Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati School of Medicine, Cincinnati, Ohio, United States of America.
Department of Anesthesia, Cincinnati Children Hospital Medical Center, Cincinnati, Ohio, United States of America.
PLoS One. 2018 May 24;13(5):e0197955. doi: 10.1371/journal.pone.0197955. eCollection 2018.
Clinical data suggest that the neuroendocrine stress response is chronically dysregulated in a subset of patients with temporal lobe epilepsy (TLE), potentially contributing to both disease progression and the development of psychiatric comorbidities such as anxiety and depression. Whether neuroendocrine dysregulation and psychiatric comorbidities reflect direct effects of epilepsy-related pathologies, or secondary effects of disease burden particular to humans with epilepsy (i.e. social estrangement, employment changes) is not clear. Animal models provide an opportunity to dissociate these factors. Therefore, we queried whether epileptic mice would reproduce neuroendocrine and behavioral changes associated with human epilepsy. Male FVB mice were exposed to pilocarpine to induce status epilepticus (SE) and the subsequent development of spontaneous recurrent seizures. Morning baseline corticosterone levels were elevated in pilocarpine treated mice at 1, 7 and 10 weeks post-SE relative to controls. Similarly, epileptic mice had increased adrenal weight when compared to control mice. Exposure to acute restraint stress resulted in hypersecretion of corticosterone 30 min after the onset of the challenge. Anatomical analyses revealed reduced Fos expression in infralimbic and prelimbic prefrontal cortex, ventral subiculum and basal amygdala following restraint. No differences in Fos immunoreactivity were found in the paraventricular nucleus of the hypothalamus, hippocampal subfields or central amygdala. In order to assess emotional behavior, a second cohort of mice underwent a battery of behavioral tests, including sucrose preference, open field, elevated plus maze, 24h home-cage monitoring and forced swim. Epileptic mice showed increased anhedonic behavior, hyperactivity and anxiety-like behaviors. Together these data demonstrate that epileptic mice develop HPA axis hyperactivity and exhibit behavioral dysfunction. Endocrine and behavioral changes are associated with impaired recruitment of forebrain circuits regulating stress inhibition and emotional reactivity. Loss of forebrain control may underlie pronounced endocrine dysfunction and comorbid psychopathologies seen in temporal lobe epilepsy.
临床数据表明，在一部分颞叶癫痫（TLE）患者中，神经内分泌应激反应存在慢性失调，这可能导致疾病进展和焦虑、抑郁等精神共病的发生。神经内分泌失调和精神共病是反映与癫痫相关病理的直接影响，还是癫痫患者特有的疾病负担的间接影响（即社会隔离、工作变化）尚不清楚。动物模型提供了一个区分这些因素的机会。因此，我们研究了癫痫小鼠是否会重现与人类癫痫相关的神经内分泌和行为变化。雄性 FVB 小鼠接受匹罗卡品诱导癫痫持续状态（SE）和随后的自发性反复性癫痫发作。与对照组相比，SE 后 1、7 和 10 周，匹罗卡品处理的小鼠的清晨皮质酮基线水平升高。同样，与对照组相比，癫痫小鼠的肾上腺重量增加。急性束缚应激暴露导致应激开始后 30 分钟皮质酮分泌过度。解剖分析显示，束缚后边缘下皮层、前扣带回皮层腹侧亚区和基底杏仁核中的 Fos 表达减少。下丘脑室旁核、海马亚区或中央杏仁核中的 Fos 免疫反应无差异。为了评估情绪行为，第二组小鼠接受了一系列行为测试，包括蔗糖偏好、旷场、高架十字迷宫、24 小时笼内监测和强迫游泳。癫痫小鼠表现出快感缺失行为、过度活跃和焦虑样行为增加。这些数据表明，癫痫小鼠会出现 HPA 轴活性亢进，并表现出行为功能障碍。内分泌和行为变化与调节应激抑制和情绪反应的前脑回路的募集受损有关。前脑控制的丧失可能是颞叶癫痫中明显的内分泌功能障碍和共病精神病理学的基础。
