Role of deltaFosB in hippocampal gene expression and function in neurological disease

deltaFosB 在神经系统疾病中海马基因表达和功能中的作用

• 批准号: 10394933
• 负责人: JEANNIE CHIN
• 金额: $ 59.46万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394933
• 关键词: Alzheimer' s Disease; Alzheimer' s disease model; Benchmarking; Biochemical; Biological; Brain; Calcium; Cells; ChIP-seq; Chloride Channels; Chromatin; Cognition; Cognitive deficits; Data; Dominant-Negative Mutation; Epigenetic Process; Epilepsy; Epileptogenesis; Exhibits; Gene Expression; Gene Targeting; Genes; Goals; Hippocampus (Brain); Impaired cognition; Intervention; Lead; Longevity; Mediating; Memory; Memory Loss; Modeling; Molecular; Motor Seizures; Mus; National Institute of Neurological Disorders and Stroke; Neurologic; Neurons; Pathologic; Pathway Analysis; Patients; Pharmacology; Phenotype; Pilocarpine; Play; Publishing; Recurrence; Regulation; Research; Role; Seizures; Signal Transduction; Specific qualifier value; Synaptic plasticity; Testing; Therapeutic; Transgenic Mice; Viral; Wild Type Mouse; Work; adverse outcome; antagonist; cognitive function; comorbidity; cost; dentate gyrus; gene function; gene network; improved; mouse model; nervous system disorder; neuronal excitability; novel; novel strategies; novel therapeutic intervention; overexpression; prevent; programs; public health relevance; theories; therapy design; transcription factor

Project Summary Cognitive impairment is a devastating co-morbidity of conditions with recurrent seizures, such as Alzheimer's disease and epilepsy, which persists even in seizure-free periods. We recently published that one critical reason for this is that seizures induce dentate gyrus (DG) expression of ∆FosB, a transcription factor that epigenetically suppresses key target genes that are crucial for plasticity and memory. ∆FosB expression is associated with cognitive deficits in patients and mouse models of epilepsy as well as Alzheimer's disease, demonstrating common mechanisms of cognitive dysfunction in conditions with seizures. Our new studies indicate ∆FosB acts on more than memory-related genes; it also represses genes that enhance intrinsic excitability, and thereby limits overall DG excitability. These findings indicate that seizure-induced ∆FosB expression is a “double-edged sword” that caps DG excitability, but at the cost of plasticity and cognitive function. Our goals are to build a comprehensive understanding of functional domains regulated by ∆FosB in the hippocampus, and identify novel strategies to improve cognition but maintain regulation of neuronal excitability in conditions with seizures, such as Alzheimer's disease and epilepsy. We previously used hypothesis-driven approaches to identify ∆FosB targets in hippocampus, but it was necessary to also obtain an unbiased, comprehensive view of ∆FosB in seizure-related conditions. To do so, we performed ChIP- sequencing to identify all genes bound by ∆FosB in the hippocampus of a well-characterized transgenic mouse model of Alzheimer's disease (AD mice) that exhibits recurrent seizures and high ∆FosB levels. In AD mice, ∆FosB bound to a novel network of genes involved in multiple aspects of neuronal excitability. Many of these genes were also bound by ∆FosB in hippocampus of wild-type mice treated with pilocarpine, a pharmacological model of epilepsy. In wild-type mice, AAV-mediated overexpression of ∆FosB decreased excitability whereas ∆JunD, a dominant negative antagonist of ∆FosB, increased excitability. Notably, long- term blockade of ∆FosB signaling in DG of AD mice changed the phenotype of their seizures from primarily nonconvulsive to primarily convulsive, supporting the theory that the typically low excitability and sparse activation of DG cells acts as a filter or gate that restricts epileptogenesis. Our work indicates ∆FosB plays critical roles in neuronal function in conditions with recurrent seizures. Understanding the mechanisms by which ∆FosB coordinately regulates expression of genes that control synaptic plasticity or neuronal excitability may reveal novel therapeutic strategies to reduce epileptogenesis while improving cognition. To this end, we will examine both Alzheimer's mice and pilocarpine mice to: 1) Investigate the role of ∆FosB in controlling intrinsic and network excitability of the DG, 2) identify and characterize the repertoire of hippocampal genes targeted by ∆FosB to control excitability, and 3) test whether specific ∆FosB target genes are key determinants of DG excitability and cognition.

