Early life stress influences epilepsy outcomes in mice

IF 2.3 3区 医学 Q2 BEHAVIORAL SCIENCES Epilepsy & Behavior Pub Date : 2025-02-01 DOI:10.1016/j.yebeh.2024.110217
Emanuel M. Coleman, Maya White, Pantelis Antonoudiou, Grant L. Weiss, Garrett Scarpa, Bradly Stone, Jamie Maguire
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Abstract

Stress is a common seizure trigger that has been implicated in worsening epilepsy outcomes, which encompasses psychiatric and cognitive comorbidities and sudden unexpected death in epilepsy (SUDEP) risk. The neuroendocrine response to stress is mediated by the hypothalamic–pituitary–adrenal (HPA) axis and HPA axis dysfunction worsens epilepsy outcomes, increasing seizure burden, behavioral comorbidities, and risk for SUDEP in mice. Early life stress (ELS) reprograms the HPA axis into adulthood, impacting both the basal and stress-induced activity. Thus, we propose that ELS may influence epilepsy outcomes by influencing the function of the HPA axis. To test this hypothesis, we utilized the maternal separation paradigm and examined the impact on seizure susceptibility. We show that ELS exerts a sex dependent effect on seizure susceptibility in response to acute administration of the chemoconvulsant, kainic acid, which is associated with an altered relationship between seizure activity and HPA axis function. To further examine the impact of ELS on epilepsy outcomes, we utilized the intrahippocampal kainic acid model of chronic epilepsy in mice previously exposed to maternal separation. We find that the relationship between corticosterone levels and the extent of epileptiform activity is altered in mice subjected to ELS. We demonstrate that ELS impacts behavioral outcomes associated with chronic epilepsy in a sex-dependent manner, with females being more affected. We also observe reduced mortality (presumed SUDEP) in female mice subjected to ELS, consistent with previous findings suggesting a role for HPA axis dysfunction in SUDEP risk. These data demonstrate for the first time that ELS influences epilepsy outcomes and suggest that previous life experiences may impact the trajectory of epilepsy.

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早期生活压力影响小鼠癫痫的结果。
压力是一种常见的癫痫触发因素,与癫痫预后恶化有关,包括精神和认知合并症以及癫痫猝死(SUDEP)风险。神经内分泌对应激的反应是由下丘脑-垂体-肾上腺(HPA)轴介导的,HPA轴功能障碍会恶化癫痫结局,增加癫痫发作负担、行为合并症和小鼠发生SUDEP的风险。早期生活压力(ELS)将HPA轴重新编程到成年期,影响基础和压力诱导的活动。因此,我们认为ELS可能通过影响下丘脑轴的功能来影响癫痫的预后。为了验证这一假设,我们采用了母亲分离范式,并检查了癫痫发作易感性的影响。我们发现ELS对急性给药化学惊厥药kainic酸的发作易感性有性别依赖性,这与发作活动和HPA轴功能之间的关系改变有关。为了进一步研究ELS对癫痫预后的影响,我们使用了先前暴露于母亲分离的小鼠慢性癫痫海马内卡因酸模型。我们发现皮质酮水平和癫痫样活动程度之间的关系在受到ELS的小鼠中被改变。我们证明ELS以性别依赖的方式影响与慢性癫痫相关的行为结果,女性受到的影响更大。我们还观察到,经ELS治疗的雌性小鼠死亡率降低(假定为SUDEP),这与先前的研究结果一致,表明HPA轴功能障碍在SUDEP风险中起作用。这些数据首次证明ELS影响癫痫结局,并提示既往生活经历可能影响癫痫的发展轨迹。
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来源期刊
Epilepsy & Behavior
Epilepsy & Behavior 医学-行为科学
CiteScore
5.40
自引率
15.40%
发文量
385
审稿时长
43 days
期刊介绍: Epilepsy & Behavior is the fastest-growing international journal uniquely devoted to the rapid dissemination of the most current information available on the behavioral aspects of seizures and epilepsy. Epilepsy & Behavior presents original peer-reviewed articles based on laboratory and clinical research. Topics are drawn from a variety of fields, including clinical neurology, neurosurgery, neuropsychiatry, neuropsychology, neurophysiology, neuropharmacology, and neuroimaging. From September 2012 Epilepsy & Behavior stopped accepting Case Reports for publication in the journal. From this date authors who submit to Epilepsy & Behavior will be offered a transfer or asked to resubmit their Case Reports to its new sister journal, Epilepsy & Behavior Case Reports.
期刊最新文献
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