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 认知功能障碍是一种毁灭性的共病的条件与复发性癫痫发作，如阿尔茨海默氏症 疾病和癫痫，即使在没有癫痫的时期也会持续存在。我们最近发表了一篇关于 其原因是癫痫发作诱导齿状回（DG）表达FosB，FosB是一种转录因子， 表观遗传抑制了对可塑性和记忆至关重要的关键靶基因。FosB表达是 与癫痫患者和小鼠模型以及阿尔茨海默病的认知缺陷相关， 证明了癫痫发作时认知功能障碍的常见机制。我们的新研究 这表明FosB不仅作用于记忆相关的基因，它还抑制增强内在记忆的基因。 兴奋性，从而限制了整体DG兴奋性。这些发现表明，尿素诱导的FosB 表达是一把“双刃剑”，它限制了DG的兴奋性，但代价是可塑性和认知能力。 功能我们的目标是建立一个全面的了解功能域的调节， 海马，并确定新的策略，以改善认知，但维持调节神经元 在癫痫发作的情况下，如阿尔茨海默病和癫痫。我们以前使用 假设驱动的方法来确定海马中的CAMPFosB靶点，但也有必要获得一个 公正，全面的观点，在相关的条件下的ARFosB。为此，我们进行了ChIP- 测序以鉴定在充分表征的转基因小鼠的海马体中由cDNAFosB结合的所有基因 阿尔茨海默病模型（AD小鼠），表现出反复发作和高水平的ADFosB。在AD小鼠中， FosB与一个新的基因网络结合，这些基因参与神经元兴奋性的多个方面。许多这些 在用匹鲁卡品治疗的野生型小鼠的海马中， 癫痫的药理学模型。在野生型小鼠中，AAV介导的HSPFosB过表达降低了 而α-FosB的显性负性拮抗剂α-JunD则增加兴奋性。值得注意的是，长- 长期阻断AD小鼠DG中的FosB信号传导改变了其癫痫发作的表型， 非惊厥性到主要惊厥性，支持了典型的低兴奋性和稀疏性的理论， DG细胞的激活起到限制癫痫发生的过滤器或门的作用。我们的研究表明， 在复发性癫痫的神经元功能中的关键作用。通过以下方式了解机制 它与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 可能揭示新的治疗策略，以减少癫痫发生，同时改善认知。为此我们 将检查阿尔茨海默氏症小鼠和毛果芸香碱小鼠，以：1）研究️ FosB在控制阿尔茨海默氏症中的作用 DG的内在和网络兴奋性，2）识别和表征海马基因的库 被BFosB靶向以控制兴奋性，以及3）测试特定的BFosB靶基因是否是关键决定因素 DG兴奋性和认知的关系。

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