Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


25763.pdf (28.37 MB)

ETD Abstract Container

Abstract Header

Glucocorticoid Mechanisms of Epileptogenesis and Comorbid Emotional Dysregulation

Chávez Wulsin, Aynara
http://orcid.org/0000-0002-4501-6845
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504787143992431

Abstract Details

2017, PhD, University of Cincinnati, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary.
Dysregulation of the hypothalamo-pituitary-adrenocortical (HPA) axis is common in temporal lobe epilepsy. It is characterized by excess glucocorticoid signaling, a process that is similar to what is seen in a subset of patients with major depression. Although activation of the glucocorticoid receptor (GR) is essential for survival, exposure to excess glucocorticoids can lead to disruption of key neuronal circuits, particularly in the hippocampus. This disruption may compromise physiological and behavioral adaptations to stress. It is well documented that chronic exposure to excess corticosterone in rodents may be linked to the development of depressive and anxiety-like phenotypes. These effects can be blocked by treatment with GR antagonists. In addition to modulating behavior, glucocorticoids have been shown to exhibit pro-convulsant effects in several animal models of epilepsy. Thus hyperactivity of the HPA axis may be a common pathological mechanism that may help explain the high incidence of psychopathologies in epilepsy. The underlying mechanisms and long-term consequences of HPA axis hyperactivity in epilepsy are currently unknown. Exposure to elevated glucocorticoids may be particularly deleterious in epilepsy, as it may exacerbate hippocampal pathologies, increase brain excitability (pro-convulsant) and raise susceptibility for the development of depressive and anxiety-like phenotypes. These data support a role for GR in epileptogenesis. The studies presented in this dissertation aimed at testing our underlying hypothesis, that chronic hyper-activation of GR occurs early in the disease and contributes to the comorbid development of epilepsy and depression/anxiety-like phenotypes. In chapter 2, I used the pilocarpine induced status epilepticus (SE) mouse model of TLE to characterize changes in stress-regulatory circuitry and emotional behavior associated with TLE. These studies demonstrate that SE results in hypersecretion of baseline glucocorticoids. This elevation persists through the chronic period of epilepsy and is accompanied by increased glucocorticoid secretion in response to acute stress. Importantly, epilepsy generates profound impairments in the recruitment of forebrain circuits that are key in regulating stress inhibition and emotional reactivity. In chapter 3 I utilized the glucocorticoid antagonist RU486 to block glucocorticoid receptor signaling in the hours following SE. Glucocorticoid blockade successfully normalizes corticosterone secretion and reduces hippocampal pathologies associated with epileptogenesis, including reduction of mossy cell loss and decreased ectopic placement of post-SE generated cells. These findings support a role for GR in epileptogenesis. In chapter 4 we utilized a newly-develop glucocorticoid receptor modulator C108297 to test whether modulation rather than complete blockade has beneficial potential in epileptogenesis. Results from this study demonstrate a disease modifying effect of C108297 in the hippocampus and promising reduction in seizure severity. The studies conducted as a part of this dissertation research may prove critical for understanding mechanisms of epileptogensis, and suggest the potential of GR as a therapeutic target for the treatment of epilepsy and its comorbidities.
Matia Solomon, Ph.D. (Committee Chair)
Steve Danzer, Ph.D. (Committee Member)
James Herman, Ph.D. (Committee Member)
Louis Muglia, M.D. (Committee Member)
Michael Privitera, M.D. (Committee Member)
160 p.
Neurology
glucocorticoids; temporal lobe epilepsy; status epilepticus; C108297; Mifepristone; mice

Recommended Citations

Citations

  • Chávez Wulsin, A. (2017). Glucocorticoid Mechanisms of Epileptogenesis and Comorbid Emotional Dysregulation [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504787143992431

    APA Style (7th edition)

  • Chávez Wulsin, Aynara. Glucocorticoid Mechanisms of Epileptogenesis and Comorbid Emotional Dysregulation. 2017. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504787143992431.

    MLA Style (8th edition)

  • Chávez Wulsin, Aynara. "Glucocorticoid Mechanisms of Epileptogenesis and Comorbid Emotional Dysregulation." Doctoral dissertation, University of Cincinnati, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504787143992431

    Chicago Manual of Style (17th edition)

ucin1504787143992431
95
© 2017, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.