Role of endocannabinoid signaling in a preference/aversion circuitry

内源性大麻素信号传导在偏好/厌恶电路中的作用

基本信息

批准号：
10608111
负责人：
Su Guo
金额：
$ 44.41万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2022-04-15 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608111
关键词：
Ablation Address Affect Animals Anti-Anxiety Agents Behavior Behavioral Brain Brain region CNR1 gene CNR2 gene Calcium Cannabinoids Cannabis policy Classification Clustered Regularly Interspaced Short Palindromic Repeats Complex Corticotropin-Releasing Hormone Cues Darkness Data Dependence Development Diagnosis Disease Drug Addiction Drug abuse Elements Endocannabinoids Enzymes Food Foundations Frequencies Functional Imaging Future Genes Genetic Genetic Models Glutamates Head Human Hypothalamic structure Image Immune Knock-in Life Ligands Light Lipids Mammals Molecular Monitor Motivation Motor Motor Activity Movement Mus Neurons Neuropeptides Neurotransmitters Outcome Pathway Analysis Pharmaceutical Preparations Pharmacotherapy Phenotype Policies Property Proteins Public Health RIPK1 gene Receptor Inhibition Regulation Research Resolution Resources Rewards Role Sensory Shapes Signal Pathway Signal Transduction Slide Specificity Stimulus Stress System Tail Testing Time Vision Zebrafish approach behavior avoidance behavior brain cell cell type computational platform drug of abuse endocannabinoid signaling exogenous cannabinoid fitness genetic regulatory protein imaging platform improved in vivo calcium imaging interest knockout animal model organism motivated behavior neural neural circuit optogenetics pharmacologic postsynaptic preference receptor response sensory stimulus social stressor tool treatment strategy

Ablation Address Affect Animals Anti-Anxiety Agents Behavior Behavioral Brain Brain region CNR1 gene CNR2 gene Calcium Cannabinoids Cannabis policy Classification Clustered Regularly Interspaced Short Palindromic Repeats Complex Corticotropin-Releasing Hormone Cues Darkness Data Dependence Development Diagnosis Disease Drug Addiction Drug abuse Elements Endocannabinoids Enzymes Food Foundations Frequencies Functional Imaging Future Genes Genetic Genetic Models Glutamates Head Human Hypothalamic structure Image Immune Knock-in Life Ligands Light Lipids Mammals Molecular Monitor Motivation Motor Motor Activity Movement Mus Neurons Neuropeptides Neurotransmitters Outcome Pathway Analysis Pharmaceutical Preparations Pharmacotherapy Phenotype Policies Property Proteins Public Health RIPK1 gene Receptor Inhibition Regulation Research Resolution Resources Rewards Role Sensory Shapes Signal Pathway Signal Transduction Slide Specificity Stimulus Stress System Tail Testing Time Vision Zebrafish approach behavior avoidance behavior brain cell cell type computational platform drug of abuse endocannabinoid signaling exogenous cannabinoid fitness genetic regulatory protein imaging platform improved in vivo calcium imaging interest knockout animal model organism motivated behavior neural neural circuit optogenetics pharmacologic postsynaptic preference receptor response sensory stimulus social stressor tool treatment strategy

