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Functional Mapping of Dopamine-Dependent Fear Circuitry Through Advanced Genetic

通过先进遗传学绘制多巴胺依赖性恐惧回路的功能图谱

基本信息

批准号：
8914037
负责人：
LARRY S ZWEIFEL
金额：
$ 40.26万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-16 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8914037
关键词：
Acoustics Address Amygdaloid structure Anxiety Anxiety Disorders Attention Attenuated Behavior Behavioral Genetics Brain Brain region Calcium Canis familiaris Cells Code Cues Development Disease Dissection Dopamine Dopamine D1 Receptor Event Failure Fiber Optics Fluorescence Microscopy Fright Gene Silencing Gene Transfer Genes Genetic Goals Injection of therapeutic agent Knockout Mice Learning Life Experience Maps Mediating Memory Mental disorders Methods Molecular Biology Monitor Mus NR1 NMDA receptor Neurons Neurotransmitters Operative Surgical Procedures Pedunculopontine Tegmental Nucleus Post-Traumatic Stress Disorders Prefrontal Cortex Prevention Process Receptor Signaling Rewards Signal Transduction Site Stimulus Structure System Techniques Testing Time Viral Viral Vector Virus adeno-associated viral vector anxiety-like behavior anxiety-related behavior base brain tissue calcium indicator combinatorial conditioned fear conditioning dopaminergic neuron experience generalized anxiety hindbrain in vivo innovation insight interdisciplinary approach neural circuit novel optical imaging receptor expression recombinase reconstitution restoration selective expression tool traumatic event vector

项目摘要

DESCRIPTION (provided by applicant): Anxiety disorders, such as post-traumatic stress disorder (PTSD) are hypothesized to result from a failure of fear processing centers in the brain to form appropriate associative memories during a traumatic event. Emerging evidence suggests that the dopamine neurotransmitter system is important for associative fear learning, raising the intriguing possibility that disregulation of this system during a fearful experience could be a contributing factor in the development of some anxiety disorders. Consistent with this hypothesis, we recently discovered that genetic disruption of the phasic activation of dopamine neurons impairs Pavlovian fear conditioning in mice, resulting the manifestation of generalized anxiety- like behavior. To date, very little is known about the neural circuitry regulating, or regulated by phasic dopamine signaling. Our hypothesis is that a select excitatory input to dopamine neurons facilitates the phasic activation of a subset of these cells during a fearful experience. Subsequent phasic dopamine release into discrete brain regions engages the dopamine D1 receptor to facilitates the formation of memories related to the fearful event. To test this hypothesis, we will utilize a multidisciplinary approach involving mouse behavior, genetics, molecular biology, viral-mediated gene transfer, and in vivo fiber- optic imaging of dopamine neuron activity in freely behaving mice. We are innovating a technique that will allow for fibered fluorescence microscopy of real-time activity-dependent calcium dynamics within dopamine neurons projecting to specific targets during Pavlovian fear conditioning in mice that will allow us to generate a map of phasic dopamine neuron activation. Additionally, we are establishing a combinatorial viral vector based approach for the conditional inactivation of specific genes in neurons projecting to select targets that will allow us to map the critical inputs to dopamine neurons for fear conditioning. Finally, we have developed a method for conditional gene reconstitution that will allow us to generate a map of the minimal essential brain regions requiring D1R expression for fear conditioning. Together these techniques will help us to establish the precise neural circuitry of dopamine-dependent fear processing and will provide broadly useful tools for the dissection of behaviorally relevant circuits throughout the brain.

描述（由申请人提供）：焦虑症，例如创伤后应激障碍（PTSD），被假设是由于大脑中的恐惧处理中心在创伤事件期间未能形成适当的联想记忆而引起的。新的证据表明，多巴胺神经递质系统对于联想恐惧学习很重要，这提出了一个有趣的可能性，即在恐惧经历期间该系统的失调可能是某些焦虑症发展的促成因素。与这一假设相一致的是，我们最近发现多巴胺神经元阶段性激活的基因破坏会损害小鼠的巴甫洛夫恐惧调节，导致广泛性焦虑样行为的表现。迄今为止，人们对神经回路调节或受阶段性多巴胺信号传导的调节知之甚少。我们的假设是，在恐惧经历期间，对多巴胺神经元的选择性兴奋性输入促进了这些细胞子集的阶段性激活。随后阶段性多巴胺释放到离散的大脑区域，与多巴胺 D1 受体结合，促进与可怕事件相关的记忆的形成。为了检验这一假设，我们将利用多学科方法，涉及小鼠行为、遗传学、分子生物学、病毒介导的基因转移以及自由行为小鼠多巴胺神经元活动的体内光纤成像。我们正在创新一种技术，该技术将允许纤维荧光显微镜观察多巴胺神经元内实时活动依赖性钙动力学，在小鼠巴甫洛夫恐惧条件反射期间投射到特定目标，这将使我们能够生成阶段性多巴胺神经元激活图。此外，我们正在建立一种基于组合病毒载体的方法，用于有条件地灭活神经元中投射到选择目标的特定基因，这将使我们能够将关键输入映射到多巴胺神经元以进行恐惧调节。最后，我们开发了一种条件基因重建方法，使我们能够生成需要 D1R 表达来调节恐惧的最小必需大脑区域的图谱。这些技术将帮助我们建立多巴胺依赖性恐惧处理的精确神经回路，并将为剖析整个大脑的行为相关回路提供广泛有用的工具。