Neurobiological basis of Depression as a Comorbidity in Epilepsy

描述（由申请人提供）：该项目的目的是验证抑郁症和颞叶癫痫（TLE）之间共病的实验模型，并建立两种状态之间的机制联系。抑郁症已被确定为癫痫患者最常见的精神并发症，特别是在儿童人群中。虽然抑郁症已经在缺席和特发性全身性癫痫的动物模型中得到了很好的描述，但TLE相关抑郁症的实验模型却很少。同样，没有实验数据可用于TLE和抑郁症之间的相关性。这一实验研究的空白是研究抑郁症与TLE共病的机制和发展合理治疗的障碍。这项研究将检验这样一个假设，即癫痫患者的抑郁不一定取决于癫痫发作的存在或神经变性的程度，而是取决于网络兴奋性和癫痫发作易感性的慢性增加。为了诱导TLE，两周龄的Wistar大鼠将经受LiCl和匹鲁卡品癫痫持续状态（SE）。慢性癫痫状态的特征在于通过其发生率、频率和严重程度量化自发性癫痫发作，以及通过研究发作间期锋电位发生和海马中诱发的后放电的性质来检查慢性增加的兴奋性。抑郁症的特征将通过使用行为测试（强迫游泳测试，以检查在不可避免的压力情况下适应主动策略的能力;糖精摄入，以检查体验快乐的能力;食物摄入以检查食欲），β-肾上腺素能传递的生物化学测定（HPLC检测海马组织中的5-羟色胺浓度，快速循环伏安法研究中缝-海马多巴胺能神经支配的强度），海马5-HT 1A 5-羟色胺受体和5-羟色胺转运体的定量放射自显影。研究将在SE后3周至1年的不同时间点重复进行。癫痫状态和抑郁症的参数将在统计学上相关，以确定癫痫的哪些标志有助于抑郁症的发展。所获得的数据将有助于提高对机制的理解，并有助于开发这种共病的新的有效疗法。公共卫生相关性：抑郁症在癫痫患者中经常观察到，并导致生活质量下降。癫痫相关性抑郁症的发病机制目前还知之甚少，也缺乏有效的治疗方法.拟议的研究旨在开发和表征实验动物中癫痫相关抑郁症的模型;这种模型的存在将有助于理解癫痫患者中抑郁症的机制和开发治疗方法。

DESCRIPTION (provided by applicant): The objective of the project is to validate an experimental model of co-morbidity between depression and temporal lobe epilepsy (TLE), and to establish the mechanistic connection between the two states. Depression has been identified as the most frequent psychiatric co-morbidity in patients with epilepsy, particularly among pediatric population. While depression has been well described in animal models of absence and idiopathic generalized epilepsies, experimental models of TLE-associated depression are scarce. Likewise, no experimental data are available on the correlation between TLE and depression. Such a void in experimental research is a handicap to both studying the mechanisms and to developing rational therapy of depression-TLE co-morbidity. The study will test the hypothesis that in epilepsy patients depression does not necessarily depend on the presence of epileptic seizures or the extent of neurodegeneration, but rather on the chronic increase in network excitability and predisposition to seizures. To induce TLE, two weeks-old Wistar rats will be subjected to LiCl and pilocarpine status epilepticus (SE). Chronic epileptic state will be characterized by quantifying spontaneous seizures by their incidence, frequency and severity, as well as by examining chronically increased excitability through studying interictal spike occurrence, and properties of afterdischarge evoked in the hippocampus. Depression will be characterized by using behavioral tests (forced swim test to examine an ability to adapt active strategies in inescapable stressful situation; saccharin intake to examine an ability to experience pleasure; food intake to examine appetite), biochemical assays of serotonergic transmission (HPLC to detect serotonin concentration in hippocampal tissue and fast cyclic voltammetry to study the strength of raphe-hippocampal serotonergic innervation), and quantitative autoradiography of 5-HT1A serotonin receptors and serotonin transporter in the hippocampus. The studies will be performed repeatedly at different time points, between 3 weeks and 1 year after SE. The parameters of epileptic state and depression will statistically correlated, in order to identify which hallmarks of epilepsy are instrumental for the development of depression The obtained data will contribute to both improved understanding of the mechanisms and to the development of novel effective therapies of such co-morbidity. PUBLIC HEALTH RELEVANCE: Depression is frequently observed in, and contributes to a lowered quality of life in patients with epilepsy. The mechanisms that underlie epilepsy - associated depression are poorly understood, and effective therapies of this condition are lacking. The proposed study is purposed to develop and to characterize a model of epilepsy - associated depression in experimental animals; the existence of such a model will help to both understand the mechanisms and to develop treatments of depression in epilepsy patients.