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

基本信息

批准号：
10557182
负责人：
Vaishnav Krishnan
金额：
$ 21.82万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10557182
关键词：
Address Adult Anhedonia Anticonvulsants Anxiety Behavior Behavioral Bilateral Biomedical Research Brain region Chronic stress Clozapine Convulsants Development Diagnosis Disease Eating Electroencephalography Electrophysiology (science)Emotional Environment Epilepsy Etiology Freedom Frequencies Functional disorder Funding Future Generations Genes Genetic Glutamates Health Sciences Hippocampus Home Human Hyperactivity Hyperphagia Iatrogenesis Impact Seizures Impairment International Loss of Heterozygosity Major Depressive Disorder Measurement Medial Mediating Mediator Medicine Mental Depression Mentors Mentorship Molecular Monitor Moods Mus Neuroanatomy 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 spectrum disorders anxiety-related behavior autism spectrum disorder career college comorbid depression comorbidity depression model depressive symptoms design disability drinking drinking water emotional behavior experience experimental study feeding genetic approach 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

项目摘要

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.

项目摘要/摘要严重抑郁和焦虑的症状是导致患者总体拒绝的关键因素癫痫病，并与癫痫发作自由的速率显着降低。在癫痫发作开始之前或之后，许多HABE都支持了共同的病因疾病机制同时提高了癫痫发作的风险并导致情绪低落。这种合并症的神经解剖学和分子介质在这里较差划定的治疗策略可能会协调解决“ ICTAL”（癫痫发作 - 相关的）和“癫痫发作之间）和“癫痫发作之间）在各种膀胱综合症中不像。在颞叶癫痫中解决这一SSUE，这是成年人中最常见的癫痫的形式，使用遗传小鼠模型，分子工具和长期家庭笼子监测的组合这种原始的假设是海马腹侧CA1区域的超级运动协调提高癫痫发作的风险，并在AIM 1中产生与深度相关的症状。 emplay在小鼠中靶向的化学生成方法，以检查这些神经元中的多动症如何可能使用无线脑电图影响抑郁症相关的行为和癫痫发作阈值。候选人将研究如何有选择地抑制thibiting thibiting thitititins可能会增加癫痫发作和临时性颞叶癫痫和合并症的遗传有效的小鼠模型中的深度样症状抑郁量。与剥夺综合症一样，用仪器内的构造的小鼠测量旨在捕获多个行为的无偏长时间测量（> 23H）的家居笼室在最小化人类接触的同时，候选者是癫痫学家抑郁，焦虑和自闭症谱系障碍的模型将受到杰弗里博士的指导。 Noebels，国际知名的医师科学家，具有癫痫神经术的专业知识拥有独立NIH资金和K指导的良好记录。在贝勒医学院的设施中在生物医学研究领域建立了声誉。培训计划以癫痫精神病合并症领域的医师科学家的职业发展，以此为基础并具体纳入了无线脑电图中的基于间隙的培训和各种先进的培训统计技术。顾问。在癫痫发作和情感行为中扮演角色的途径，以及（ii）基于病理生理的新型途径旨在解决在发射异常谱系中癫痫的拒绝性的治疗策略。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

On the Digital Psychopharmacology of Valproic Acid in Mice.

DOI：
10.3389/fnins.2020.594612
发表时间：
2020
期刊：
Frontiers in neuroscience
影响因子：
4.3
作者：
Bass JS;Tuo AH;Ton LT;Jankovic MJ;Kapadia PK;Schirmer C;Krishnan V
通讯作者：
Krishnan V

Actigraphic correlates of neuropsychiatric symptoms in adults with focal epilepsy.

DOI：
10.1111/epi.17611
发表时间：
2023-06
期刊：
Epilepsia
影响因子：
5.6
作者：
通讯作者：

Home-cage behavior in the Stargazer mutant mouse.

DOI：
10.1038/s41598-022-17015-3
发表时间：
2022-07-27
期刊：
SCIENTIFIC REPORTS
影响因子：
4.6
作者：
Schirmer, Catharina;Abboud, Mark A.;Lee, Samuel C.;Bass, John S.;Mazumder, Arindam G.;Kamen, Jessica L.;Krishnan, Vaishnav
通讯作者：
Krishnan, Vaishnav

Depression and Anxiety in the Epilepsies: from Bench to Bedside.