Neuroinflammation is now regarded to be a contributing factor in the etiology of a wide range of psychiatric disorders and a potential mediator of the extensive co-morbidities that are present between these disorders. It has been suggested that psychiatric disorders may result when normal neuroinflammatory responses to stimuli that induce these responses become exaggerated. The experience of both acute and more chronic stressors also are associated with the development of a number of disorders. It has been tempting to suppose that these two processes are related, but neither acute nor chronic stress have proved to produce persistent neuroinflammation beyond the stressor exposure. However, we have recently found that both acute and chronic stressors, even though they do not produce either large or long-lasting neuroinflammation, potently exaggerate neuroinflammatory responses to both peripheral and central inflammatory stimuli that are administered later. Importantly, this sensitized neuroinflammatory reaction persists for many days after stressor exposure. However, the mechanisms that lead stressors to sensitize subsequent neuroinflammation remain largely unknown. Within the past decade there has been a revolution in understanding the mechanisms involved in mediating peripheral innate immunity/inflammation. These new mechanisms and processes have been studied almost exclusively in the periphery, and whether or not they occur in the CNS is unknown. Our Preliminary Studies strongly encourage the possibility that these are present in CNS innate immune cells (microglia) and that they are involved in mediating stress-induced sensitization of neuroinflammatory responses to subsequent inflammatory challenges. The global goals of the proposed research are to a) firmly establish the presence of these processes, heretofore unstudied in brain, in brain, and b) explore the role of these processes in stress- induced sensitization of neuroinflammation, as well as the behavioral changes that typically induced by the activation of innate immune cells in the brain.

Public Health Relevance

Both neuroinflammation in response to infection in the periphery, outside the brain, and stress, are thought to be involved in the etiology of a number of different psychiatric disorders. The two have been regarded as separate processes, but our research has shown that prior stress exaggerates the neuroinflammation that follows infection in the body. An understanding of the mechanisms involved will provide new therapeutic targets and therapies.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Tonelli, Leonardo H
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University of Colorado at Boulder
Schools of Arts and Sciences
United States
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Frank, Matthew G; Fonken, Laura K; Dolzani, Samuel D et al. (2018) Immunization with Mycobacterium vaccae induces an anti-inflammatory milieu in the CNS: Attenuation of stress-induced microglial priming, alarmins and anxiety-like behavior. Brain Behav Immun 73:352-363
Fonken, Laura K; Frank, Matthew G; Gaudet, Andrew D et al. (2018) Neuroinflammatory priming to stress is differentially regulated in male and female rats. Brain Behav Immun 70:257-267
Frank, Matthew G; Fonken, Laura K; Annis, Jessica L et al. (2018) Stress disinhibits microglia via down-regulation of CD200R: A mechanism of neuroinflammatory priming. Brain Behav Immun 69:62-73
Fonken, Laura K; Frank, Matthew G; D'Angelo, Heather M et al. (2018) Mycobacterium vaccae immunization protects aged rats from surgery-elicited neuroinflammation and cognitive dysfunction. Neurobiol Aging 71:105-114
Fonken, Laura K; Frank, Matthew G; Gaudet, Andrew D et al. (2018) Stress and aging act through common mechanisms to elicit neuroinflammatory priming. Brain Behav Immun 73:133-148
Fleshner, Monika; Frank, Matthew; Maier, Steven F (2017) Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders. Neuropsychopharmacology 42:36-45
Frank, Matthew G; Weber, Michael D; Fonken, Laura K et al. (2016) The redox state of the alarmin HMGB1 is a pivotal factor in neuroinflammatory and microglial priming: A role for the NLRP3 inflammasome. Brain Behav Immun 55:215-224
Frank, Matthew G; Weber, Michael D; Watkins, Linda R et al. (2016) Stress-induced neuroinflammatory priming: A liability factor in the etiology of psychiatric disorders. Neurobiol Stress 4:62-70
Fonken, Laura K; Weber, Michael D; Daut, Rachel A et al. (2016) Stress-induced neuroinflammatory priming is time of day dependent. Psychoneuroendocrinology 66:82-90