UNRAVELLING THE MECHANISMS OF EPILEPSY-DEPRESSION COMORBIDITY IN A GENETIC MOUSE MODEL OF TEMPORAL LOBE EPILEPSY

项目摘要/摘要 严重抑郁和焦虑的症状是导致患者总体残疾的关键因素 癫痫和癫痫的自由率明显较低。因为癫痫患者的抑郁可以 发生在癫痫发作之前或之后，许多人提出了共同病因的存在 疾病机制，同时增加癫痫发作的风险，并导致情绪障碍和快感缺失。 这种共病的神经解剖学和分子介体知之甚少。开发特定的 改善这些疾病机制的治疗策略可能会协调解决“发作期”(癫痫- 在各种癫痫综合征中，癫痫发作间歇期(与癫痫相关)和“发作间歇期”残疾。这项建议 在颞叶癫痫(成人最常见的癫痫形式)的背景下解决这个问题，使用 结合遗传小鼠模型、分子工具和长期的家庭笼子监测。中环 这一建议的假设是，海马区腹侧CA1区神经元内的过度活动 协同增加癫痫发作的风险并产生与抑郁相关的症状。在目标1中，候选人将 在小鼠身上使用有针对性的化学发生方法来检查这些神经元内的过度活动如何 影响抑郁相关行为和癫痫发作阈值。在目标2中，使用无线脑电图仪， 候选人将研究选择性抑制这些神经元如何改善癫痫发作负担和发作间歇期。 遗传性有效的小鼠颞叶癫痫及其共病模型中的抑郁样症状 抑郁症。量化无处不在的精神运动改变和相关的神经植物性错乱 对于抑郁症综合征，将在仪器内进行老鼠行为的测量 家庭笼室旨在捕获对多个行为的无偏延长测量(&gt；23h) 变数，同时最大限度地减少人类接触。候选人是一名癫痫专家，曾受过老鼠方面的培训 抑郁症、焦虑症和自闭症谱系障碍的模型。这项提案将由杰弗里博士指导 在癫痫的神经遗传学方面有专长的国际知名内科科学家诺贝尔斯 在独立的NIH资助和K导师方面有着良好的记录。所有的实验都将进行 在贝勒医学院的设施内，一所排名很高的健康科学大学 在生物医学研究领域享有盛誉。候选人的职业发展和 培训计划是为了成为癫痫精神合并症领域的内科科学家， 并具体结合了基于GAP的无线脑电培训和各种高级 统计技术。莱斯大学统计学教授丹尼斯·考克斯博士将担任统计学家 顾问。这些目标的完成将为了解特定的颞叶的功能提供新的线索 在癫痫发生和情绪行为中发挥作用的通路，以及(Ii)基于新的病理生理学 旨在解决癫痫发作-发作间歇期残疾的治疗策略。

PROJECT SUMMARY/ABSTRACT Symptoms of major depression and anxiety are a critical contributor to the overall disability in patients with epilepsy and are associated with significantly lower rates of seizure freedom. Since depression in epilepsy can arise either before or after the onset of seizures, many have proposed the presence of shared etiological disease mechanisms that simultaneously elevate seizure risk and result in mood impairments with anhedonia. The neuroanatomical and molecular mediators of this comorbidity are poorly understood. Developing specific treatment strategies to ameliorate these disease mechanisms may coordinately address “ictal” (seizure- related) and “interictal” (in between seizures) disability in a variety of epilepsy syndromes. This proposal tackles this issue in the context of temporal lobe epilepsy, the most common form of epilepsy in adults, using a combination of genetic mouse models, molecular tools and long-term home cage monitoring. The central hypothesis of this proposal is that hyperactivity within neurons of the ventral CA1 region of the hippocampus coordinately elevate seizure risk and produce depression-related symptoms. In Aim 1, the candidate will employ a targeted chemogenetic approach in mice to examine how hyperactivity within these neurons may impact depression-related behavior and seizure threshold. In Aim 2, using wireless electroencephalography, the candidate will examine how selectively inhibiting these neurons might improve seizure burden and interictal depression-like symptoms in a genetically valid mouse model of temporal lobe epilepsy and comorbid depression. To quantify the pervasive psychomotor alterations and neurovegetative derangements associated with depression-like syndromes, measurements of mouse behavior will be conducted within instrumented home cage chambers designed to capture unbiased prolonged measurements (>23h) of multiple behavioral variables while minimizing human contact. The candidate is an epileptologist with prior training in mouse models of depression, anxiety and autism spectrum disorders. This proposal will be mentored Dr. Jeffrey Noebels, an internationally renowned physician-scientist with expertise in the neuroqenetics of epilepsy who has a strong track record of independent NIH funding and K mentorship. All experiments will be conducted within the facilities of the Baylor College of Medicine, a highly ranked health sciences university with an established reputation in the field of biomedical research. The candidate’s professional development and training plan builds towards a career as a physician-scientist in the field of epilepsy psychiatric comorbidities, and specifically incorporates gap-based training in wireless electroencephalography and various advanced statistical techniques. Dr. Dennis Cox, Professor of Statistics at Rice University, will serve as a statistical consultant. The completion of these aims will shed new light into the (i) function of specific temporal lobe pathways that play roles in seizure generation and emotional behavior, and (ii) novel pathophysiology-based treatment strategies that are designed to address the disability of epilepsy across the ictal-interictal spectrum.