Mechanisms underlying addiction to cocaine after traumatic injury to the developing rodent brain

发育中的啮齿动物大脑创伤后可卡因成瘾的机制

基本信息

批准号：
9913381
负责人：
Ramona E. von Leden
金额：
$ 3.81万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-06 至 2020-12-04
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9913381
关键词：
4 year old Acute Acute Brain Injuries Addictive Behavior Adolescence Adolescent Adult Age Anatomy Animals Anti-Inflammatory Agents Behavior Behavioral Behavioral Paradigm Biochemical Brain Brain Injuries Carrier Proteins Child Childhood Childhood Injury Chronic Clinical Clinical Management Cocaine Cocaine Dependence Cocaine Users Corpus striatum structure Data Dependence Development Dopamine Dopamine Receptor Drug Addiction Electrophysiology (science)Female Foundations Genes Glial Fibrillary Acidic Protein High Prevalence Hippocampus (Brain)Histologic Immune Targeting Immune response Immunohistochemistry Infant Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Interleukin-1 Interleukin-1 Receptors Interleukin-1 beta Interleukin-6 Learning Life Ligands Link Measures Mediating Mediator of activation protein Memory Midbrain structure Modeling Molecular Neuroglia Neurons Neurotransmitters Nuclear Nucleus Accumbens Pathogenesis Pathway interactions Pharmaceutical Preparations Prefrontal Cortex Rattus Recovery Reporting Reverse Transcriptase Polymerase Chain Reaction Rewards Risk Risk Factors Rodent Self Administration Signal Pathway Signal Transduction Structure Substance abuse problem TNF gene Techniques Testing Time Toddler Traumatic Brain Injury Traumatic injury Tyrosine 3-Monooxygenase Up-Regulation Ventral Striatum Ventral Tegmental Area addiction age group age related aged astrogliosis behavioral pharmacology cocaine use cytokine disability dopamine transporter dopaminergic neuron drug of abuse high risk improved insight male neuroinflammation neuron loss postnatal preservation resilience sham surgery targeted treatment trait transmission process

项目摘要

Traumatic brain injury (TBI) is the leading cause of disability in children in the U.S., with the highest risk reported in infants and young children (0-4 years old). There is a high prevalence of previous TBI among cocaine users and an association between early age at time of TBI and cocaine use in adolescence. Thus, early age at time of TBI is an important risk factor for development of addiction. Here I will propose to study the relationship between injury to the rodent brain at postnatal day 21 (pnd21), an age that approximates the toddler-aged child, neuroinflammation, and addiction to cocaine at adolescence. Cocaine and other common drugs of abuse share a mechanistic link between increasing dopaminergic transmission in the mesolimbic and mesocortical pathways and addictive behavior. Dopaminergic neurons originate in the ventral tegmental area (VTA) of the midbrain, and project to the ventral striatum, including the nucleus accumbens (NAc), and the prefrontal cortex (PFC). TBI at pnd21 reduces dopaminergic signaling in the striatum and VTA at adulthood. Such a decreased dopaminergic state may increase the likelihood for sensitivity to addiction as a mechanism to restore dopamine. What remains unclear is whether disruption to this signaling is evident during the adolescent period, where there is an established high risk of substance abuse, and the extent to which immune responses, expressed within in the acutely injured brain, alter long-term addictive behaviors. The young brain shows a profound inflammatory response to TBI; we have found that interleukin-1 related signaling is upregulated in cortical and subcortical structures within the first week after injury at pnd21. I will determine if this upregulation likewise occurs in the reward pathways, a possibility that is reinforced by studies of TBI to the adolescent brain where there is an upregulation of IL-1 cytokines and factors in the cortex and NAc. I hypothesize that traumatic injury to the developing brain produces a robust early inflammatory response in the reward pathway that enhances addictive liability to cocaine at adolescence. To test this hypothesis, Aim 1 will determine if TBI at pnd21 leads to disruption of the reward pathway and enhanced addictive liability of cocaine during subsequent brain development, utilizing a self-administration model of cocaine addiction at adolescence and adulthood, and stereology to assess dopaminergic signaling in the reward pathways. Aim 2 will evaluate inflammatory signaling in the reward pathway in the acutely injured brain, and determine if IL-1 signaling contributes to addictive liability to cocaine at adolescence. Biochemical techniques will be used to profile inflammation in the reward pathway after early age TBI. Brain-injured animals will be acutely treated with an IL-1R antagonist or vehicle to assess impact of IL-1 on addictive liability at adolescence. The data generated in these aims will broaden our understanding of age-dependent vulnerability to TBI, including mechanistic insights into long-term maladaptive behaviors including drug addiction. Such findings will contribute to a platform for optimizing recovery in the brain injured child.

创伤性脑损伤 (TBI) 是美国儿童残疾的主要原因，据报告，婴儿和幼儿（0-4 岁）的风险最高。既往 TBI 患病率很高可卡因使用者的比例以及 TBI 时的年龄与青春期可卡因使用之间的关联。因此，TBI 发生时年龄较早是成瘾的一个重要危险因素。在此我将提议研究啮齿类动物出生后第 21 天 (pnd21) 大脑损伤之间的关系，该年龄约为幼儿、神经炎症和青春期可卡因成瘾。可卡因及其他常见的滥用药物与增加的多巴胺能传递之间存在机制联系中脑边缘和中皮质通路和成瘾行为。多巴胺能神经元起源于腹侧中脑的被盖区（VTA），并投射到腹侧纹状体，包括伏隔核（NAc）和前额皮质（PFC）。 pnd21 处的 TBI 减少纹状体和 VTA 中的多巴胺能信号传导成年时。这种多巴胺能状态的降低可能会增加对成瘾敏感的可能性恢复多巴胺的机制。目前尚不清楚的是，这种信号传导的破坏是否在青少年时期，药物滥用的风险很高，以及滥用药物的程度在严重受伤的大脑中表达的免疫反应会改变长期的成瘾行为。这年轻的大脑对 TBI 表现出严重的炎症反应；我们发现白细胞介素1相关信号传导 pnd21 损伤后第一周内皮质和皮质下结构中的表达上调。我会确定是否这种上调同样发生在奖赏途径中，对 TBI 的研究强化了这种可能性。青春期大脑的皮层和 NAc 中 IL-1 细胞因子和因子上调。我假设发育中的大脑受到创伤会产生强烈的早期炎症奖励途径中的反应增强了青春期可卡因的成瘾倾向。为了测试这个假设，目标 1 将确定 pnd21 处的 TBI 是否会导致奖励途径中断并增强利用自我管理模型研究可卡因在随后的大脑发育过程中的成瘾倾向青春期和成年期的可卡因成瘾，以及评估多巴胺能信号传导的体视学奖励途径。目标 2 将评估急性损伤大脑奖赏通路中的炎症信号传导，并确定 IL-1 信号传导是否会导致青春期可卡因成瘾。生化技术将用于分析早期 TBI 后奖励途径中的炎症。脑损伤的动物将用 IL-1R 拮抗剂或载体进行急性治疗，以评估 IL-1 对成瘾倾向的影响青春期。这些目标生成的数据将拓宽我们对年龄依赖性脆弱性的理解 TBI，包括对药物成瘾等长期适应不良行为的机制见解。这样的研究结果将有助于建立一个优化脑损伤儿童康复的平台。