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

揭示颞叶癫痫遗传小鼠模型中癫痫-抑郁症共病的机制

• 批准号: 10341172
• 负责人: Vaishnav Krishnan
• 金额: $ 18.55万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341172
• 关键词: Address; Adult; Anhedonia; Anticonvulsants; Anxiety; Behavior; Behavioral; Bilateral; Biomedical Research; Brain region; Chronic stress; Clozapine; Development; Diagnosis; Disease; Eating; Electroencephalography; Electrophysiology (science); Emotional; Environment; Epilepsy; Etiology; Freedom; Frequencies; Functional disorder; Funding; Future; Generations; Genes; Genetic; Glutamates; Health Sciences; Hippocampus (Brain); Home; Human; Hyperactivity; Hyperphagia; Iatrogenesis; Impact Seizures; Impairment; International; Light; Major Depressive Disorder; Measurement; Medial; Mediating; Mediator of activation protein; Medicine; Mental Depression; Mentors; Mentorship; Molecular; Monitor; Moods; Mus; Neurons; Nucleus Accumbens; Pathway interactions; Patient Care; Patients; Physicians; Play; Prefrontal Cortex; Quality of life; Recurrence; Rice; Risk; Rodent; Role; Running; Scientist; Seizures; Structure; Subclinical Seizures; Symptoms; Syndrome; System; Techniques; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Training; United States National Institutes of Health; Universities; Viral; Virus; Voltage-Gated Potassium Channel; Withdrawal; anxiety-related behavior; autism spectrum disorder; base; career; college; comorbid depression; comorbidity; depression model; depressive symptoms; design; disability; drinking; drinking water; emotional behavior; experience; experimental study; feeding; hippocampal pyramidal neuron; improved; indexing; insight; instrument; loss of function mutation; mouse model; neurobiological mechanism; novel; professor; psychiatric comorbidity; psychosocial; receptor; side effect; social; social stigma; statistics; suicide rate; targeted treatment; tool; treatment strategy; wireless

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.

项目总结/摘要 重度抑郁症和焦虑症的症状是导致患者整体残疾的关键因素， 癫痫和与显著较低的癫痫发作自由率相关。由于癫痫患者的抑郁症 在癫痫发作之前或之后出现，许多人提出存在共同的病因学 疾病机制，同时提高癫痫发作的风险，并导致情绪障碍与快感缺乏。 这种合并症的神经解剖学和分子介质知之甚少。制定具体 改善这些疾病机制的治疗策略可以协调地解决“发作性”（癫痫发作， 相关）和“发作间期”（癫痫发作之间）残疾的各种癫痫综合征。这项建议 在颞叶癫痫的背景下处理这个问题，颞叶癫痫是成年人最常见的癫痫形式，使用 遗传小鼠模型、分子工具和长期笼舍监测的组合。中央 该建议假设是海马体腹侧CA 1区的神经元内的过度活跃 协同提高癫痫发作风险并产生抑郁相关症状。在目标1中，候选人将 在小鼠中采用靶向化学发生学方法来研究这些神经元内的过度活跃如何可能 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， 候选人将研究如何选择性地抑制这些神经元可能会改善癫痫负担和发作间期 抑郁样症状在颞叶癫痫和共病的遗传有效的小鼠模型 萧条量化与之相关的普遍性精神改变和植物神经紊乱 对于抑郁样综合征，小鼠行为的测量将在仪器内进行， 设计用于捕获多种行为的无偏长期测量（> 23小时）的笼室 变量，同时尽量减少人类接触。候选人是一名癫痫病学家，之前接受过小鼠 抑郁、焦虑和自闭症谱系障碍的模型。这份提案将由杰弗里博士指导 Noebels是一位国际知名的医学科学家，在癫痫的神经遗传学方面具有专业知识， 拥有独立NIH资助和K导师的良好记录。所有的实验都将在 在贝勒医学院的设施内，这是一所排名靠前的健康科学大学， 在生物医学研究领域建立了声誉。候选人的专业发展和 培训计划建立在癫痫精神共病领域的医生-科学家的职业生涯， 并特别结合了无线脑电图和各种先进的基于间隙的训练 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 顾问。这些目标的实现将为研究特定颞叶的功能提供新的思路 在癫痫发作和情绪行为中发挥作用的途径，以及（ii）基于新的病理生理学的 治疗策略，旨在解决整个发作-发作间期谱的癫痫残疾。