Adolescent THC, microglial activation, neuroinflammation, and their long-term consequences

青少年 THC、小胶质细胞激活、神经炎症及其长期后果

基本信息

批准号：
8872290
负责人：
Kenneth Mackie
金额：
$ 19.5万
依托单位：
TRUSTEES OF INDIANA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8872290
关键词：
2-arachidonylglycerol Adolescence Adolescent Adult Affect Behavior Blinking Brain Breeding CNR1 gene Cannabidiol Cannabis Childhood Chronic Complex Data Development Disease Dose Drug usage Endocannabinoids Environment Environmental Risk Factor Enzyme-Linked Immunosorbent Assay Enzymes Etiology Family Female Future Gene Expression Profile Genetic Heritability Immigration Individual Infection Inflammation Inflammatory Ingestion Interleukin-6 Lead Life Male Adolescents Malnutrition Mass Spectrum Analysis Medial Mediating Mental disorders Messenger RNA Microglia Mitogen-Activated Protein Kinases Mus Nervous system structure Neurons Perinatal Phenotype Play Population Predisposition Prefrontal Cortex Prevalence Protein Isoforms Psychotic Disorders Public Health Rattus Receptor Protein-Tyrosine Kinases Risk Risk Factors Role Schizophrenia Series Severities Signal Transduction Stress Structure Synapses Synaptic Transmission THC exposure Tetrahydrocannabinol Time Transactivation Transcript Western Blotting Work anandamide conditioning critical period cytokine design early adolescence immunocytochemistry innovation lipid mediator male marijuana use mouse model neurodevelopment neuroinflammation neuronal excitability neuropsychiatry postnatal prenatal prevent public health relevance research study treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Schizophrenia is a common and debilitating psychiatric disease, often presenting late in the second decade of life. The etiology of schizophrenia is multifactorial, with both genetic and environmental components increasing an individual's risk to develop schizophrenia. Accumulating evidence suggests that schizophrenia develops following the accumulation of progressive "insults" to the developing nervous system-that is, schizophrenia is a neurodevelopmental disease. Thus, to reduce the societal and individual burden of schizophrenia it is important to identify, understand the mechanisms, and to limit these insults. Work over the last two decades has identified early, heavy adolescent Cannabis use as a risk factor for developing schizophrenia. As the prefrontal cortex is maturing during adolescence, and deficits in prefrontal cortex function are prominent in schizophrenia, it is logical to hypothesize that Cannabis adversely impacts the developing adolescent prefrontal cortex. The primary psychoactive component of Cannabis is delta-9-tetrahydrocannabinol (THC). While THC modulates synaptic transmission, it also affects neurodevelopment. In a recent study on the effect of THC on adolescent eye blink conditioning in rats, we made the intriguing observation that low dose adolescent THC impaired the acquisition of eye blink conditioning, and also activated cerebellar microglia. Interestingly, both the impaired eye blink conditioning and microglial activation were absent when THC was co- administered with cannabidiol (CBD), a bioactive, but not overtly psychoactive occasional component of cannabis. In pilot experiments we have replicated the finding that adolescent, low-dose THC activates microglia in the prefrontal cortex via CB1 cannabinoid receptors and increases IL-6 mRNA. The increase in IL- 6 was prevented by concurrent cannabidiol. These results lead us to propose the following innovative hypotheses: (1) THC activates microglial cells in the adolescent prefrontal cortex, which may lead to impaired synaptic pruning, with long lasting effects on synaptic structure. (2) CBD counteracts the effects of THC and serves a protective role. We will evaluate these hypotheses through a series of targeted experiments aimed at elucidating the role and extent of THC activation of microglial cells and their impact on prefrontal cortex development. This will be accomplished by completing two specific aims: 1. Does adolescent THC permanently alter the mPFC transcriptome? 2. Will cannabidiol suppress neuroinflammation produced by THC? Completing these specific aims will define the extent, duration, and consequences of microglial activation in the prefrontal cortex following adolescent THC administration. This will lay the groundwork for future studies that will examine the implications of THC-induced microglial activation on PFC neuronal network activity and PFC-mediated behaviors.

描述（由申请人提供）：精神分裂症是一种常见且使人衰弱的精神疾病，通常在生命的第二个十年中出现。精神分裂症的病因是多因素的，越来越多的证据表明，遗传和环境因素都会增加个体患精神分裂症的风险。精神分裂症是在神经系统发育过程中不断受到“侮辱”的积累之后形成的——也就是说，精神分裂症是一种因此，为了减轻精神分裂症的社会和个人负担，重要的是要确定、了解其机制并限制这些伤害，过去二十年的工作已确定青少年早期大量使用大麻是发生精神分裂症的危险因素。由于前额皮质在青春期成熟，并且前额皮质功能缺陷在精神分裂症中很突出，因此大麻对发育中的青少年产生不利影响是合乎逻辑的。大麻的主要精神活性成分是 delta-9-四氢大麻酚 (THC)，虽然 THC 调节突触传递，但它也会影响神经发育。观察发现，低剂量的青少年 THC 损害了眨眼调节能力的获得，并且还激活了小脑小胶质细胞。在试点实验中，我们重复了这一发现，即青少年低剂量 THC 通过 CB1 大麻素受体激活前额皮质中的小胶质细胞，并增加 IL-6 mRNA。同时使用的大麻二酚可阻止 IL-6 的增加。这些结果使我们提出以下创新假设：(1) THC 激活青少年前额皮质中的小胶质细胞。导致突触修剪受损，对突触结构产生长期持续影响 (2) CBD 抵消 THC 的影响并发挥保护作用。我们将通过一系列旨在阐明 THC 激活的作用和程度的有针对性的实验来评估这些假设。这将通过完成两个具体目标来实现：1. 青少年 THC 是否会永久改变 mPFC 转录组？ THC 产生的神经炎症？完成这些具体目标将确定青少年 THC 给药后前额皮质小胶质细胞激活的程度、持续时间和后果，这将为未来研究 THC 诱导的小胶质细胞激活对神经炎症的影响奠定基础。 PFC 神经网络活动和 PFC 介导的行为。