Functional disruption of stress modulatory circuits in a model of temporal lobe epilepsy.
Functional disruption of stress modulatory circuits in a model of temporal lobe epilepsy.
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DOI：
10.1371/journal.pone.0197955
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Herman JP
中科院分区：
文献类型：
--
作者：
Wulsin AC;Franco-Villanueva A;Romancheck C;Morano RL;Smith BL;Packard BA;Danzer SC;Herman JP
临床数据表明，神经内分泌应激反应在颞叶癫痫（TLE）患者的一个子集中长期失调，可能导致疾病进展和精神共病（如焦虑和抑郁）的发展。神经内分泌失调和精神共病是否反映了癫痫相关病理的直接影响，或癫痫患者特有的疾病负担的继发影响（即社会疏远，就业变化）尚不清楚。动物模型为分离这些因素提供了机会。因此，我们质疑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。将雄性FVB小鼠暴露于毛果芸香碱以诱导癫痫持续状态（SE）和随后自发复发性癫痫发作的发展。相对于对照组，在SE后1、7和10周，毛果芸香碱处理的小鼠中早晨基线皮质酮水平升高。同样，与对照小鼠相比，癫痫小鼠肾上腺重量增加。暴露于急性束缚应激导致高分泌的皮质酮30分钟后开始的挑战。解剖学分析显示，减少Fos的表达在边缘下和边缘前额叶皮层，腹侧下托和基底杏仁核以下的限制。在下丘脑室旁核、海马和中央杏仁核Fos免疫反应性无明显差异。为了评估情绪行为，第二组小鼠进行了一系列行为测试，包括蔗糖偏好、旷场、高架十字迷宫、24小时笼舍监测和强迫游泳。癫痫小鼠表现出增加的快感缺失行为，多动和焦虑样行为。总之，这些数据表明，癫痫小鼠发展HPA轴活动过度，并表现出行为功能障碍。内分泌和行为变化与调节压力抑制和情绪反应的前脑回路的招募受损有关。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。
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.
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