Skip to Main Content
 

Global Search Box

 
 
 
 

ETD Abstract Container

Abstract Header

Repeated Social Defeat Stress Promotes Reactive Brain Endothelium and Microglia-Dependent Pain Sensitivity

Sawicki, Caroline

Abstract Details

2020, Doctor of Philosophy, Ohio State University, Oral Biology.
Exposure to chronic stress disrupts the homeostatic communication pathways between the central nervous system (CNS) and peripheral immune system, leading to dysregulated and heightened neuroinflammation that contributes to the pathophysiology of anxiety and pain. Repeated social defeat (RSD) is a murine model of psychosocial stress that recapitulates many of the behavioral and immunological effects observed in humans in response to stress, including activation of the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis. In both humans and rodents, the brain interprets physiological stress within fear and threat appraisal circuitry. RSD promotes the trafficking of bone marrow-derived inflammatory monocytes to the brain within discrete stress-responsive brain regions where neuronal and microglial activation are observed. Notably, RSD induces the expression of adhesion molecules on vascular endothelial cells within the same brain regions where microglial activation and monocyte trafficking occur in response to stress (Chapter 2). Further studies demonstrated that these monocytes express high levels of Interleukin (IL)-1β, activating brain endothelial IL-1 receptors to promote the onset of anxiety-like behavior. In addition to promoting anxiety, psychological stress increases susceptibility to experience pain and exacerbates existing pain. Notably, clinical studies indicate that enhanced neuroimmune activation elicits adaptive changes in the nervous system that can contribute to exaggerated pain sensation. Therefore, the next series of experiments investigated whether stress-induced neuroimmune responses contribute to increased pain sensitivity in mice exposed to RSD (Chapter 3). RSD increased mechanical allodynia in an exposure-dependent manner that persisted for at least one week following cessation of the stressor. Additionally, we showed that blocking peripheral nociception was effective in inhibiting enhanced pain signaling without altering stress-induced innate immune or behavioral responses. Despite these findings, the mechanism by which stress caused increased pain sensitivity was unclear. Therefore, the next series of experiments mechanistically tested the role of microglia in promoting increased mechanical allodynia during RSD. We showed that microglia were activated selectively within the nociceptive neurocircuitry of the dorsal horn of the lumbar spinal cord during RSD independent of peripheral monocyte recruitment. Notably, pharmacological ablation of microglia prevented the development of mechanical allodynia during RSD that corresponded with a reduction in inflammatory mediators associated with nociceptive signaling. Taken together, these findings provide significant insight into the neuroimmune interactions that mediate stress-related psychiatric disorders and chronic pain states. Furthermore, these studies may lead to the development of novel therapeutic strategies for the management of behavioral complications associated with stress.
John Sheridan (Advisor)
Jonathan Godbout (Committee Member)
Brian Foster (Committee Member)
Michelle Humeidan (Committee Member)
188 p.

Recommended Citations

Citations

  • Sawicki, C. (2020). Repeated Social Defeat Stress Promotes Reactive Brain Endothelium and Microglia-Dependent Pain Sensitivity [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1586338402925441

    APA Style (7th edition)

  • Sawicki, Caroline. Repeated Social Defeat Stress Promotes Reactive Brain Endothelium and Microglia-Dependent Pain Sensitivity. 2020. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1586338402925441.

    MLA Style (8th edition)

  • Sawicki, Caroline. "Repeated Social Defeat Stress Promotes Reactive Brain Endothelium and Microglia-Dependent Pain Sensitivity." Doctoral dissertation, Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1586338402925441

    Chicago Manual of Style (17th edition)