This region is particularly important for conditioned forms of learning. It helps an organism establish associations between environmental cues and whether or not that particular experience was rewarding or aversive, for example, remembering what accompanied finding food or fleeing a predator.


Decreased interest in, and ability to experience, pleasure. A common symptom of depression.


Assay for transposase-accessible chromatin-seq provides a genome-wide measure of accessible chromatin and nucleosome occupancy.

Atypical antidepressants.

Clinically effective antidepressants whose mechanisms of action are unknown (e.g., bupropion, mirtazepine, tianeptine).

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BDNF (brain derived neurotrophic factor).

A major nerve growth factor in brain, which regulates depression-like behavior in the VTA-NAc as well as in other brainn regions.

Brain reward regions.

Regions of the brain that regulate an individual's responses to natural rewards. These regions are also the cites in brain where drugs of abuse act to cause addiction. The VTA-NAc are the major reward regions of brain, but are part of larger limbic circuits also involving prefrontal cortex, amygdala, and hippocampus, among other regions.


A transcription factor that drives resilience when acting in the NAc. It is downstream of WNT signaling pathways.

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The major contents of the cell's nucleus, composed primarily of DNA, histones, and other proteins.

Chromatin conformation capture.

Known as 3C, a method used to study the 3-dimensional structure of chromatin, including "loopings"—sites where distant portions of the genome come into close proximity. Variants of this approach are termed 4C and 5C.

Chromatin immunoprecipitation.

Experimental technique used to study chromatin structure at genes regulated by stress, antidepressants, or other stimuli.

Chromatin remodeling proteins.

Large families of proteins that control the spacing of nucleosomes. Many such protein complexes contain ATPase activity, which is thought to provide the energy for "molecular motors" to move nucleosomes closer together or farther apart. BAZ1A is an example of a chromatin remodeling protein which our Center has demonstrated to be a crucial determinant of stress susceptibility.


A method that enables a global analysis of genes associated with a particular histone modification or transcriptional regulatory protein. Immunoprecipitated chromatin is analyzed on a microarray gene chip, enriched in promoter regions.


This is similar to ChIP-chip in that it allows for global identification of histone modifications or transcriptional regulatory proteins. However, in this assay, ChIP is coupled to high-throughput sequencing to obtain analysis across the entire genome, not just promoter-enriched regions.

Chronic variable stress.

A chronic stress paradigm in which rodents are exposed to a different stress each day. Females are more susceptible than males to this form of stress.


The major circadian gene in the body. The loss of Clock induces a manic-like state in mice, which is reversed by lithium and is at least partially mediated via the VTA.


The major stress hormone in the body, secreted by the adrenal glands. It is under control of the hypothalamus and pituitary gland.

CREB (cAMP response element binding protein).

A major transcription factor in brain, which regulates depression-like behavior in the VTA-NAc as well as in other brain regions.

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Deep brain stimulation.

An experimental treatment where electrodes are placed in certain cites of the brain and stimulated at high frequency. A standard treatment for Parkinson's Disease and other movement disorders, increasingly evidence supports antidepressant activity in a subset severely ill patients.

DNA expression arrays.

Also called "DNA chips", these arrays make it possible to study changes in messenger RNA levels for thousands of genes in a relatively high throughput manner.

DNA methyltransferases (DNMTs).

Enzymes that catalyze the methylation of cytosine nucleotides, in CpG sequences, in DNA.

Dorsal raphe.

This region is the primary site of serotonergic neurons in the brain, which, like noradrenergic neurons, pervasively modulate brain function to regulate the state of activation and mood of the organism.

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Electroconvulsive therapy (ECT).

Repeated generalized seizures, induced electrically, as a treatment for depression. A form of "somatic therapy".


Mechanisms of stable changes in gene expression occurring independently of a change in DNA sequence. A small subset of epigenetic changes may be transmitted to subsequent generations.

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Fiber photometry.

A method that enables recording the activity of an identified subpopulation of neurons (via measurement of Ca2+ signals) in awake, behaving animals.

Forced swim test.

Rodents immersed in a vessel of water develop an immobile posture after initial struggling. Most antidepressants, given acutely before the test, reverse the immobility and promote struggling.


A transcription factor that drives resilience to chronic stress when induced in the NAc.

Frontal cortex.

These regions are probably the most important, but least understood, and include frontal regions of cerebral cortex, such as medial prefrontal cortex, anterior cingulate cortex, and orbitofrontal cortex, which provide executive control over choices made in the environment (for example, whether to seek a reward).

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G proteins.

Proteins that tranduce the actions of a neurtransmitter, acting on a receptor located on the outside of a neuron, into the interior of the cell, where intracellular signaling pathways are activated.

Gene expression.

Processes that control the expression of genes in cells. Selective expression of the body's 20,000 genes is critical during development to form different organs. More subtle regulation of gene expression occurs in brain throughout life and mediates long-lived changes in behavior, both good (e.g., learning, antidepressant responses) and bad (e.g., depression, addiction).

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Halorhodopsin (NpHR).

A yellow-light activated chloride pump which is used in optogenetic experiments to inhibit neuronal activity. Hippocampus. This region is critical for declarative memory, the memory of persons, places, or things.


