Most of our brain's 100 billion neurons are created before we're born, but the trickle of neurons created in the adult brain hippocampus could be instrumental in preventing depression, suggest findings from a new study by researchers at Columbia University Vagelos College of Physicians and Surgeons.
The study shows for the first time that neurogenesis stalls in the brains of adults with major depressive disorder and identifies the molecular programs that control neurogenesis, which may help researchers develop new therapies.
"Historically, depression was thought to be a disease of neurotransmitter deficiency, especially serotonin, but we now think that depression stems from multiple issues that affect our neurons' ability to adapt to stress and changing environments," says Maura Dupont, professor of psychiatry, who led the research.
"Without the ability to create new neurons, people with depression may not have the resilience to effectively adapt to the environment."
Role of new neurons in the brain's hippocampus
The new study focused on the brain's hippocampus-a region known for its central role in episodic memory and emotional responses to the environment and one of the few places in the adult brain that creates new neurons. The region isn't the only part of the brain involved in depression, but with its role in emotions and memory, it's thought to play a role in pushing patients to interpret events in a negative light.
"The hippocampus is important for our ability to distinguish between similar but different memories and separate the emotional connotation of past memories and current events," Dupont says. When this ability, called pattern separation, is impaired, memories, together with their emotional value, become less distinct and more likely to blend together.
"You may be out with a friend for lunch, but she's tired and doesn't talk much. With intact pattern separation, you remember this as a unique event. With impaired pattern separation, it becomes mixed with previous memories of feeling rejected, leading you to think, "They're upset with me," Dupont explains. "And I see this a lot in my patients, where they can only retrieve negative information from their memories."
Studies in mice have established that pattern separation is dependent on adult neurogenesis, and a recent study in patients with brain tumors-in whom neurogenesis was ablated by radiation therapy directed to the hippocampus-suggests the same is true in people.
"It's important to emphasize that we do not yet know the complete mechanism, particularly in humans, but the newborn neurons seem to enhance pattern separation because they are especially responsive to new experiences and can be incorporated into new memory circuits more easily, allowing new memories to be stored separately from the old ones," Dupont says. "Turning neurogenesis back on may be a way to treat depression in some people by rewiring their hippocampus circuit."
Depression associated with widespread changes in the brain
Neurogenesis does not work alone in the brain, but as part of a hippocampus circuit where episodic memories and their emotional valence are stored. The study shows that the whole circuit suffers from molecular changes.
Those changes include alterations in genes that are involved in creating new connections and cross-talk between neurons, providing energy, and transporting cargo within cells. The hippocampus's primary means of establishing new emotional memories-the trisynaptic circuit- also showed signs of inflammation and cellular stress in the depressed patients.
The researchers were able to detect these changes after examining an extraordinary number of brain cells-nearly half a million-collected from depressed patients and control subjects soon after each donor's death.
With an array of recently developed cutting-edge techniques, the researchers recorded the activity of every gene in each cell and if the cells' proteins were altered. The massive amount of data provided an unprecedented view of each cell's activities and the exact anatomical location in the hippocampus circuit where the affected cells are positioned.
Their data also identified some genes with altered activity that have been shown to have genetic variants associated with major depression, while other dysregulated genes were affected by epigenetic changes reflecting environmental factors at play. "These are like dimmer switches that control how active genes are, and they are affected by life experiences such as stress, learning, aging, chemicals, etc.," Dupont says.
"Overall, the wide range of effects we found could reflect different pathogenetic mechanisms, perhaps indicating that depression is not just one disease," she adds.
Right now, researchers have only a rudimentary understanding of the biological causes of depression, Dupont says. But studies like hers will define what depression looks like at the cellular level, which could lead to the development of new treatments.
"We want to reclassify depression based on its molecular features, similar to what has been done in cancer," Dupont says. "Classifying cancers based on their cellular characteristics, not their locations, has led to new and improved treatments. We hope the same will be true for depression and other psychiatric or brain diseases."
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