Endocannabinoids regulate microglia in developing brain

内源性大麻素调节大脑发育中的小胶质细胞

基本信息

批准号：
9028927
负责人：
MARGARET M. MCCARTHY
金额：
$ 34.73万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9028927
关键词：
2-arachidonylglycerol Adolescent Adult Agonist Amygdaloid structure Animal Model Anxiety Area Astrocytes Attitude Behavior Brain Brain region CNR1 gene CNR2 gene Cannabinoids Cannabis Cell Count Cells Cellular Structures Cognitive Date of birth Development Embryonic Development Emotional Endocannabinoids Enzymes Female Foundations Future Gonadal Steroid Hormones Hippocampus (Brain)Immune Immunohistochemistry Inflammation Injury Laboratory Rat Learning Legal Life Ligands Light Link Marijuana Medial Mediating Mediator of activation protein Memory Microglia Neonatal Nervous system structure Neuroglia Neurons Neurophysiology - biologic function Perception Phagocytosis Pharmaceutical Preparations Phenotype Play Pregnancy Pregnant Women Proliferating Rattus Receptor Activation Regulation Research Role Safety Sex Characteristics Site Social Behavior Social Change Source Spinal Cord Stress Synapses System TRPV1 gene Work Yolk Sac anandamide behavior test brain cell cell type emotional behavior fetal illicit drug use killings macrophage male marijuana use neuronal survival neuroregulation novel postnatal public health relevance pup receptor relating to nervous system sex social

项目摘要

DESCRIPTION (provided by applicant): Changing views on cannabis use subsequent to decriminalization, medicalization and in some cases legalization is likely to increase perceptions of safety for use by pregnant women. The endocannabinoids are the endogenous ligands for the CB1 and CB2 receptors on which components of cannabis act to alter neural function. The role of endocannabinoids in mediating brain development is poorly understood, yet these neural modulators are ubiquitously distributed and expressed relatively early in fetal life. Sex differences in the brain are also established early in life and endocannabinoids have been implicated as essential mediators of cell number in the developing amygdala in the laboratory rat animal model. More recently, microglia, specialized immune cells of the brain, have also been implicated as essential mediators of sex differences in the brain. These observations led us to explore whether endocannabinoids modulate microglial activity and resulted in the surprising discovery of sex differences in phagocytic activity in the developing amygdala that is mediated by CB1 (and possibly CB2) receptor activation. Even more surprising, identification of the contents of microglial phagocytic cups suggests the engulfment of both mature and newly born live neurons. Thus microglia appear to be controlling both cell number and phenotype in a sex-specific manner, with the source of the sex difference being endocannabinoid tone. We have also observed a sex difference in cell genesis in the hippocampus but in the opposite direction to that of the amygdala. Endocannabiniods are integral to hippocampal functioning, much of which is different in males and females, but whether this relates to cell genesis is unknown. We now propose to build on these novel observations via completion of three specific aims which will 1) fully characterize the effect of endocannabinoids on microglial phagocytic activity in the developing amygdala and hippocampus of male and female rat pups, 2) more thoroughly identify the cellular substrates being engulfed by microglia, and 3) establish a correlation between endocannabinoid mediated phagocytosis and behaviors which are controlled by the amygdala or hippocampus and impacted by sex. These include juvenile social play behavior, stress and anxiety responding and aspects of learning and memory. Approaches used include immunohistochemistry, cell birth dating, Flow cytometery, drug administration, and extensive behavioral testing. Completion of these studies will elucidate the role of endocannabinoids in development of two key brain areas, the hippocampus and amygdala, and provide the foundations for future work on cannabis use during pregnancy and its impact on the developing brain of both males and females.

说明（由申请人提供）：在非刑罪化、医疗化和某些情况下合法化之后，人们对大麻使用的看法可能会增加孕妇使用大麻的安全性认知。内源性大麻素是 CB1 和 CB2 受体的内源性配体。大麻改变神经功能的作用人们对内源性大麻素在调节大脑发育中的作用知之甚少，但这些神经调节剂在胎儿生命的早期就普遍分布和表达。大脑也在生命早期形成，并且内源性大麻素被认为是实验室大鼠动物模型中杏仁核发育中细胞数量的重要介质。最近，小胶质细胞（大脑的特殊免疫细胞）也被认为是细胞数量的重要介质。这些观察结果引导我们探索内源性大麻素是否会调节小胶质细胞的活性，并令人惊讶地发现发育中的杏仁核中由 CB1 介导的吞噬细胞活性存在性别差异。更令人惊讶的是，小胶质细胞吞噬杯内容物的识别表明，成熟的和新生的活神经元都被吞噬，因此小胶质细胞似乎以性别特异性的方式控制着细胞数量和表型。性别差异的根源是内源性大麻素音调，我们还观察到海马体细胞发生的性别差异，但与杏仁核的性别差异相反。海马功能，其中大部分在男性和女性中是不同的，但这是否与细胞发生有关尚不清楚，我们现在建议通过完成三个具体目标来建立这些新的观察结果，这将1）充分表征内源性大麻素对小胶质细胞的影响。雄性和雌性幼鼠发育中的杏仁核和海马体的吞噬活性，2）更彻底地识别被小胶质细胞吞噬的细胞底物，3）建立内源性大麻素介导的细胞基质之间的相关性由杏仁核或海马体控制并受性别影响的吞噬作用和行为，包括青少年的社交游戏行为、压力和焦虑反应以及学习和记忆方面的方法，包括免疫组织化学、细胞出生年代测定、流式细胞术、药物管理和。广泛的行为测试的完成将阐明内源性大麻素在海马体和杏仁核这两个关键大脑区域发育中的作用，并为以下研究奠定基础。未来关于怀孕期间使用大麻及其对男性和女性大脑发育的影响的工作。