It is widely-accepted by both clinicians and basic scientists that stress can trigger and worsen seizuresin animal models and in patients with epilepsy through the actions of stress mediators. The body'sphysiological response to stress is mediated by the hypothalamic-pituitary-adrenal (HPA) axis. The majority ofstudies investigating the relationship between the HPA axis and epilepsy focus on the role of stress and theproconvulsant 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 toreevaluate the role of the HPA axis in epilepsy. These findings suggest that seizure-induced activation of theHPA axis may directly contribute to changes in seizure susceptibility. Further, hyperexcitability of the HPA axisis a hallmark feature of depression, implicating seizure-induced activation of the HPA axis in the comorbidity ofdepression and epilepsy. The overarching objective of the current study is to investigate the pathophysiologicalconsequences of this seizure-induced activation of the HPA axis, investigating the impact on the process ofepileptogenesis (Specific Aim 1), seizure activity in chronically epileptic mice (Specific Aim 2), and the role inthe comorbidity with depression in epilepsy (Specific Aim 3).
These Aims will determine whether seizure-induced activation of the HPA axis is culpable in worsening seizure activity, associated pathology, anddepression-like behaviors in chronically epileptic mice.

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Seizures activate the hypothalamic-pituitary-adrenal (HPA) axis; increasing circulating levels of the stresshormones; corticotropin-releasing hormone (CRH) and corticosterone; which are known to be proconvulsantand a prominent feature of depression. Thus; we propose that seizure-induced activation of the HPA axis maycontribute to the process of epileptogenesis; increase seizure frequency; and increase depression-likebehaviors in chronically epileptic mice. The overarching objective of this proposal is to investigate thepathological consequences of seizure-induced activation of the HPA axis.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
High Priority, Short Term Project Award (R56)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Leenders, Miriam
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Tufts University
Schools of Medicine
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