From lost productivity that costs the workplace to a feeling of hopelessness that robs individuals and families of joy and even takes lives, depression is a serious foe. But the mood disorder may yield to a new treatment, according to a recent study of male mice. Essentially, the study activated the SIRT1 gene in male mice, helping to excite their prefrontal cortex neurons. The researchers found this was a way to reverse symptoms of depression including social isolation.

Any stride in combatting the effects of depression is welcome news. In the 15-44 age bracket alone, Major Depressive Disorder is the leading cause of disability in the U.S., according to the Anxiety and Depression Association of America. In its most extreme form, depression still affects 6.7 percent of the adult population each year and women are more likely to suffer than men.

How depression plays out on the prefrontal cortex

The brain’s frontal lobe was the last region of the brain that evolved and scientists loosely agree that this area of the brain tends to be larger in primates. The term “prefrontal” was probably first used by researchers as far back as 1884 and this region of the brain grew proportionally to the rest of the cortex. This bit at the very front of the brain is known for performing “executive functions” like problem-solving and self-control, along with the ability to think of long-term consequences.

Recent scientific advancements have linked depression to abnormal function in the medial prefrontal cortex, an area of the brain associated with the way individuals think about themselves.

People suffering from depression have a brain basis for having negative self-images and having difficulty moving on from thoughts about themselves into thinking about the world around them. They tend to think about themselves more negatively, they spend more time thinking about themselves and they have trouble switching between thinking about themselves and thinking about the world outside them. All this is linked to a medial prefrontal cortex with more influence over depressed people’s brains and actions than average.

This area of the brain has already been determined to play a role in a human’s emotional response, along with mood regulation through its control of neurotransmitters including serotonin. As neuron activity levels in the prefrontal cortex area decrease, depression symptoms become more severe.

Link between gene activation and depression reversal

Researchers from the Medical College of Georgia at Augusta University tapped what was known about the prefrontal cortex and depression to reach a possible solution for reversing depression. The study suggests drugs that activate SIRT1 may be an effective therapy for some with major depression. The researchers also found how the prefrontal cortex assisted when the brain made self-appraisals. As one of its “executive functions,” this area of the brain regulated activity in a brain site known as the posterior cingulate cortex.

To reach these conclusions with a study of mice, researchers first made the SIRT1 gene that excites neurons in the prefrontal cortex inactive in one group. This made the male mice studied experience depression symptoms They were less social and became loners, for example. They also lost interest in sex, a common marker of depression.

After determining what happened when they artificially deactivated the genes, the researchers used a drug to directly activate the same gene to excite the neurons. They found this gene-activation reversed the male mice depression symptoms, causing a reaction similar to antidepressants. The researchers concluded that drugs that could activate SIRT1 and chemically induce the high-level of excited neurons in the prefrontal cortex could someday be a weapon in the battle against human MDD.

Why didn’t this work on female mice?

This link between a SIRT1 gene without enough excitatory neurons and symptoms of depression first emerged from a large-scale gene study. A 2015 genome-wide study of more than 5,000 Chinese women with MDD identified two variants associated with the disorder, and one of them was the SIRT1 gene variant. Because of that link, scientists from the MCGAU study were surprised to find that female mice did not experience the same depression reversal through the SIRT1 gene activation as their male counterparts.

The researchers put this down to physical differences in the prefrontal cortex region between males and females. Their research also reinforced the idea that depression is a combination of environmental and genetic factors. Likely, some people have the SIRT1 variant at birth. But they also reiterate that this genetic SIRT1 variant is probably rare and only linked to depression, not a cause of the symptoms.

Next steps

Dr. Xin-Yun Lu is the study’s corresponding author and a professor in MCGAU’s Department of Neuroscience and Regenerative Medicine. She is already on the case studying other areas of the brain to see if she detects similar gender-related differences. Her studies will focus next on the hippocampus region of the brain, itself a key influencer of depression. Along with looking for more gene-activated solutions to depression and noting possible sex-disparities in the hippocampus functions, this research could aid in the understanding of Alzheimer’s, which is also influenced by that region of the brain.

Lu is also a pharmacologist, so she will not just rely on this study’s research drug in finding possible ways to activate the SIRT1 gene and counter depression. She plans to examine drugs we already have to see if they might create the same depression-reversing effect as the research drug used in the study. Some of these older drugs she’ll test have never been implemented to treat depression.