Beyond the neuron: Role of non-neuronal cells in stress disorders

Abstract

Stress disorders are leading causes of disease burden in the U.S. and worldwide, yet available therapies are fully effective in less than half of all individuals with these disorders. Although to date, much of the focus has been on neuron-intrinsic mechanisms, emerging evidence suggests that chronic stress can affect a wide range of cell types in the brain and periphery, which are linked to maladaptive behavioral outcomes. Here, we synthesize emerging literature and discuss mechanisms of how non-neuronal cells in limbic regions of brain interface at synapses, the neurovascular unit, and other sites of intercellular communication to mediate the deleterious, or adaptive (i.e., pro-resilient), effects of chronic stress in rodent models and in human stress-related disorders. We believe that such an approach may one day allow us to adopt a holistic "whole body" approach to stress disorder research, which could lead to more precise diagnostic tests and personalized treatment strategies. Stress is a major risk factor for many psychiatric disorders. Cathomas et al. review new insight into how non-neuronal cells mediate the deleterious effects, as well as the adaptive, protective effects, of stress in rodent models and human stress-related disorders.

Fig 1.. Interactions among non-neuronal cells in brain.

Non-neuronal cells interact at cellular barriers, including the blood brain barrier (BBB), synapses, and other sites of intercellular communication in the brain. Oligodendrocytes (turquoise); astrocytes (yellow); monocytes (white); microglia (blue); endothelial cells (brown); neurons (purple).

Fig 2.. Stress effects on astrocytes.

Stress effects on astrocytes (yellow) and their interaction with the blood-brain barrier (BBB). As shown in the inset, SLC1A2 (also known as GLT1 or EAAT2) removes glutamate from the extracellular space. SLC1A2 is downregulated in both humans and rodent models of stress and depression. Additionally, loss of astrocyte endfeet integrity may loosen the BBB and allow peripheral factors into the brain.

Fig 3.. Stress effects on central and peripheral myeloid cells.

Stress results in trafficking of peripheral monocytes (white) to the brain via upregulation of chemokine receptors. In the brain, stress leads to activation of microglia (blue) and increased secretion of cytokines and production of reactive oxygen species.

Fig 4.. Stress impairs function of the blood-brain barrier (BBB).

Stress leads to a damage of endothelial cells (brown), including brain-region specific downregulation of the tight junction protein claudin-5 (inset) resulting in increased permeability of the BBB and infiltration of peripheral factors such as cytokines.

Fig 5.. Stress effects on oligodendrocyte lineage (OL) cells.

Stress induces brain-region-specific impairments of myelination that is a result of reduced OL cell differentiation and maturation potentially through mechanisms such as oxidative stress or immune dysregulation in the periphery.