Psychiatric comorbidities in epilepsy contribute significantly to the disease burden of epilepsy, a problem which is now increasingly recognized by clinicians, scientists, patient advocacy groups and the federal government. Indeed, 40% of patients with epilepsy suffer from stress-related psychopathologies such as anxiety and depression. Animal models of epilepsy corroborate clinical observations, evident as an array of depressive and anxiety-like phenotypes. Together these observations are suggestive of a common etiological mechanism that may influence disease progression of epilepsy itself and of its comorbidities. Recent clinical and preclinical evidence suggests that abnormalities in the stress system may contribute to epilepsy development and progression, as well as the development of psychiatric comorbidities. To date, however, very few mechanistic studies have been conducted to elucidate the relationship between stress hormone dysregulation and the development of epilepsy or its comorbidities. Patients and animals with epilepsy exhibit chronic hyperactivity of the hypothalamic-pituitaryadrenocortical (HPA) axis, which regulates the stress response, resulting in chronically elevated glucocorticoids and over-activation of glucocorticoid receptors; a feature shared with major depression. Elevated glucocorticoids can damage neurons, increase brain excitability (pro-convulsant) and induce depressive symptoms in rodents and people. Thus we propose that HPA axis dysfunction in epilepsy contributes to disease progression and the development of psychiatric comorbidities. Our guiding hypothesis, therefore, is that the comorbid development of epilepsy and depression is mediated by chronic hyper-activation of the glucocorticoid stress receptor (GR). We will test this hypothesis utilizing the well-characterized pilocarpine mouse model of temporal lobe epilepsy. In these animals, we will temporally and conditionally delete the glucocorticoid receptor in forebrain regions implicated in epilepsy and stress-regulation. We predict that such temporal and region-specific glucocorticoid receptor deletion will have disease modifying effects in epilepsy, evident as reduced seizures and reduced comorbid depressive-like behaviors. These studies will lay the groundwork for developing a mechanistic understanding of the relationship between stress and epilepsy, and will aid in the development of novel therapies.

Public Health Relevance

Stress hormones are dramatically increased during the development of epilepsy, and are chronically dysregulated after the disease develops. The experiments outlined in this application seek to understand the mechanisms by which the stress circuitry is involved in epileptogenesis and the development of depression and anxiety in epilepsy. Our efforts have the potential to lead to entirely new approaches to treat epilepsy and its psychiatric comorbidities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30NS095578-04
Application #
9544339
Study Section
Neurological Sciences Training Initial Review Group (NST)
Program Officer
Leenders, Miriam
Project Start
2015-09-30
Project End
2019-09-29
Budget Start
2018-09-30
Budget End
2019-09-29
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Psychiatry
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Wulsin, Aynara C; Franco-Villanueva, Ana; Romancheck, Christian et al. (2018) Functional disruption of stress modulatory circuits in a model of temporal lobe epilepsy. PLoS One 13:e0197955
Nguyen, Elizabeth T; Streicher, Joshua; Berman, Sarah et al. (2017) A mixed glucocorticoid/mineralocorticoid receptor modulator dampens endocrine and hippocampal stress responsivity in male rats. Physiol Behav 178:82-92
Wulsin, Aynara C; Wick-Carlson, Dayna; Packard, Benjamin A et al. (2016) Adolescent chronic stress causes hypothalamo-pituitary-adrenocortical hypo-responsiveness and depression-like behavior in adult female rats. Psychoneuroendocrinology 65:109-17
Herman, James P; McKlveen, Jessica M; Ghosal, Sriparna et al. (2016) Regulation of the Hypothalamic-Pituitary-Adrenocortical Stress Response. Compr Physiol 6:603-21
Wulsin, Aynara C; Herman, James P; Danzer, Steve C (2016) RU486 Mitigates Hippocampal Pathology Following Status Epilepticus. Front Neurol 7:214
Wulsin, Aynara C; Solomon, Matia B; Privitera, Michael D et al. (2016) Hypothalamic-pituitary-adrenocortical axis dysfunction in epilepsy. Physiol Behav 166:22-31
Solomon, Matia B; Loftspring, Matthew; de Kloet, Annette D et al. (2015) Neuroendocrine Function After Hypothalamic Depletion of Glucocorticoid Receptors in Male and Female Mice. Endocrinology 156:2843-53
Solomon, Matia B; Wulsin, Aynara C; Rice, Taylor et al. (2014) The selective glucocorticoid receptor antagonist CORT 108297 decreases neuroendocrine stress responses and immobility in the forced swim test. Horm Behav 65:363-71
Solomon, M B; Furay, A R; Jones, K et al. (2012) Deletion of forebrain glucocorticoid receptors impairs neuroendocrine stress responses and induces depression-like behavior in males but not females. Neuroscience 203:135-43
Wulsin, Aynara C; Herman, James P; Solomon, Matia B (2010) Mifepristone decreases depression-like behavior and modulates neuroendocrine and central hypothalamic-pituitary-adrenocortical axis responsiveness to stress. Psychoneuroendocrinology 35:1100-12