Immune mechanisms of stress susceptibility and resilience: Lessons from animal models.

Stress has an impact on the brain and the body. A growing literature demonstrates that feedback between the peripheral immune system and the brain contributes to individual differences in the behavioral response to stress. Here we examine preclinical literature to demonstrate a holistic vision of risk and resilience to stress. We identify a variety of cellular, cytokine and molecular mechanisms in adult animals that act in concert to produce a stress susceptible individual response. We discuss how cross talk between immune cells in the brain and in the periphery act together to increase permeability across the blood brain barrier or block it, resulting in susceptible or stress resilient phenotype. These preclinical studies have importance for understanding how individual differences in the immune response to stress may be contributing to mood related disorders such as depression, anxiety and posttraumatic stress disorders.

Deciphering sex differences in the immune system and depression.

Certain mood disorders and autoimmune diseases are predominately female diseases but we do not know why. Here, we explore the relationship between depression and the immune system from a sex-based perspective. This review characterizes sex differences in the immune system in health and disease. We explore the contribution of gonadal and stress hormones to immune function at the cellular and molecular level in the brain and body. We propose hormonal and genetic sex specific immune mechanisms that may contribute to the etiology of mood disorders.

Circadian rhythms and mood disorders: Time to see the light.

The importance of time is ever prevalent in our world, and disruptions to the normal light/dark and sleep/wake cycle have now become the norm rather than the exception for a large part of it. All mood disorders, including seasonal affective disorder (SAD), major depressive disorder (MDD), and bipolar disorder (BD), are strongly associated with abnormal sleep and circadian rhythms in a variety of physiological processes. Environmental disruptions to normal sleep/wake patterns, light/dark changes, and seasonal changes can precipitate episodes. Moreover, treatments that target the circadian system have proven to be therapeutic in certain cases. This review will summarize much of our current knowledge of how these disorders associate with specific circadian phenotypes, as well as the neuronal mechanisms that link the circadian clock with mood regulation. We also discuss what has been learned from therapies that target circadian rhythms and how we may use current knowledge to develop more individually designed treatments.

Chronic variable stress leads to sex specific gut microbiome alterations in mice.

Stress has been implicated in the incidence and severity of psychiatric and gastrointestinal disorders. The immune system is capable of modulating the activity and composition of the gut following stress and vice versa. In this study we sought to examine the sequential relationship between immune signaling and microbiome composition occurring in male and female mice over time using a variable stress paradigm. Tissue was collected prior to, during, and after the stress paradigm from the same mice. Cytokines from plasma and brain were quantified using a multiplexed cytokine assay. Fecal samples were collected at the same timepoints and 16S rRNA amplicon sequencing was performed to determine the relative abundance of microbiota residing in the guts of stressed and control mice. We found sex differences in the response of the gut microbiota to stress following 28 days of chronic variable stress but not 6 days of sub-chronic variable stress. Immune activation was quantified in the nucleus accumbens immediately following Sub-chronic variable when alterations of gut composition had not yet occurred. In both sexes, 28 days of stress induced significant changes in the proportion of Erysipelotrichaceae and Lactobacillaceae, but in opposite directions for male and female mice. Alterations to the gut microbiome in both sexes were associated with changes in cytokines related to eosinophilic immune activity. Our use of an animal stress model reveals the immune mechanisms that may underly changes in gut microbiome composition during and after stress. This study reveals potential drug targets and microbiota of interest for the intervention of stress related conditions.

Sex and region-specific effects of variable stress on microglia morphology.

Major Depressive Disorder (MDD) is a common and debilitating mood disorder that is more prevalent in women than men. In humans, PET imaging of microglia activation is currently being explored as a potential biomarker of MDD and suicidal ideation. Stress is a trigger for many mood disorders, including MDD. Microglial changes in morphology and activation state in response to stress has been reported in various brain regions, but most studies only examined male subjects. Here we report changes in microglia morphology in the nucleus accumbens (NAc) and subregions of the hippocampus (HPC) in both male and female mice following variable stress of 6 or 28 days in duration. Our data demonstrate that after 6 days of stress, microglia in the female NAc and dentate gyrus have a reduction in homeostatic associated morphology and an increase in primed microglia. After 28 days some of these sex specific stress effects were still present in microglia within the NAc but not the dentate gyrus. There were no effects of stress in either sex at either timepoint in CA1. In female mice, anti-inflammatory activation of microglia using rosiglitazone promoted sociability behavior after 6 days of stress. Furthermore, both drug and stress have impact on microglia morphology and activation state in the NAc. These data suggest that microglia morphology and activation state are altered by 6 days of variable stress in a region-specific manner and may contribute to, or potentially compensate for, the onset of stress susceptibility rather than impacting long term exposure to stress.