Neurobiological basis of Depression as a Comorbidity in Epilepsy

项目描述（由申请人提供）：本项目旨在验证抑郁症与颞叶癫痫（TLE）共发病的实验模型，并建立两者之间的机制联系。抑郁症已被确定为癫痫患者中最常见的精神合并症，特别是在儿科人群中。虽然抑郁症在缺失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，没有关于TLE与抑郁症之间相关性的实验数据。这种实验研究的空白，不利于研究抑郁症- tle合发的机制，也不利于制定合理的治疗方法。这项研究将检验这样一个假设，即癫痫患者的抑郁并不一定取决于癫痫发作的存在或神经退行性的程度，而是取决于神经网络兴奋性的慢性增加和癫痫发作的易感性。为了诱导TLE，将2周龄Wistar大鼠给予LiCl和匹罗卡品癫痫持续状态（SE）。慢性癫痫状态将通过自发性癫痫发作的发生率、频率和严重程度来量化，并通过研究间期峰的发生和海马诱发的后放电特性来检测慢性兴奋性的增加。抑郁症将通过行为测试来表征(强迫游泳测试来测试在不可避免的压力情况下适应积极策略的能力；糖精摄入量来测试体验快乐的能力；5-羟色胺能传递的生化分析（HPLC检测海马组织中的5-羟色胺浓度，快速循环伏安法研究海马- 5-羟色胺能神经支配的强度），以及海马中5-HT1A 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。癫痫状态和抑郁的参数将在统计上相关，以便确定癫痫的哪些特征有助于抑郁症的发展。获得的数据将有助于提高对机制的理解，并有助于开发新的有效治疗这种合并症的方法。公共卫生相关性：抑郁症在癫痫患者中经常观察到，并有助于降低生活质量。癫痫相关抑郁的机制尚不清楚，缺乏有效的治疗方法。该研究的目的是在实验动物中建立癫痫相关抑郁模型并对其进行表征；这种模型的存在将有助于了解癫痫患者抑郁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.