Extensive research over several decades, some of it led by investigators supported by BBRF, has demonstrated that stress, including psychosocial stress (stress that arises from social interactions) is one of the most important risk factors for depression.

Great effort has therefore been devoted to research seeking to reveal precisely how stress perturbs the biology of the brain and other bodily systems to produce the diverse range of depression symptoms.

A new study appearing in the journal Nature reports on experiments that add an important new dimension to what is known about how, when someone is experiencing social stress, the functioning of the body’s immune system may be involved in helping to cause depression or increase its risk.

The new study was led by 2020 BBRF Young Investigator Flurin Cathomas, M.D., of the Icahn School of Medicine at Mount Sinai; the senior author of the team’s paper was Scott J. Russo, Ph.D., a member of BBRF’s Scientific Council, a two-time BBRF Young Investigator grantee, and Director of the Brain-Body Research Center at Mount Sinai. Seven other BBRF grantees were involved in this study, including Eric J. Nestler, M.D., Ph.D., a member of BBRF’s Scientific Council, a three-time BBRF prize winner, and 1996 Distinguished Investigator.

As authors of the new study note, immune system interactions with the central nervous system (the CNS: the brain and spinal cord) and organs of the body are tightly regulated, biologically. Psychosocial stress can affect the two-way communications between these two elements—the CNS and the rest of the body. In people experiencing chronic stress, past research has shown that the innate immune system is activated, resulting in the mobilization of immune cells including white blood cells in peripheral organs and blood, as well as the production of tiny proteins called cytokines, which can trigger inflammation.

One intriguing discovery in psychiatry research has been that a subset of people with stress-related psychiatric disorders, including major depression, “display a state of chronic low-grade inflammation.” Two phenomena associated with such inflammation are an increase in the affected individual’s pro-inflammatory cytokines in circulation throughout the body, as well as an increase in white blood cell numbers. In experiments in mice, it has been shown that stress also can induce changes to the thin but vital membrane separating the brain and the rest of the body, the blood-brain barrier (BBB), which normally plays a protective role, keeping toxins and microbes out of the brain. When modified by stress-induced inflammation, the BBB in mice allows the entry of circulating proteins into the brain that normally can not pass through the barrier. One region in the brain affected by such invasion, in mice, is the nucleus accumbens (NAc), which is central in the processing of rewards and also in the response to aversive stimuli, and implicated in depression.

All of these processes are potentially involved in causing depression symptoms in people, although much remains to be learned about the mechanisms that enable these changes to occur. The new study by Drs. Cathomas, Russo and colleagues reveals new detail about mechanisms through which stress-induced immune changes can affect the function of the brain’s neurons and ultimately, behavior.

In the presence of stress, immune factors at work in the body’s periphery, such as a rise in the circulation of pro-inflammatory cytokines, likely have a direct impact on neurons—for example, by binding directly to receptors expressed in neurons. The new study demonstrates a distinct way in which stress promotes interactions of immune cells in the periphery with the brain—an indirect way that appears to result in adverse changes in social behavior.

The new research focuses on the role in this process of enzymes called MMPs (matrix metalloproteinases) and in particular MMP8. This enzyme, like others in the MMP family, has roles in shaping and regulating the space between neurons, called extracellular space (ECS), as well as the extracellular matrix (ECM), which is a dense web-like material that individual neurons extend out into ECS.

Experiments by the team in mice and humans leads them to conclude that MMP8, which is released during chronic social stress by immune cells circulating in the body’s periphery, can invade the brain perhaps due to damage to the BBB, and alter the shape of ECS and ECM in the brain’s nucleus accumbens and possibly other brain areas. In mouse experiments, such changes were causally linked by the team with changes in behavior—changes analogous to those observed when a person experiences chronic social stress (social avoidance, for example).

In short, therefore, the new research provides evidence for a specific mechanism by which the peripheral immune system can affect, via alteration of the ECS, the functioning of neurons in the brain and alter behavior. One potential implication is that it may be possible to develop treatments that target not the brain directly (which is always difficult), but rather molecules such as MMP8 in the peripheral immune system—a totally novel approach to potentially treat psychiatric illnesses including depression.

The researchers note the need for further studies to “more specifically manipulate different components of the ECS in various brain regions,” to link them with specific changes in brain physiology and behavioral changes, and also to identify additional factors that might alter the ECS under conditions of chronic stress. A mouse experiment in which MMP8 was depleted resulted in stressed mice that were not socially avoidant; this approach had no impact on non-social behaviors. “Further research is needed to untangle neuroimmune mechanisms of stress-induced vs. non-social behavior alterations,” they say. Still, the current results suggest MMP8 or ECS changes may serve as biomarkers for psychiatric illness as well as novel targets for future treatments.

The research team also included: James W. Murrough, M.D., 2009 BBRF Young Investigator; Eric M. Parise, Ph.D., 2021 Young Investigator; Romain Durand-de Cuttoli, Ph.D., 2022 BBRF Young Investigator; Lyonna F. Parise, Ph.D., 2022 BBRF Young Investigator; Long Li, Ph.D., 2021 BBRF Young Investigator; and Kenny L. Chan, Ph.D., 2022 BBRF Young Investigator.