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.
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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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.).
The authors declare no competing financial interests.
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.
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Russo, S., Nestler, E. The brain reward circuitry in mood disorders. Nat Rev Neurosci 14, 609–625 (2013). https://doi.org/10.1038/nrn3381
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