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The role of AC3 in neuronal activity and depression-related phenotype

AC3 在神经元活动和抑郁相关表型中的作用

基本信息

批准号：
9069521
负责人：
Xuanmao Chen
金额：
$ 18.03万
依托单位：
UNIVERSITY OF NEW HAMPSHIRE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9069521
关键词：
Acute Adenylate Cyclase Adult Affect Animals Area Atrophic Behavior Behavioral Biological Biological Markers Blood Blood Platelets Brain Breeding Calcium Cells Characteristics Cilia Cognition Cognitive Data Defect Dendrites Development Eating Electromyography Electrophysiology (science)Exhibits Fiber Optics Fluorescence Genes Health Heritability Hippocampus (Brain)Human Image Imaging Device Knock-out Knockout Mice Label Lead Location LoxP-flanked allele Major Depressive Disorder Mediating Membrane Potentials Memory Mental Depression Mental disorders Molecular Monitor Moods Mouse Strains Mus Nesting Behavior Neuraxis Neurons Newborn Infant Odors Patients Pattern Phenotype Population Prefrontal Cortex Prosencephalon Proteins Reporter Role Series Signal Transduction Sleep Sleep Architecture Slice Structure Subfamily lentivirinae Synapses Synaptic Transmission Synaptic plasticity Tamoxifen Testing Time Tissues Tomatoes Transcript Wit adenylyl cyclase III density endophenotype excitatory neuron genetic risk factor genome wide association study human disease in vivo in vivo imaging kainate knock-down morris water maze neurogenesis neuronal cell body neuronal excitability novel object recognition olfactory sensory neurons protein biomarkers pup research study response smoothened signaling pathway socioeconomics time use way finding

项目摘要

DESCRIPTION (provided by applicant): Although major depressive disorder (MDD) is heterogeneous and has very low heritability, a genome-wide association study in humans has implicated type III adenylyl cyclase (AC3, adcy3) in MDD. The expression level of human blood AC3 has also been considered as a MDD biomarker, but there is lack of supporting evidence from animal studies. My preliminary data demonstrate that AC3 conventional knockouts exhibit depression-like behaviors and many other related phenotypes including an altered sleeping pattern, supporting AC3 as a candidate depression gene. AC3 is predominantly expressed in primary cilia in the central nervous system (CNS) and is used as a protein marker for primary cilia throughout the brain. However, it is also distributed in other tissues so the pathophysiological role of AC3 in depression is unclear. To overcome the limitation of conventional knockouts and clearly dissect the functions of AC3 in the brain, I have generated an AC3 floxed mouse strain. This mouse strain has been crossed with the "EMX1-Cre" mouse strain to specifically ablate AC3 in excitatory neurons in the forebrain. It has also been bred wit a tamoxifen-inducible Cre line "UBC-Cre/ERT2" in order to knockdown AC3 temporally in adult mice. Moreover, I have prepared a GFP-AC3 lentiviral construct for an AC3-rescue experiment. I will combine molecular biological, morphological, behavioral, electrophysiological and in vivo imaging tools to study the functions of AC3 in the brain. Given that AC3 in olfactory cilia governs the excitation of olfactory sensory neurons, I will first determine if AC3 can similarly regulate neuronal electrical activity in CNS neurons. I will further investigate if AC3 modulates synaptic density and dendritic arborization. Since primary cilia are required for neurogenic Hedgehog signaling, I will test an alternative hypothesis that knockdown of AC3 leads to altered adult hippocampal neurogenesis. In addition, this project will further determine if specifically disrupting AC3 in the forebrain or temporally knockdown of AC3 in adult mice leads to depression-like behaviors in mice. Together, this study could increase our understanding of the functions of AC3 in the brain and has the potential to experimentally consolidate AC3 as a genetic risk factor for major depression.

描述（由申请人提供）：尽管重度抑郁症（MDD）是异质性的，遗传性非常低，但一项人类全基因组关联研究表明MDD中存在III型腺苷酸环化酶（AC 3，adcy 3）。人血液AC 3的表达水平也被认为是MDD生物标志物，但缺乏来自动物研究的支持证据。我的初步数据表明，AC 3常规敲除表现出抑郁样行为和许多其他相关的表型，包括改变睡眠模式，支持AC 3作为候选抑郁症基因。AC 3主要在中枢神经系统（CNS）的初级纤毛中表达，并用作整个脑中初级纤毛的蛋白质标记物。然而，它也分布在其他组织中，因此AC 3在抑郁症中的病理生理作用尚不清楚。为了克服传统敲除的局限性，并清楚地剖析AC 3在大脑中的功能，我已经产生了AC 3 floxed小鼠品系。该小鼠品系已与“EMX 1-Cre”小鼠品系杂交，以特异性消除前脑中兴奋性神经元中的AC 3。它还与他莫昔芬诱导型Cre系“UBC-Cre/ERT 2”一起繁殖，以便在成年小鼠中暂时敲低AC 3。此外，我还准备了用于AC 3拯救实验的GFP-AC 3慢病毒构建体。我将结合联合收割机、分子生物学、形态学、行为学、电生理学和活体成像等工具来研究AC 3在脑中的功能。鉴于嗅觉纤毛中的AC 3控制着在研究嗅觉感觉神经元的兴奋时，我将首先确定AC 3是否可以类似地调节CNS神经元中的神经元电活动。我将进一步研究AC 3是否调节突触密度和树突分支。由于初级纤毛是神经源性Hedgehog信号传导所必需的，我将检验另一种假设，即AC 3的敲低导致成年海马神经发生的改变。此外，该项目还将进一步确定在成年小鼠中特异性破坏前脑中的AC 3或暂时敲低AC 3是否会导致小鼠的抑郁样行为。总之，这项研究可以增加我们对AC 3在大脑中功能的理解，并有可能通过实验巩固AC 3作为重度抑郁症的遗传风险因素。