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Anzela Niraula - Dissertation.pdf (3.8 MB)

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Blood-borne factors regulate monocyte function during psychosocial stress: A case of corticosterone and IL6

Niraula, Anzela
http://rave.ohiolink.edu/etdc/view?acc_num=osu1521546421236938

Abstract Details

2018, Doctor of Philosophy, Ohio State University, Neuroscience Graduate Studies Program.
Chronic exposure to stress triggers the development of prolonged anxiety that is attributed to a maladaptive immune response in the CNS and the periphery. The primary responses to stress in the mouse model of psychosocial stress, repeated social defeat (RSD), include activation of: microglia, the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal axis (HPS) axis. In brief, RSD promotes the release of bone marrow-derived inflammatory monocytes that are recruited to the brain during stress via chemotactic signals from microglia and increased cell adhesion molecules on the brain vasculature. These monocytes, expressing high levels of IL-1ß, activate the brain endothelial IL-1 receptors, triggering the onset of anxiety-like behavior. Chronic exposure to stress in humans induces resistance to the immune-suppressive effects of glucocorticoids, an effect recapitulated in mice exposed to RSD. This glucocorticoid resistance renders the inflammatory response unchecked during stress, resulting in physiological and behavioral impairments. Chronic exposure to stress has also been shown to impair neurogenesis that is associated with cognitive and affective deficits. We therefore first sought to examine the role of inflammatory signals on neurogenesis and behavior (Chapter 2). RSD induced spatial memory deficits and dampened the proportion of newly born neurons, without altering cell proliferation in the dentate gyrus. Furthermore, preventing inflammatory signaling via minocycline administration prevented the memory deficits but did not rescue impaired neurogenesis, indicating that these two effects are regulated via independent mechanisms. Corticosterone is the primary byproduct of HPA activation, and plays an important role in immune modulation. Therefore, we examined the effects of corticosterone on the immune responses to RSD in adrenalectomized mice (Chapter 3). Adrenalectomy did not alter monocyte production during stress but prevented the release of these cells from the bone marrow in a CXCL12-dependent manner. Glucocorticoid resistance and cell adhesion molecule expression in the brain vasculature were also prevented in the adrenalectomized mice, demonstrating that corticosterone is the direct cause of these downstream effects of stress. Findings from the adrenalectomy studies were paralleled in follow up studies using metyrapone, a corticosterone synthesis inhibitor. One of the downstream products of HPA activation and a strong predictor of symptom severity in mood disorders is IL6. Both adrenalectomized and metyrapone-treated mice showed attenuated plasma concentration of IL6. Therefore, we next examined the effects of RSD on immune regulation in IL6 knockout (KO) mice (Chapter 4). Despite seemingly normal immune responses (increased monocyte production and recruitment to the brain), IL6 knockout mice did not show enhanced IL-1ß expression in the brain or the development of anxiety-like behavior. Since inflammatory monocytes, with high IL-1ß expression, recruited to the brain are the triggers of anxiety after RSD, we examined the gene expression profile of the brain monocytes after RSD. Monocytes from the IL6KO mice had significantly lower levels of IL-1ß, MyD88 and Ly6C compared to the wildtype monocytes, indicating that although peripheral monocytes migrated to the brain in the IL6KO mice after stress, these cells did not propagate the inflammatory signaling necessary for the induction of anxiety-like behavior. Together, these findings provide important insight into regulation of monocyte function during stress, and its implications to behavioral deficits.
John Sheridan (Advisor)
Jonathan Godbout (Advisor)
177 p.
Neurosciences
stress; microglia; monocytes; immunology; corticosterone; IL-6

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Citations

  • Niraula, A. (2018). Blood-borne factors regulate monocyte function during psychosocial stress: A case of corticosterone and IL6 [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1521546421236938

    APA Style (7th edition)

  • Niraula, Anzela. Blood-borne factors regulate monocyte function during psychosocial stress: A case of corticosterone and IL6 . 2018. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1521546421236938.

    MLA Style (8th edition)

  • Niraula, Anzela. "Blood-borne factors regulate monocyte function during psychosocial stress: A case of corticosterone and IL6 ." Doctoral dissertation, Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1521546421236938

    Chicago Manual of Style (17th edition)

osu1521546421236938
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