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项目摘要

PROJECT SUMMARY The ability to seek reward and avoid potential threats is fundamental to the fitness and survival of all animals from early life stages. Our research aims to address circuit-wide mechanisms with cellular and molecular clarity employing larval zebrafish. As a vertebrate genetic model organism, zebrafish shares considerable similarity with mammals. In both mammals and larval zebrafish (See Preliminary data section), the lipid neurotransmitters endocannabinoids (eCB) and the neuropeptide hypothalamic corticotropin releasing factor (Hy CRF) are known to regulate motivated behaviors. However, an understanding of their roles circuit-wide at cellular resolution is currently lacking. Larval zebrafish with a relatively simple and transparent brain of ~100K neurons (compared to ~75 million in the mouse, and ~100 billion in the human brain) is well suited to address this question. New regulatory principles uncovered in simpler systems will lay foundation for studying more complex systems. Free-living with the need to hunt for food and avoid predators, larval zebrafish display readily observable approach and avoidance behaviors in response to environmental stimuli, drugs, or social cues. Here I propose to elucidate the role of eCB and Hy CRF, brain-wide at cellular resolution, in the context of light/dark preference, a fundamental motivated behavior conserved across species. Larval zebrafish avoid dark, which can be enhanced by stressors and alleviated by anxiolytics. Our preliminary data show that ablation of Hy CRF neurons ameliorates, whereas inhibition of the cannabinoid receptor CB1 enhances, dark avoidance. We have genetically disrupted major genes in the eCB signaling pathway, including CB1 (primarily neural) and CB2 (primarily immune) receptors, receptor-interacting proteins (CNRIP1a and CNRIP1b), eCB synthesis enzymes (e.g. DAGLa, DAGLb, ABHD4), and eCB degradation enzymes (MGLL, FAAH). These knockout animals are valuable resources for understanding signaling specificity by uncovering which receptors and ligands and associated regulatory proteins are involved in specific behavioral regulation. Furthermore, we have established brain-wide calcium imaging and computational platforms for examining the activity and plasticity of distributed neural circuits at cellular resolution. In this application, built on these preliminary data and our expertise in studying brain development and function employing zebrafish, we will test the hypothesis that eCB signaling regulates dark avoidance circuitry that involves Hy CRF neurons. We will gain circuit-wide understanding and uncover new cell types/molecules for future studies of circuit assembly and plasticity under stress or drug treatment in a highly accessible brain. Impact and Outcomes: If successful, this project will achieve, for the first time to our knowledge, a cellular resolution circuit-wide understanding of eCB signaling in relation to Hy CRF in a fundamental motivated behavior. Such improved understanding at the whole circuitry level shall lay foundation for informing future marijuana policy and for tackling disease states associated with perturbed CRF or eCB signaling.

项目摘要寻求奖励和避免潜在威胁的能力对于所有动物的健身和生存至关重要从早期阶段。我们的研究旨在解决细胞和分子清晰度的全电路机制使用幼虫斑马鱼。作为脊椎动物遗传模型生物，斑马鱼具有相当的相似性与哺乳动物。在哺乳动物和幼虫斑马鱼中（请参阅初步数据部分），脂质神经递质内源性大麻素（欧洲央行）和神经肽下丘脑皮质激素释放因子（HY CRF）是已知的调节动机行为。但是，了解他们在细胞分辨率上电路范围范围的角色的理解目前缺乏。幼虫斑马鱼具有〜100K神经元的相对简单和透明的大脑（比较在老鼠中约有7500万，在人脑中约有1000亿美元）非常适合解决这个问题。新的在简单系统中发现的监管原理将为研究更复杂的系统奠定基础。自由生活需要寻找食物并避免捕食者，幼虫斑马鱼很容易观察到响应环境刺激，毒品或社会提示的方法和回避行为。我在这里提出为了阐明欧洲央行和hy crf的作用，在光/黑暗偏好的背景下，在细胞分辨率上的脑部范围跨物种的基本动机行为。幼虫斑马鱼避免黑暗，这可以是受压力源增强，并被抗焦虑药缓解。我们的初步数据表明，HY CRF神经元的消融改善，而大麻素受体CB1的抑制会增强，避免黑暗。我们有遗传欧洲央行信号通路中破坏了主要基因，包括CB1（主要是神经）和CB2（主要是免疫）受体，受体相互作用蛋白（CNRIP1A和CNRIP1B），欧洲央行合成酶（例如 dagla，daglb，abhd4）和欧洲央行降解酶（MGLL，FAAH）。这些淘汰动物很有价值通过发现哪些受体和配体以及相关的配体来理解信号特异性的资源调节蛋白参与特定的行为调节。此外，我们已经建立了大脑钙成像和计算平台，用于检查分布式神经回路的活性和可塑性在细胞分辨率下。在此应用程序中，建立在这些初步数据以及我们研究大脑发育和功能方面的专业知识使用斑马鱼，我们将检验以下假设：欧洲央行信号传导调节黑暗避免电路涉及Hy CRF神经元。我们将获得范围内电路的理解并发现新的细胞类型/分子在高度可访问的大脑中，在压力或药物治疗下对电路组装和可塑性的未来研究。影响和结果：如果成功，该项目将首次实现我们所知的蜂窝在基本动机行为中，对与Hy CRF有关的欧洲央行信号的解决方案范围内的理解。在整个电路级别上的这种改善的理解应为未来的大麻政策提供奠定基础以及解决与扰动的CRF或欧洲央行信号相关的疾病状态。