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
Competing interests statement
The authors declare no competing interests.
Scott J. Russo
Scott J. Russo is Assistant Professor of Neuroscience in the Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai, New York, USA. He received a B.A. in psychology from University at Buffalo, New York, USA, and a Ph.D. from the Graduate School and University Center of the City University of New York, USA, before completing his postdoctoral fellowship with Eric J. Nestler at the University of Texas Southwestern Medical Center at Dallas, Texas, USA. His research focuses on plasticity of reward circuits in stress disorders, such as depression and anxiety. Scott J. Russo's homepage.
Eric J. Nestler
Eric J. Nestler is the Nash Family Professor of Neuroscience, Chair of the Department of Neuroscience and Director of the Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai, New York, USA. He previously served on the faculties of Yale University, New Haven, Connecticut, USA, and the University of Texas Southwestern Medical Center at Dallas, Texas, USA. He received his B.A., Ph.D. and M.D. from Yale University, and completed his residency training in psychiatry there. He was elected to the Institute of Medicine in 1998 and to the American Academy of Arts and Sciences in 2005. His research focuses on molecular mechanisms of drug addiction and depression in animal models. Eric J. Nestler's homepage.
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.