Photopharmacological interrogation of presynaptic neuromodulation of cortico-amygdalar circuits

皮质杏仁核回路突触前神经调节的光药理学研究

基本信息

批准号：
10666359
负责人：
Joshua Levitz
金额：
$ 61.13万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10666359
关键词：
Acute Agreement Amygdaloid structure Anti-Anxiety Agents Anxiety Auditory Aversive Stimulus Behavior Behavior Control Behavioral Behavioral Mechanisms Brain Brain region Cells Chronic Chronic stress Clinical Data Complex Consensus Data Development Disease Drug Targeting Electrophysiology (science)Emotional Extinction Family Fiber Fright Future G-Protein-Coupled Receptors Genetic Genetic study Impairment Interneurons Learning Link Long-Term Depression Maps Measures Medial Mediating Mediator Metabotropic Glutamate Receptors Molecular Mus Nature Neurons Opsin Optics Pathway interactions Pattern Pharmacology Study Photometry Play Post-Traumatic Stress Disorders Prefrontal Cortex Process Property Regulation Role Shapes Signaling Molecule Slice Social Interaction Stress Structure Synapses Synaptic plasticity System Techniques Testing Viral acute stress anxiety treatment anxiety-related behavior avoidance behavior behavioral response behavioral study cell type comparative conditioned fear experimental study feeding genetic approach hippocampal pyramidal neuron in vivo insight metabotropic glutamate receptor 2 neural neuropsychiatric disorder neuroregulation novel novel strategies optogenetics pharmacologic photoactivation pre-clinical presynaptic rapid technique receptor response social somatosensory spatiotemporal synaptic inhibition therapeutically effective tool transcriptome sequencing treatment of anxiety disorders

项目摘要

PROJECT SUMMARY The basolateral amygdala (BLA) serves as a neural hub for the integration of various inputs from across the brain to, in turn, control fear and anxiety-related behaviors and the response to chronic stress. Given this central role in neuropsychiatric disease-relevant emotional processing, neuromodulatory G protein-coupled receptors (GPCRs) that can control BLA function have been proposed as targets for the treatment of anxiety disorders and post-traumatic stress disorder. However, due to the complexity of BLA circuits and the lack of tools for spatiotemporally and genetically precise manipulation of GPCRs in vivo, it remains difficult to understand how specific receptors in defined cell types or projections mediate their effects on BLA circuit function and behavior. Here we will focus on an understanding of how metabotropic glutamate receptor 2 (mGluR2) modulates anxiety and fear-related behaviors using recently developed genetically-targeted photopharmacology in conjunction with slice electrophysiology, behavior, fiber photometry and RNA sequencing. mGluR2 is a critical presynaptic G protein-coupled receptor (GPCR) which mediates both rapid synaptic inhibition and the induction of long-term depression (LTD), although connecting these dynamic synaptic processes to behavioral modulation has been challenging. Our preliminary mapping studies using a Grm2-Cre mouse have shown that mGluR2 is enriched in projections from the ventromedial prefrontal cortex (vmPFC) and posterior insular cortex (pIC) to the BLA, motivating our comparative analysis of these two projection classes. We will define the ability of mGluR2 in each projection to control the synaptic strength of cortical connection to BLA pyramidal neurons and interneurons and use our photopharmacological toolset to link presynaptic modulation to behavioral changes across a battery of measures of avoidance to aversive stimuli and auditory fear conditioning (aim 1, aim 2). We hypothesize that depending on the nature of the aversive stimulus (spatial, somatosensory, social) either inputs from the vmPFC or pIC will play primary roles in behavioral control. In aim 3, we will use a dual optogenetic and projection-targeted RNA sequencing approach to define the synaptic and molecular adaptations that occur in each pathway in response to chronic unpredictable stress. Such analysis should inform future studies of novel projection-defined drug targets that can have desired effects on different aspects of fear and anxiety. Together this project will introduce a novel approach to mapping the synaptic and circuit mechanisms of behavioral control by neuromodulatory GPCRs while providing new insights into neuromodulatory control of the BLA by presynaptic mGluR2.

项目概要基底外侧杏仁核（BLA）作为神经中枢，整合来自整个大脑的各种输入。反过来，大脑控制与恐惧和焦虑相关的行为以及对慢性压力的反应。鉴于这个中央在神经精神疾病相关情绪处理、神经调节 G 蛋白偶联受体中的作用可以控制 BLA 功能的 GPCR（GPCR）已被提议作为治疗焦虑症和创伤后应激障碍。然而，由于BLA电路的复杂性和缺乏工具在体内对 GPCR 进行时空和基因精确操作，仍然很难理解如何特定细胞类型或投射中的特定受体介导其对 BLA 回路功能和行为的影响。在这里，我们将重点了解代谢型谷氨酸受体 2 (mGluR2) 如何调节使用最近开发的基因靶向光药理学来治疗焦虑和恐惧相关行为结合切片电生理学、行为学、纤维光度测定和 RNA 测序。 mGluR2 是一个关键突触前 G 蛋白偶联受体 (GPCR)，介导快速突触抑制和诱导长期抑郁症（LTD），尽管将这些动态突触过程与行为调节联系起来一直具有挑战性。我们使用 Grm2-Cre 小鼠进行的初步作图研究表明，mGluR2 是富含从腹内侧前额叶皮层（vmPFC）和后岛叶皮层（pIC）到 BLA，激发了我们对这两个投影类别的比较分析。我们将定义 mGluR2 的能力在每个投射中控制皮质与 BLA 锥体神经元连接的突触强度中间神经元并使用我们的光药理学工具集将突触前调节与行为变化联系起来跨越一系列避免厌恶刺激和听觉恐惧调节的措施（目标 1，目标 2）。我们假设根据厌恶刺激的性质（空间、体感、社交）或者输入来自 vmPFC 或 pIC 的信号将在行为控制中发挥主要作用。在目标 3 中，我们将使用双重光遗传学和投影靶向 RNA 测序方法来定义突触和分子适应应对慢性不可预测压力的每条途径。这种分析应该为未来的小说研究提供信息预测定义的药物靶点可以对恐惧和焦虑的不同方面产生预期的效果。一起该项目将引入一种新方法来绘制行为控制的突触和电路机制神经调节 GPCR 的作用，同时提供突触前 BLA 神经调节控制的新见解 mGluR2。