Dynamic cross-talk between microglia and peripheral monocytes underlies stress-induced neuroinflammation and behavioral consequences

Psychological stress promotes the development and recurrence of anxiety and depressive behavioral symptoms. Basic and clinical research indicates that stress exposure can influence the neurobiology of mental health disorders through dysregulation of neuroimmune systems. Consistent with this idea several studies show that repeated stress exposure causes microglia activation and recruitment of peripheral monocytes to the brain contributing to development of anxiety- and depressive-like behavior. Further studies show that stress-induced re-distribution of peripheral monocytes leads to stress-sensitized neuroimmune responses and recurrent anxiety-like behavior. These stress-associated immune changes are important because brain resident and peripheral immune cells contribute to physiological processes that support neuroplasticity. Thus, perturbations in neuroimmune function can lead to impaired neuronal responses and synaptic plasticity deficits that underlie behavioral symptoms of mental health disorders. In this review we discuss recent advances in neuroimmune regulation of behavior and summarize studies showing that stress-induced microglia activation and monocyte trafficking in the brain contribute to the neurobiology of mental health disorders

How Stress Shapes Neuroimmune Function: Implications for the Neurobiology of Psychiatric Disorders

Chronic stress causes physiological and hormonal adaptations that lead to neurobiological consequences and behavioral and cognitive impairments. In particular, chronic stress has been shown to drive reduced neurogenesis and altered synaptic plasticity in brain regions that regulate mood and motivation. The neurobiological and behavioral effects of stress resemble the pathophysiology and symptoms observed in psychiatric disorders, suggesting that there are similar underlying mechanisms. Accumulating evidence indicates that neuroimmune systems, particularly microglia, have a critical role in regulating the neurobiology of stress. Preclinical models indicate that chronic stress provokes changes in microglia phenotype and increases inflammatory cytokine signaling, which affects neuronal function and leads to synaptic plasticity deficits and impaired neurogenesis. More recent work has shown that microglia can also phagocytose neuronal elements and contribute to structural remodeling of neurons in response to chronic stress. In this review we highlight work by the Duman research group (as well as others) that has revealed how chronic stress shapes neuroimmune function and, in turn, how inflammatory mediators and microglia contribute to the neurobiological effects of chronic stress. We also provide considerations to engage the therapeutic potential of neuroimmune systems, with the goal of improving treatment for psychiatric disorders. © 2020 Society of Biological Psychiatry1

Monocyte Trafficking to the Brain with Stress and Inflammation: A Novel Axis of Immune-to-Brain Communication that Influences Mood and Behavior

Psychological stressors cause physiological, immunological, and behavioral alterations in humans and rodents that can be maladaptive and negatively affect quality of life. Several lines of evidence indicate that psychological stress disrupts key functional interactions between the immune system and brain that ultimately affects mood and behavior. For example, activation of microglia, the resident innate immune cells of the brain, has been implicated as a key regulator of mood and behavior in the context of prolonged exposure to psychological stress. Emerging evidence implicates a novel neuroimmune circuit involving microglia activation and sympathetic outflow to the peripheral immune system that further reinforces stress-related behaviors by facilitating the recruitment of inflammatory monocytes to the brain. Evidence from various rodent models, including repeated social defeat (RSD), revealed that trafficking of monocytes to the brain promoted the establishment of anxiety-like behaviors following prolonged stress exposure. In addition, new evidence implicates monocyte trafficking from the spleen to the brain as key regulator of recurring anxiety following exposure to prolonged stress. The purpose of this review is to discuss mechanisms that cause stress-induced monocyte re-distribution in the brain and how dynamic interactions between microglia, endothelial cells, and brain macrophages lead to maladaptive behavioral responses

Microglia in neuronal plasticity: Influence of stress

The central nervous system (CNS) has previously been regarded as an immune-privileged site with the absence of immune cell responses but this dogma was not entirely true. Microglia are the brain innate immune cells and recent findings indicate that they participate both in CNS disease and infection as well as facilitate normal CNS function. Microglia are highly plastic and play integral roles in sculpting the structure of the CNS, refining neuronal circuitry and connectivity, and contribute actively to neuronal plasticity in the healthy brain. Interestingly, psychological stress can perturb the function of microglia in association with an impaired neuronal plasticity and the development of emotional behavior alterations. As a result it seemed important to describe in this review some findings indicating that the stress-induced microglia dysfunction may underlie neuroplasticity deficits associated to many mood disorders. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'

Circuit and synaptic mechanisms of repeated stress: Perspectives from differing contexts, duration, and development

The current review is meant to synthesize research presented as part of a symposium at the 2016 Neurobiology of Stress workshop in Irvine California. The focus of the symposium was âStress and the Synapse: New Concepts and Methodsâ and featured the work of several junior investigators. The presentations focused on the impact of various forms of stress (altered maternal care, binge alcohol drinking, chronic social defeat, and chronic unpredictable stress) on synaptic function, neurodevelopment, and behavioral outcomes. One of the goals of the symposium was to highlight the mechanisms accounting for how the nervous system responds to stress and their impact on outcome measures with converging effects on the development of pathological behavior. Dr. Kevin Bath's presentation focused on the impact of disruptions in early maternal care and its impact on the timing of hippocampus maturation in mice, finding that this form of stress drove accelerated synaptic and behavioral maturation, and contributed to the later emergence of risk for cognitive and emotional disturbance. Dr. Scott Russo highlighted the impact of chronic social defeat stress in adolescent mice on the development and plasticity of reward circuity, with a focus on glutamatergic development in the nucleus accumbens and mesolimbic dopamine system, and the implications of these changes for disruptions in social and hedonic response, key processes disturbed in depressive pathology. Dr. Kristen Pleil described synaptic changes in the bed nuclei of the stria terminalis that underlie the behavioral consequences of allostatic load produced by repeated cycles of alcohol binge drinking and withdrawal. Dr. Eric Wohleb and Dr. Ron Duman provided new data associating decreased mammalian target of rapamycin (mTOR) signaling and neurobiological changes in the synapses in response to chronic unpredictable stress, and highlighted the potential for the novel antidepressant ketamine to rescue synaptic and behavioral effects. In aggregate, these presentations showcased how divergent perspectives provide new insights into the ways in which stress impacts circuit development and function, with implications for understanding emergence of affective pathology. Keywords: Early-life stress, Hippocampus, Susceptibility, Resilience, Nucleus accumbens, Bed nuclei of the stria terminalis, Neuropeptide Y, Corticotropin-releasing factor, Prefrtonal cortex, Mammalian target of rapamycin, Major depressive disorde