Researchers have identified a gene that plays a central role in amplifying or reducing stress, depending on its level of activity, an advance that may lead to targeted therapies to treat depression. Globally, depression affects over 300 million people annually. Nearly 800,000 die from suicide every year – it is the second-leading cause of death among people between the ages of 15 to 29, researchers said. The study, published in the Journal of Neuroscience, is the first to illuminate in detail how the gene, known as Slc6a15, works in a kind of neuron that plays a key role in depression. It found the link in both animals and humans.
“This study really shines a light on how levels of this gene in these neurons affects mood,” said Mary Kay Lobo, an assistant professor at the University of Maryland School of Medicine in the US. “It suggests that people with altered levels of this gene in certain brain regions may have a much higher risk for depression and other emotional disorders related to stress,” said Lobo.
Lobo and her team focused on a part of the brain called the nucleus accumbens which plays a central role in the brain’s “reward circuit.” When you eat a delicious meal, have sex, drink alcohol, or have any other kind of enjoyable experience, neurons in the nucleus accumbens are activated, letting you know that the experience is pushing the proper buttons, researchers said. In depression, any kind of enjoyment becomes difficult or impossible; this symptom is known as anhedonia, which in Latin means the inability to experience pleasure.
The researchers focused on a subset of neurons in the nucleus accumbens called D2 neurons. These neurons respond to the neurotransmitter dopamine, which plays a central role in the reward circuit. They studied mice susceptible to depression; when subjected to social stress – exposure to larger, more aggressive mice – they tend to withdraw and exhibit behaviour that indicates depression, such as social withdrawal and lack of interest in food that they normally enjoy.
Lobo found that when these animals were subjected to chronic social stress, levels of the Slc6a15 gene in the D2 neurons of the nucleus accumbens was markedly reduced. The researchers also studied mice in which the gene had been reduced in D2 neurons. When those mice were subjected to stress, they also exhibited signs of depression. Conversely, when the researchers enhanced Slc6a15 levels in D2 neurons, the mice showed a resilient response to stress.
Next, Lobo looked at the brains of humans who had a history of major depression and who had committed suicide. In the nucleus accumbens of these brains, the gene was reduced. This indicates that the link between gene and behaviour extends from mice to humans, researchers said. It is not clear exactly how Slc6a15 works in the brain. Lobo said it may work by altering neurotransmitter levels in the brain, a theory that has some evidence from other studies.