Neurobiological basis of Depression as a Comorbidity in Epilepsy

抑郁症作为癫痫合并症的神经生物学基础

• 批准号: 7522938
• 负责人: ANDREY M MAZARATI
• 金额: $ 24.75万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-20 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7522938
• 关键词: Abbreviations; Acids; Animal Model; Animals; Behavioral; Biochemical; Biological Assay; Brain; Childhood; Chronic; Comorbidity; Data; Desire for food; Development; Disabled Persons; Disease; Eating; Epilepsy; Evolution; Experimental Models; Frequencies; Generalized Epilepsy; Goals; High Pressure Liquid Chromatography; Hippocampus (Brain); Hydroxyindoleacetic Acid; Incidence; Intake; Intervention; Metabolism; Modeling; Morbidity - disease rate; Nerve Degeneration; Neurobiology; Neuronal Injury; Neurons; Patients; Physiological; Pilocarpine; Plastics; Population; Predisposition; Property; Quality of life; Quantitative Autoradiography; Recurrence; Saccharin; Seizures; Serotonin; Serotonin Receptor 5-HT1A; Severities; Status Epilepticus; Stress; Swimming; Syndrome; Taste Perception; Temporal Lobe Epilepsy; Testing; Time; Tissues; Wistar Rats; base; behavior test; density; depression; design; effective therapy; experience; handicapping condition; improved; nerve supply; novel; pleasure; preference; psychosocial; public health relevance; research study; response; serotonin receptor; serotonin transporter; transmission process

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.

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）之间合并症的实验模型，并建立两种状态之间的机械联系。抑郁症已被确定为癫痫患者，尤其是小儿人群中最常见的精神病合并症。尽管抑郁症在缺乏和特发性全身性癫痫的动物模型中得到了很好的描述，但与TLE相关的抑郁症的实验模型很少。同样，没有关于TLE与抑郁之间相关性的实验数据。在实验研究中的这种空白是研究机制和发展抑郁症合作息合理治疗的障碍。该研究将检验以下假设：在癫痫患者中，抑郁症不一定取决于癫痫发作或神经退行性的程度，而是取决于网络兴奋性和癫痫发作的倾向的慢性增加。为了诱导TLE，两周历史的Wistar大鼠将遭受LICL和毛果皮状态癫痫持续状态（SE）。慢性癫痫状态的特征是通过其发生率，频率和严重程度来量化自发性癫痫发作，以及通过研究伴有孔中的尖峰的发生以及在海马中引起的后递送的特性来检查长期增加的兴奋性。 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 5-ht1a 5-羟色胺受体和5-羟色胺转运蛋白在海马中的血清素能神经）和定量自显影术。研究将在SE之后3周至1年之间在不同的时间点反复进行。癫痫状态和抑郁症的参数将在统计上相关，以确定哪种癫痫的标志对抑郁症的发展起了重要的作用。所获得的数据将有助于提高对机制的理解，并有助于发展这种新型合并疗法的有效疗法。公共卫生相关性：经常观察到抑郁症，并导致癫痫患者的生活质量降低。癫痫症基础的机制 - 相关抑郁症的理解很少，并且缺乏这种病情的有效疗法。拟议的研究旨在发展和表征实验动物中相关抑郁的模型。这种模型的存在将有助于了解癫痫患者的抑郁症的机制和发展抑郁症的治疗方法。