How Stress and Depression Shrink the Brain

People suffering from major depression or chronic stress suffer loss of brain volume, a condition that contributes to both emotional and cognitive impairment.

A team of researchers led by Yale scientists has discovered the cause behind this condition— a single genetic switch that triggers loss of brain connections in humans and depression in animal models.

The findings showed that the genetic switch known as a transcription factor represses the expression of several genes that are necessary for the formation of synaptic connections between brain cells, which in turn could contribute to loss of brain mass in the prefrontal cortex.

Ronald Duman, the Elizabeth Mears and House Jameson Professor of Psychiatry and professor of neurobiology and of pharmacology said they
wanted to test the idea that stress causes a loss of brain synapses in humans and show that circuits normally involved in emotion, as well as cognition, are disrupted when this single transcription factor is activated.

The research team analyzed tissue of depressed and non-depressed patients donated from a brain bank and looked for different patterns of gene activation.

The brains of patients who had been depressed exhibited lower levels of expression in genes that are required for the function and structure of brain synapses.

Lead author and postdoctoral researcher H.J. Kang discovered that at least five of these genes could be regulated by a single transcription factor called GATA1. When the transcription factor was activated, rodents exhibited depressive-like symptoms, suggesting GATA1 plays a role not only in the loss of connections between neurons but also in symptoms of depression.

Duman theorizes that genetic variations in GATA1 may one day help identify people at high risk for major depression or sensitivity to stress. He hoped that by enhancing synaptic connections, either with novel medications or behavioural therapy, more effective antidepressant therapies can be developed .

The findings were reported in latest issue of the journal Nature Medicine.

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