项目摘要 认知障碍是阿尔茨海默氏症等反复发作的疾病的毁灭性并存。 疾病和癫痫，即使在无癫痫的时期也会持续存在。我们最近发表了一篇批评文章 其原因是癫痫发作诱导齿状回(DG)表达∆FosB，这是一种转录因子，可 表观遗传学抑制对可塑性和记忆至关重要的关键靶基因。∆FosB表达为 与癫痫和阿尔茨海默病患者和小鼠模型的认知缺陷有关， 展示了癫痫发作条件下认知功能障碍的常见机制。我们的新研究 表明∆FosB不仅作用于与记忆相关的基因；它还抑制增强内源性的基因 兴奋性，从而限制了DG的整体兴奋性。这些发现表明，癫痫诱导的∆FosB 表达是一把“双刃剑”，限制了DG的兴奋性，但代价是可塑性和认知性。 功能。我们的目标是全面了解∆FosB在 海马体，并找出新的策略来改善认知但维持神经元的调节 癫痫发作时的兴奋性，如阿尔茨海默病和癫痫。我们之前使用的是 假说驱动的方法来识别海马区的∆FosB靶点，但也有必要获得 公正、全面地观察∆FosB在癫痫相关情况下的情况。为了做到这一点，我们进行了芯片- 对一只特征良好的转基因小鼠的海马区∆FosB结合的所有基因进行测序 阿尔茨海默病(AD)小鼠的模型，表现出反复发作和高∆FosB水平。在AD小鼠中， ∆FosB结合了一个新的基因网络，涉及神经元兴奋性的多个方面。其中许多 在用匹罗卡品处理的野生型小鼠的海马区，基因也被∆FosB结合。 癫痫的药理模型。在野生型小鼠中，腺病毒介导的∆FosB过表达减少 兴奋性增强，而∆的主要负性拮抗剂∆-FosB增加兴奋性。值得注意的是，长久以来- 长期阻断AD小鼠DG内的∆FosB信号改变了其癫痫发作的表型 无抽搐到主要抽搐，支持典型的低兴奋性和稀疏性的理论 DG细胞的激活起着限制癫痫发生的过滤器或闸门的作用。我们的工作表明∆FosB发挥了作用 反复发作条件下神经元功能的关键作用。通过以下方式了解这些机制 哪个∆FosB协调调节控制突触可塑性或神经元兴奋性的基因的表达 可能会揭示新的治疗策略，在改善认知的同时减少癫痫的发生。为此，我们 将研究阿尔茨海默病小鼠和匹罗卡品小鼠：1)研究∆FosB在控制 DG的内在兴奋性和网络兴奋性，2)识别和表征海马区基因谱系 以∆FosB为靶点来控制兴奋性，以及3)测试特定的∆FosB靶基因是否为关键决定因素 DG的兴奋性和认知力。

项目成果

Can I Get a Witness? Using Vicarious Defeat Stress to Study Mood-Related Illnesses in Traditionally Understudied Populations.

• DOI: 10.1016/j.biopsych.2020.02.004
• 发表时间: 2020-09-01
• 期刊: Biological psychiatry
• 影响因子: 10.6
• 作者: Warren BL;Mazei-Robison MS;Robison AJ;Iñiguez SD
• 通讯作者: Iñiguez SD

Neuroimmunology of depression.

• DOI: 10.1016/bs.apha.2021.03.004
• 发表时间: 2021
• 期刊: Advances in pharmacology (San Diego, Calif.)
• 作者: Sarno E;Moeser AJ;Robison AJ
• 通讯作者: Robison AJ

Serum- and glucocorticoid-inducible kinase 1 activity reduces dendritic spines in dorsal hippocampus.

血清和糖皮质激素诱导激酶 1 活性减少背侧海马的树突棘。

• DOI: 10.1016/j.neulet.2020.134909
• 发表时间: 2020
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Steffke,EmilyE;Kirca,Deniz;Mazei-Robison,MichelleS;Robison,AlfredJ
• 通讯作者: Robison,AlfredJ

Corticothalamic network dysfunction and Alzheimer's disease.

• DOI: 10.1016/j.brainres.2017.09.014
• 发表时间: 2019-01-01
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Jagirdar R;Chin J
• 通讯作者: Chin J

Distinct patterns of dentate gyrus cell activation distinguish physiologic from aberrant stimuli.

齿状回细胞激活的不同模式区分生理刺激和异常刺激。

• DOI: 10.1371/journal.pone.0232241
• 发表时间: 2020
• 期刊: PloS one
• 影响因子: 3.7
• 作者: You,JasonC;Muralidharan,Kavitha;Fu,Chia-Hsuan;Park,Jin;Tosi,Umberto;Zhang,Xiaohong;Chin,Jeannie
• 通讯作者: Chin,Jeannie