It is widely-accepted by both clinicians and basic scientists that stress can trigger and worsen seizures in animal models and in patients with epilepsy through the actions of stress mediators. The body's physiological response to stress is mediated by the hypothalamic-pituitary-adrenal (HPA) axis. The majority of studies investigating the relationship between the HPA axis and epilepsy focus on the role of stress and the proconvulsant actions of corticosterone (cortisol in humans) and corticotropin-releasing hormone (CRH). Interestingly, our lab recently demonstrated that seizures themselves activate the HPA axis, forcing us to reevaluate the role of the HPA axis in epilepsy. These findings suggest that seizure-induced activation of the HPA axis may directly contribute to changes in seizure susceptibility. Further, hyperexcitability of the HPA axis is a hallmark feature of depression, implicating seizure-induced activation of the HPA axis in the comorbidity of depression and epilepsy. The overarching objective of the current study is to investigate the pathophysiological consequences of this seizure-induced activation of the HPA axis, investigating the impact on the process of epileptogenesis (Specific Aim 1), seizure activity in chronically epileptic mice (Specific Aim 2), and the role in the comorbid depression (Specific Aim 3).
These Aims will determine whether seizure-induced activation of the HPA axis is culpable in worsening seizure activity, associated pathology, and depression-like behaviors in chronically epileptic mice.

Public Health Relevance

Seizures activate the hypothalamic-pituitary-adrenal (HPA) axis, increasing circulating levels of the stress hormones, corticotropin-releasing hormone (CRH) and corticosterone, which are known to be proconvulsant and a prominent feature of depression. Thus, we propose that seizure-induced activation of the HPA axis may contribute to the process of epileptogenesis, increase seizure frequency, and increase depression-like behaviors in chronically epileptic mice. The overarching objective of this proposal is to investigate the pathological consequences of seizure-induced activation of the HPA axis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS102937-05
Application #
10130005
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Leenders, Miriam
Project Start
2017-06-01
Project End
2022-02-28
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
5
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Tufts University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Melón, Laverne; Hammond, Rebecca; Lewis, Mike et al. (2018) A Novel, Synthetic, Neuroactive Steroid Is Effective at Decreasing Depression-Like Behaviors and Improving Maternal Care in Preclinical Models of Postpartum Depression. Front Endocrinol (Lausanne) 9:703
Molaie, Amir M; Maguire, Jamie (2018) Neuroendocrine Abnormalities Following Traumatic Brain Injury: An Important Contributor to Neuropsychiatric Sequelae. Front Endocrinol (Lausanne) 9:176
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Hooper, Andrew; Paracha, Rumzah; Maguire, Jamie (2018) Seizure-induced activation of the HPA axis increases seizure frequency and comorbid depression-like behaviors. Epilepsy Behav 78:124-133
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MacKenzie, Georgina; O'Toole, Kate K; Moss, Stephen J et al. (2016) Compromised GABAergic inhibition contributes to tumor-associated epilepsy. Epilepsy Res 126:185-96
Lee, Vallent; MacKenzie, Georgina; Hooper, Andrew et al. (2016) Reduced tonic inhibition in the dentate gyrus contributes to chronic stress-induced impairments in learning and memory. Hippocampus 26:1276-1290
Sivakumaran, Sudhir; Maguire, Jamie (2016) Bumetanide reduces seizure progression and the development of pharmacoresistant status epilepticus. Epilepsia 57:222-32
Maguire, Jamie (2016) Neurosteroid Deficiency Associated With Epilepsy. Epilepsy Curr 16:108-9

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