A brain structure crucial for declarative memory but also important for emotional behavior and implicated in stress responses and depression.


Families of proteins in the cell's nucleus that regulate gene expression.

Histone acetytransferases (HAT's).

Enzymes that activate gene expression by adding acetyl groups to histones.

Histone deacetylases (HDAC's).

Enzymes that inhibit gene expression by removing acetyl groups from histones.

Histone methyltransferases.

Enzymes that catalyze the methylation of histone amino‑terminal tails.


This region is important for coordinating an individual's interest in rewards with the body's physiological state. This region integrates brain function with the physiological needs of the organism.

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Intracranial self-stimulation.

Rodents will work (press a lever) to pass electric current into specific brain areas, including the VTA-NAc circuit. A change in the threshold current for self-stimulation is reported to provide a measure of affective state, with an increase in threshold current reflecting a depressed affect.

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A non-competitive antagonist of NMDA glutamate receptors. Ketamine is traditionally classified as a dissociative anesthetic and can cause psychotic symptoms at higher doses. It is also a drug of abuse. However, at lower doses, it has been shown to induce rapid antidepressant effects in most severely ill patients. It is now in clinical development.

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Learned helplessness test.

Reduced escape behavior in response to a stress after prior exposures to unavoidable stresses. Responds to acute or subchronic antidepressant administration.

Locus coeruleus.

This region is the primary site of noradrenergic neurons in the brain, which pervasively modulate brain function to regulate the state of activation and mood of the organism.

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Mesolimbic dopamine system.

This describes a neural circuit arising in dopaminergic neurons of the VTA and their projections to the forebrain, in particular, the NAc.

MicroRNA (miRNA).

Small RNA's found in cells that inhibit specific messenger RNA's. Experimentally, small inhibitory RNA's (called RNAi's) can be used to knockdown levels of a messenger RNA in the brain.

Monoamine oxidase inhibitors (MAOI's).

Refers to compounds, developed in the 1950s, and later shown to possess antidepressant activity in humans. Prototypical MAOI's include tranylcypromine and phenelzine. While these drugs are very effective antidepressants, their use is limited because patients must be aware of certain dietary precautions and avoid using decongestant medications.

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NAc (nucleus accumbens).

Also called ventral striatum, the NAc is a principle target of VTA dopamine neurons. This region mediates the rewarding effects of natural rewards and drugs of abuse.

Non-coding RNAs

Several classes of RNAs that do not encode proteins but play important regulatory roles in cell function. Long non-coding RNAs (lncRNAs) and microRNAs are examples.

NPAS2 (neuronal PAS domain protein 2).

A circadian gene highly enriched in NAc, which seems to exert important control over circadian fluctuations in emotional behavior. A role for NPAS2 in depression is under current investigation.


The major organizational unit of chromatin in which DNA strands are wrapped around complexes of histones and other proteins to form individual units. The DNA strands must unwind in order to be active, that is, transcribed into messenger RNA's and proteins.

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A series of tools that make use of light-activated proteins. Most frequently, light-sensitive ion channels and pumps are utilized to control the firing rate of neurons. (see Channel rhodopsin.)

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

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A chemical process by which protein kinases add phosphate groups to proteins, a process reversed by protein phosphatases. Phosphate groups, because of their large size and charge, alter the function of the proteins.

Prefrontal cortex.

See Frontal cortex..

Protein kinases.

Critical enzymes in the brain's intracellular signaling pathways that regulate other proteins by phosphorylating them (i.e., adding phosphate groups).

Protein phosphatases.

Critical enzymes in the brain's intracellular signaling pathways that regulate other proteins by dephosphorylating them (i.e., removing phosphate groups).

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The ability to maintain normal physiological and behavioral function in the face of severe stress. (See Susceptibility.)


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

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Second messengers.

Small molecules that form part of the brain's intracellular signaling pathways that mediate the actions of neurotransmitters and growth factors. Examples include cyclic AMP (cAMP) and calcium.

Social defeat.

Prolonged exposure to an aggressor causes several depression-like behavioral abnormalities, which can be reversed by chronic, but not acute, antidepressant treatment. This paradigm has recently been validated in both male and female mice.

Somatic therapies.

Refers to non-medication, non-psychotherapy treatments for depression, including electroconvulsive seizures, and several more experimental treatments: magnetic stimulation (transcranial magnetic stimulation [TMS] and magnetic seizures), and vagal nerve stimulation.


The vulnerability to succumb to the deleterious effects of stress. (See Resilience)

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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.


Receptor for BDNF. TrkB works by having protein tyrosense kinase activity which is activated upon BDNF binding.

Tricyclic antidepressants.

Refers to structurally related compounds, developed in the 1950s, and later shown to possess antidepressant activity in humans. Prototypical tricyclic antidepressants include amitriptyline, imipramine, desipramine, and many others.

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VTA (ventral tegmental area).

The site of dopaminergic neurons, which tell the organism whether an environmental stimulus (natural reward, drug of abuse, stress) is rewarding or aversive.

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Whole genome bisulfite sequencing provides a genome-wide measure of DNA methylation, including both 5-methylcytosine and 5-hydroxymethylcytosine.


Weighted gene co-expression network analysis, used to identify clusters of genes that show coordinated regulation under various experimental conditions.

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