gene chip, enriched in promoter regions.


(Chromatin immunoprecipitation followed by deep sequencing). A method that allows for global identification of histone modifications or transcriptional regulatory proteins. ChIP is coupled to high-throughput sequencing to obtain analysis across the entire genome, and in this sense differs from ChIP–chip.


A FOS family transcription factor that, once induced, is particularly long-lived in the brain owing to its stability.

Serum response factor

(SRF). A transcription factor, which, in conjunction with another factor termed ELK1, binds to serum response elements within certain genes to regulate their expression.


A transcription factor that is activated by the WNT–Frizzled–Dishevelled signalling cascade. It appears to mediate resilience to stress at the level of the nucleus accumbens.

Transcription factors

Proteins that bind to specific DNA sequences (called response elements) within responsive genes and thereby increase or decrease the rate at which those genes are transcribed.

Histone deacetylases

(HDACs). Enzymes that catalyse the deacetylation of histone amino-terminal tails.

Histone methyltransferases

(HMTs). Enzymes that catalyse the methylation of histone amino-terminal tails.

DNA methyltransferases

(DNMTs). Enzymes that catalyse the methylation of cytosine nucleotides, in CpG sequences, in DNA.

About this article

Publication history



Further reading