Cellular Sources Of Neuregulin 1 (NRG1) Regulating Neural Activity And Behavior

调节神经活动和行为的神经调节蛋白 1 (NRG1) 的细胞来源

基本信息

批准号：
9321914
负责人：
CLARE M BERGSON
金额：
$ 22.8万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9321914
关键词：
Affect Astrocytes Attenuated Behavior Brain Breeding Cell physiology Cells Chimeric Proteins Drug Design Enterobacteria phage P1 Cre recombinase Epilepsy Epileptogenesis Equilibrium ErbB4 gene Estrogen Receptors Exploratory Behavior Family Genes Glial Fibrillary Acidic Protein Glutamate Decarboxylase Goals Hippocampus (Brain)Hyperactive behavior Impairment Interneurons Knockout Mice Knowledge Learning LoxP-flanked allele Measures Memory Mus Neuregulin 1 Neurons Outcome Pain Parvalbumins Pathologic Patients Performance Play Population Process RNA Interference Receptor Protein-Tyrosine Kinases Role Schizophrenia Seizures Short-Term Memory Signal Transduction Slice Societies Source Synapses Synaptic Transmission Synaptic plasticity Tamoxifen Testing cell type cognitive enhancement cognitive function cost excitatory neuron executive function gamma-Aminobutyric Acid improved information processing insight knowledge base neuromechanism neurotrophic factor prepulse inhibition receptor relating to nervous system therapeutic target transmission process

项目摘要

Project Summary Schizophrenia (Sz) affects 1% of the population worldwide and places a costly and painful burden on patients, their families and society. Currently there are no treatments available to effectively rehabilitate Sz patients. The neurotrophic factor Neuregulin 1 (NRG1) is a promising therapeutic target because the gene is associated with Sz in various populations, and NRG1 levels are altered in Sz. NRG1 stimulates the ErbB family of tyrosine kinase receptors, including ErbB4, which is associated with Sz. NRG1 signaling via ErbB4 receptors expressed in parvalbumin (PV)-positive interneurons promotes neural processes important for executive functions which are impaired in Sz. A critical barrier to progress in improving treatment of Sz is a lack of understanding of whether the cells, which produce the NRG1 resulting in release of GABA or stimulation of gamma oscillations, also supply the NRG1 involved in suppression of LTP or seizure activity. Our goal is to improve the treatment of Sz by obtaining the information and understanding needed for designing drugs capable of quelling seizures without inhibiting neural mechanisms involved in learning and memory. Our central hypothesis is that different cellular sources of NRG1 differentially and selectively impact synaptic transmission, network activity and behavior, and that these unique cellular functions are potential mechanisms by which NRG1 could suppress seizures as well as promote network activity important for higher brain functions. Our objectives are to 1) determine the cell-type specific roles of neuronal and astrocytic NRG1 in GABA transmission, gamma oscillations, LTP, epileptogenesis, and Sz-relevant mouse behaviors and 2) provide clarification of the cellular sources of NRG1 involved in mechanisms regulating excitatory-inhibitory balance within local circuits, and facilitating transfer of information from hippocampus to cortex. Our expected outcomes include 1) knowledge of the cellular origins of NRG1 engaged during different states of synaptic and network activity, 2) improved understanding of the neuronal and astrocytic mechanisms underpinning NRG1 activation of ErbB4, and 3) new insights into the specific roles played by astrocytic and neuronal NRG1 in behaviors requiring cognitive functions often impaired in Sz. The impact of our findings will provide a stronger rationale for therapeutically targeting NRG1 during pathological conditions, as well as an improved knowledge base, which is needed for designing drugs capable of quelling seizures without inhibiting neural mechanisms involved in learning and memory. Aim 1 will test the hypothesis that NRG1 derived from principal neurons, interneurons and astrocytes differentially regulates excitatory and inhibitory synaptic transmission. Aim 2 will test the hypothesis that NRG1 derived from these three different cell types differentially regulate Sz-relevant behaviors.

项目概要精神分裂症 (Sz) 影响着全世界 1% 的人口，给患者带来了昂贵且痛苦的负担，他们的家庭和社会。目前尚无有效的治疗方法可以使 Sz 患者康复。这神经营养因子 Neuregulin 1 (NRG1) 是一个有前途的治疗靶点，因为该基因与不同人群中的 Sz，NRG1 水平随 Sz 的变化而变化。 NRG1 刺激酪氨酸 ErbB 家族激酶受体，包括与 Sz 相关的 ErbB4。通过 ErbB4 受体表达的 NRG1 信号传导小白蛋白 (PV) 阳性中间神经元促进对执行功能重要的神经过程 Sz 受损。改善 Sz 治疗进展的一个关键障碍是缺乏对以下方面的了解产生 NRG1 的细胞是否会导致 GABA 的释放或伽马振荡的刺激，还提供参与抑制 LTP 或癫痫发作活动的 NRG1。我们的目标是改善治疗 Sz 通过获取设计能够平息癫痫发作的药物所需的信息和理解不抑制参与学习和记忆的神经机制。我们的中心假设是 NRG1 的不同细胞来源会差异性地、选择性地影响突触传递、网络活动和行为，并且这些独特的细胞功能是 NRG1 可以发挥作用的潜在机制抑制癫痫发作并促进对高级大脑功能重要的网络活动。我们的目标是 1) 确定神经元和星形细胞 NRG1 在 GABA 传递中的细胞类型特异性作用，gamma 振荡、LTP、癫痫发生和 Sz 相关的小鼠行为，2) 提供细胞的澄清 NRG1 的来源涉及局部回路内兴奋抑制平衡的调节机制，以及促进信息从海马体到皮质的传递。我们的预期成果包括 1) 知识 NRG1 的细胞起源在突触和网络活动的不同状态下参与，2) 改善了解支持 NRG1 激活 ErbB4 的神经元和星形细胞机制，以及 3) 新深入了解星形胶质细胞和神经元 NRG1 在需要认知的行为中所发挥的具体作用 Sz 的功能经常受损。我们的研究结果的影响将为治疗提供更有力的理由在病理条件下靶向 NRG1，以及改进的知识库，这是设计能够平息癫痫发作而不抑制参与学习和学习的神经机制的药物记忆。目标 1 将检验 NRG1 源自主要神经元、中间神经元和星形胶质细胞的假设差异调节兴奋性和抑制性突触传递。目标 2 将检验 NRG1 的假设源自这三种不同细胞类型的细胞差异性地调节 Sz 相关行为。