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（由适用提供）：精神分裂症是一种常见且令人衰弱的精神病，通常在生命的第二个十年后期出现。精神分裂症的病因是多因素的，遗传和环境成分都会增加个人发展精神分裂症的风险。积累的证据表明，在对发展中神经系统进行性“侮辱”的积累之后，精神分裂症会发展出来，即精神分裂症是一种神经发育疾病。这是为了减少精神分裂症的社会和个人燃烧，重要的是要识别，理解机制并限制这些事件。在过去的二十年中，工作已经确定了早期的青少年大麻用作发展精神分裂症的危险因素。由于青春期期间的前额叶皮层正在成熟，并且在精神分裂症中定义前额叶皮层功能很突出，因此假设大麻会不利影响发展中的青少年前额叶皮质的逻辑上是合乎逻辑的。大麻的主要精神活性成分是Delta-9-四氢大麻酚（THC）。尽管THC调节合成传播，但也会影响神经发育。在一项关于THC对大鼠青春期眼睛眨眼调节作用的最新研究中，我们进行了一个有趣的观察，即低剂量的青春期THC损害了眼睛眨眼调节的获取，还激活了小脑小胶质细胞。有趣的是，当THC与大麻二酚（CBD）共同管理时，眼睛眨眼调节性受损和小胶质细胞激活都不存在，这是一种生物活性，但不是大麻的精神活性偶尔成分。在试验实验中，我们复制了这样的发现，即青少年低剂量THC通过CB1大麻素受体激活前额叶皮层中的小胶质细胞并增加IL-6 mRNA。同时发生的大麻二醇可预防IL-6的增加。这些结果导致我们提出以下创新假设：（1）THC激活青少年前额叶皮层中的小胶质细胞，这可能导致突触修剪受损，对合成结构产生持久的影响。（2）CBD抵消了THC的影响并发挥了保护作用。我们将通过一系列旨在阐明小胶质细胞激活的作用和程度及其对前额叶皮层发育的影响，评估这些假设。这将通过完成两个具体目标来实现：1。青少年的THC是否会永久改变MPFC转录组？ 2。大麻二醇会抑制THC产生的神经炎症吗？完成这些特定目的将定义青少年THC给药后前额叶皮层中小胶质细胞激活的程度，持续时间和后果。这将为未来的研究奠定基础，该研究将研究THC诱导的小胶质细胞激活对PFC神经元网络活性和PFC介导的行为的影响。