Thirty-five years after the first clue appeared, researchers now report they have assembled a detailed picture of one way in which inflammation can cause or create conditions favorable for the development of depression and possibly other mood disorders.
The research reveals a molecular mechanism in blood-vessel cells that promotes resilience in the presence of chronic stress. Stress is one of the main “environmental” factors known to give rise to depression in vulnerable individuals.
In the mid-1980s, a clinical study of depressed people first suggested a connection between leaks in the blood-brain barrier (BBB) and depression. The BBB selectively allows certain nutrients and other essential factors in the blood to pass into brain tissue, while keeping out pathogens, pro-inflammatory immune signals and other harmful elements.
Several years ago, research led by 2016 BBRF Young Investigator Caroline Ménard, Ph.D., of Laval University and the CERVO Brain Research Centre in Canada, showed that in mice exposed to chronic social stress, BBB integrity was breached, due to a loss of a protein called claudin-5 (cldn5). This protein forms “kissing” points that help to seal the junctions between endothelial cells that line blood vessels. In the brain, the “leakage” between cells was especially noted in an area called the nucleus accumbens, which is heavily involved in mood regulation.
Dr. Ménard and colleagues, including four other BBRF grantees, one of whom is a BBRF Scientific Council member, set out to clarify the mechanisms within neurovasculature (the vessels that bring blood to the brain) that give rise to leaks in the blood-brain barrier, promoting depression. They also sought to determine how the BBB is normally kept strong, hoping to identify factors that contribute to resilience amid challenges like chronic stress or inflammation.
Using tools that were unavailable 35 years ago when the first clue was noted, Dr. Ménard’s team discovered changes at the cellular and sub-cellular levels in endothelial cells that line the vasculature. They linked these changes to different ways certain genes are regulated—when they are switched on or off—and the way these changes impact still other molecular factors affecting the integrity of the BBB. The results were published in the Proceedings of the National Academy of Sciences.
The researchers confirmed their past research showing that the BBB was “normal” in mice that were resistant to social stress. Immune signals circulating in the blood were prevented from crossing the BBB. In comparison: in mice without natural resilience that were exposed to chronic social stress, levels of the cldn5 protein were reduced.
This reduction in cldn5 was, in turn, linked with inflammation of the BBB. Loss of cldn5 and BBB leakage were associated with activation of pro-inflammatory signaling pathways (two important ones are TNF-alpha and NFK-b) in the endothelial cells of stress-susceptible mice. These changes allow circulating inflammatory mediators, called cytokines, to “leak” through inflamed blood vessels into brain tissue, specifically within the nucleus accumbens. Mice with leaky BBBs developed depression-like symptoms.
The new research takes all of this an important step further, showing why and how levels of the key “cell-adhesion” protein cldn5, responsible for BBB integrity, dropped in vulnerable mice. The researchers documented blockage of the regulatory mechanism that causes the gene for cldn5 to become active.
Although the mechanism the team uncovered is more complex, the research confirmed that TNF-alpha, NFK-b, and a protein called hdac1 are all involved in mediating susceptibility to stress. This is important because it raises the possibility of using drugs to alter their levels to affect the impact of stress on depression vulnerability. The team tested this concept in mice, finding that by using a drug that blocks hdac1 activity, they could reverse changes in the mice that made them vulnerable to loss of cldn5 and leakage in the BBB.
Clinical trials in humans are now under way seeking to discover if measures to alter pro-inflammatory signaling could therapeutically reduce inflammation and promote recovery in mood disorders. Results obtained by Dr. Ménard’s team suggest that this approach may also have promise in protecting the brain vasculature, ameliorating responses to social stress. Dr. Ménard notes that some depressed patients, particularly those resistant to commonly prescribed antidepressant treatments, have high levels of circulating proinflammatory cytokines in their blood.
“The possibility of modulating brain inflammation by acting directly on the neurovasculature is intriguing and appealing,” the team wrote. While there is no known way to enhance cldn5 levels, they say, the new results suggest that targeting molecular pathways affecting cldn5 “might be a way to promote BBB integrity, neurovascular health and stress resilience.”
The team also included: Carol Tamminga, M.D., a BBRF Scientific Council member, 2011 Lieber Prize winner and 2010 and 1988 BBRF Distinguished Investigator; Gustavo Turecki, M.D., Ph.D., a 2016 BBRF Distinguished Investigator, 2008 Independent Investigator and 2000 Young Investigator; Scott Russo, Ph.D., a 2008 and 2006 BBRF Young Investigator; and Sam Golden, Ph.D., a 2018 BBRF Young Investigator.