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

• 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
• 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

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.

项目摘要 基底外侧杏仁核（BLA）是一个神经枢纽，用于整合各种输入 大脑反过来控制恐惧和与焦虑有关的行为以及对慢性压力的反应。考虑到这个中心 在神经精神病与疾病相关的情绪加工，神经调节性G蛋白偶联受体中的作用 （GPCR）可以控制BLA功能作为治疗焦虑症和 创伤后应激障碍。但是，由于BLA电路的复杂性以及缺乏工具 在体内对GPCR的时空和遗传上精确的操作，仍然很难理解如何 定义的细胞类型或投影中的特定受体介导了其对BLA电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）调节的理解 焦虑和与恐惧相关的行为使用最近开发的遗传靶向的光药理学 与切片电生理学，行为，纤维光度法和RNA测序的结合。 mglur2是关键 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连接到行为调制 一直具有挑战性。我们使用grm2-cre小鼠的初步映射研究表明，mglur2是 从腹侧前额叶皮层（VMPFC）和后岛皮层（PIC）中富含投影 BLA，激励我们对这两个投影类别的比较分析。我们将定义mglur2的能力 在每个投影中，以控制与BLA锥体神经元的皮质连接的突触强度和 中间神经元并使用我们的光电学工具集将突触前调节与行为变化联系起来 避免厌恶刺激和听觉恐惧条件的一系列措施（AIM 1，AIM 2）。我们 假设取决于厌恶刺激的性质（空间，体感，社交） 从VMPFC或PIC中，将在行为控制中起主要作用。在AIM 3中，我们将使用双光遗传学和 投影靶向的RNA测序方法来定义发生在中的突触和分子适应 每种途径响应慢性不可预测的压力。这样的分析应该为未来的新颖研究提供信息 投射定义的药物靶标可能会对恐惧和焦虑的不同方面产生预期的影响。一起 该项目将引入一种新的方法来绘制行为控制的突触和电路机制 通过神经调节性GPCR，同时通过突触前提供对BLA神经调节控制的新见解 mglur2。