The Septohippocampal System: Regulation by Neurotrophins

中隔海马系统：神经营养素的调节

基本信息

批准号：
7341608
负责人：
Hermes H Yeh
金额：
$ 35.06万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-01 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7341608
关键词：
Acetylcholinesterase Inhibitors Actins Address Agonist Alzheimer&apos s Disease Appendix Atropine Carbachol Cell Nucleus Characteristics Cholinergic Agents Cholinergic Fibers Coculture Techniques Condition Data Detection Diagonal Band Nucleus Diagonal Band of Broca Event Experimental Models Figs - dietary Fire - disasters Gene Activation Gene Transfer Goals Green Fluorescent Proteins Growth Factor Overexpression Hippocampus (Brain)Immunohistochemistry Impaired cognition Injection of therapeutic agent Knowledge Lead Learning Light Medial Medical Molecular Molecular Profiling Morphology Mus Muscarinic Acetylcholine Receptor Muscarinics Neostigmine Nerve Degeneration Nerve Growth Factors Nervous System Physiology Nervous system structure Neurobehavioral Manifestations Neurons Neurotrophic Tyrosine Kinase Receptor Type 1 Numbers Parkinson Disease Pathway interactions Physiological Plastics Preparation Principal Investigator Property Proteins Purpose Rate Rattus Regulation Reporting Site Slice Synapses System Techniques Testing Therapeutic Time Transgenes Transgenic Mice Transgenic Model Wernicke-Korsakoff Syndrome Work base cholinergic cholinergic neuron density gain of function immunoreactivity indexing insight laser capture microdissection neurotransmission neurotrophic factor patch clamp programs promoter receptor relating to nervous system research study selective expression septohippocampal transcriptional coactivator p75 transmission process

项目摘要

DESCRIPTION (provided by applicant): Plastic changes in cellular and subcellular mechanisms are critical determinants of neurobehavioral manifestations; of nervous system function. We propose to investigate the regulation of the septohipppocampal (S-H) system by nerve growth factor (NGF). The central hypothesis is that an intrahippocampal gain of NGF function in mice enhances activity of septal cholinergic neurons in the short term and, in the long term, leads to synantic reorganization in both the medical septum/nucleus of Diagonal Band (MS/nDB) and hippocampus and, thereby neurotransmission along the S-H system. To test this hypothesis, we will use as experimental model transgenic mice harboring a targeted intrahippocampal gain of NGF function. The experiments, incorporating patch clamp recording, immunohistochemistry and PCR-Amplified Detection of Immunoreactivity (PADI), are organized into three specific aims. Specific Aim 1 will test the hypothesis that GABAergic MS/nDB neurons are under regulation of a muscarinic tone that is maintained by cholinergic activity in the MS/nDNB. Specific Aim 2 will test the hypothesis that a targeted activation and increase in the expression of NGF in the hippocampus leads to changes in the properties of MS/nDNB neurons that are consistent with an augmented muscarinic tone and thus activity alongthe S-H pathway. Specific Aim 3 will employ a septohippocampal coculture system to test the hypothesis that the targeted activation of NGF is time- and activity-dependent. Inherent in testing these hypothesis is the notion that specific cellular and molecular changes can be correlated with NGF activation. Thus, in addition to the electrophysiological experiments, candidate proteins will be analyzed by a PCR-based protein detection technique in single neurons isolated by laser capture microdissection. Overall, this project will contribute to our understanding of the cellular and molecular bases underlying NGF-induced plasticity in the nervous system and explore the value of targeted gene transfer as a potential therapeutic strategy to ameliorate the debilitating consequences of cognitive dysfunction as seen in a variety of neurodegenerative conditions.

描述（由申请人提供）：细胞和亚细胞机制的塑性变化是神经行为表现的关键决定因素；神经系统功能。我们建议研究神经生长因子（NGF）对隔海马（S-H）系统的调节。核心假设是，小鼠海马内 NGF 功能的增强在短期内增强了间隔胆碱能神经元的活性，从长远来看，导致医学间隔/对角带核 (MS/nDB) 和海马体，从而沿着 S-H 系统进行神经传递。为了检验这一假设，我们将使用具有目标海马内 NGF 功能增益的转基因小鼠作为实验模型。这些实验结合了膜片钳记录、免疫组织化学和 PCR 扩增免疫反应性检测 (PADI)，分为三个具体目标。具体目标 1 将检验以下假设：GABA 能 MS/nDB 神经元受到 MS/nDNB 中胆碱能活性维持的毒蕈碱音调的调节。具体目标 2 将检验以下假设：海马 NGF 表达的靶向激活和增加会导致 MS/nDNB 神经元特性的变化，这些变化与毒蕈碱音调增强以及沿 S-H 通路的活动一致。具体目标 3 将采用隔海马共培养系统来测试 NGF 的靶向激活具有时间和活性依赖性的假设。检验这些假设的固有观念是特定的细胞和分子变化可能与 NGF 激活相关。因此，除了电生理学实验之外，还将通过基于 PCR 的蛋白质检测技术对通过激光捕获显微切割分离的单个神经元进行分析。总体而言，该项目将有助于我们了解 NGF 诱导的神经系统可塑性的细胞和分子基础，并探索靶向基因转移作为潜在治疗策略的价值，以改善认知功能障碍的衰弱后果，如在各种疾病中所见。神经退行性疾病。