The Brain - What Causes Depression: Depression

Content provided by the Faculty of the Harvard Medical School

The brain

Popular lore has it that emotions reside in the heart. Science, though, tracks the seat of your emotions to the brain. While researchers believe that brain chemicals and neural pathways have a major impact on depression, their understanding of the neurological underpinnings of mood is incomplete. The outer edges of the puzzle appear to be in place, but scientists are working to fill huge gaps in knowledge.

Figure 1: Areas of the brain affected by depression Depression affects several areas of the brain that play a role not just in mood, but also in memory and other mental and physical functions. The cerebral cortex coordinates functions like speech, movement, memory, and learning. The thalamus receives and relays sensory information. The hippocampus processes long-term memories, while the amygdala oversees emotionally charged memories.

Regions that affect mood

Advances in technology permit a much closer look at the working brain than was possible in the past. Increasingly sophisticated forms of brain imaging, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), enable scientists to study the brain while it's at work (see "Advances in brain imaging"). This has led to a better understanding of which areas of the brain help regulate mood and other functions, such as memory, that may be affected by depression (see Figure 1). Researchers have learned the following:

• The amygdala becomes activated when a person recalls emotionally charged memories, such as a frightening situation. This small almond-shaped mass is part of the limbic system, a group of structures deep in the brain that's associated with emotions such as anger, pleasure, sorrow, fear, and sexual arousal. Activity in the amygdala is higher when a person is sad or clinically depressed. This increased activity continues even after recovery from depression.

• The thalamus is a central structure that arches above the brainstem. It receives most sensory information and relays it to the appropriate part of the cerebral cortex, the large, domed outer part of the brain that directs high-level functions such as speech, behavioral reactions, movement, thinking, and learning. Some research suggests that bipolar disorder may result from problems in the thalamus, which helps link sensory input to pleasant and unpleasant feelings.

• The hippocampus has a central role in processing long-term memory and recollection. Like the amygdala, it's part of the limbic system. Interplay between the hippocampus and the amygdala might account for the adage "once bitten, twice shy." It is this part of the brain that registers fear when you are confronted by a loud, barking, aggressive dog, and the memory of such an experience may make you wary of dogs you come across later in life. Research suggests that the hippocampus may be smaller in some depressed people (see "The role of trauma").

Nerve cell communication

If you trained a high-powered microscope on a slice of brain tissue, you might be able to see a loosely braided network of neurons (nerve cells) that send and receive messages. While every cell in the body has the capacity to send and receive signals, neurons are specially designed for this function. Each neuron has a cell body containing the structures that any cell needs to thrive. Stretching out from the cell body are short, branchlike fibers called dendrites and one longer, more prominent fiber called the axon.

A combination of electrical and chemical signals allows communication within and between neurons. When a neuron becomes activated, it passes an electrical signal from the cell body down the axon to its end (known as the axon terminal), where chemical messengers called neurotransmitters are stored. The signal releases certain neurotransmitters into the space between that neuron and the dendrite of a neighboring neuron. That space is called a synapse. As the concentration of a neurotransmitter rises in the synapse, neurotransmitter molecules begin to bind with receptors embedded in the membranes of the two neurons (see Figure 2).

Figure 2: How neurons communicate Electrical signal travels down axon Chemical neurotransmitter is released Neurotransmitter binds to receptor sites Signal is picked up by second neuron and is either passed along or halted The signal is also picked up by the first neuron, causing reuptake to occur; neurotransmitter is transported back into the cell that released it

The release of a neurotransmitter from one neuron can activate or inhibit a second neuron. If the signal is activating, or excitatory, the message continues to pass farther along that particular neural pathway. If it is inhibitory, the signal will be suppressed. The neurotransmitter also affects the neuron that released it. Once the first neuron has released a certain amount of the chemical, a feedback mechanism (controlled by that neuron's receptors) instructs the neuron to stop pumping out the neurotransmitter and start bringing it back into the cell. This process is called reabsorption or reuptake. Enzymes break down the remaining neurotransmitter into smaller molecules.

When the system falters. Brain cells usually produce levels of neurotransmitters that keep senses, learning, movements, and moods perking along. But in some people who are severely depressed or manic, the complex systems that accomplish this go awry. For example, receptors may be oversensitive or insensitive to a specific neurotransmitter, causing their response to its release to be excessive or inadequate. Or a message might be weakened if the originating cell pumps out too little of a neurotransmitter or if an overly efficient reuptake mops up too much before the molecules have the chance to bind to the receptors on other neurons. Any of these system faults could significantly affect mood.

Kinds of neurotransmitters. Scientists have identified many different neurotransmitters. Here is a description of a few believed to play a role in depression:

• Acetylcholine enhances memory and is involved in learning and recall.

• Serotonin helps regulate sleep, appetite, and mood and inhibits pain. Research supports the idea that some depressed people have reduced serotonin transmission. Low levels of a serotonin by-product have been linked to a higher risk for suicide.

• Norepinephrine constricts blood vessels, raising blood pressure. It may trigger anxiety and be involved in some types of depression. It also seems to help determine motivation and reward.

• Dopamine is essential to movement. It also influences motivation and plays a role in how a person perceives reality. Problems in dopamine transmission have been associated with psychosis, a severe form of distorted thinking characterized by hallucinations or delusions. It's also involved in the brain's reward system, so it is thought to play a role in substance abuse.

• Glutamate is a small molecule believed to act as an excitatory neurotransmitter and to play a role in bipolar disorder and schizophrenia. Lithium carbonate, a well-known mood stabilizer used to treat bipolar disorder, helps prevent damage to neurons in the brains of rats exposed to high levels of glutamate. Other animal research suggests that lithium might stabilize glutamate reuptake, a mechanism that may explain how it smooths out the highs of mania and the lows of depression in the long term.

• Gamma-aminobutyric acid (GABA) is an amino acid that researchers believe acts as an inhibitory neurotransmitter. It is thought to help quell anxiety.

Last updated:	January 23, 2007