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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：
10754711
负责人：
Su Guo
金额：
$ 9.58万
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/10754711
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

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.

项目总结