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

创伤性脑损伤(TBI)是美国儿童残疾的主要原因， 报告的风险最高的是婴幼儿(0-4岁)。既往脑损伤的患病率很高 在可卡因使用者中，以及在脑外伤时的早期年龄和青春期使用可卡因之间的联系。 因此，脑外伤时的早期年龄是发展成瘾的重要危险因素。在这里，我将提议 研究啮齿动物出生后第21天(Pnd21)大脑损伤之间的关系。 幼儿、神经炎和青春期的可卡因成瘾。可卡因和其他 常见的滥用药物在增加多巴胺能传递之间存在机械联系 中脑边缘和中皮质通路与成瘾行为。多巴胺能神经元起源于腹侧 中脑被盖区(VTA)，投射到腹侧纹状体，包括伏隔核 (NAC)和前额叶皮质(PFC)。PND21区脑损伤减少纹状体和VTA中的多巴胺能信号 在成年时。这种降低的多巴胺能状态可能会增加对成瘾的敏感性，如 恢复多巴胺的机制。目前尚不清楚的是，这种信号的中断是否明显 青春期，药物滥用的风险很高，以及在多大程度上 在严重受损的大脑中表达的免疫反应会改变长期的成瘾行为。这个 年轻大脑对脑外伤表现出深刻的炎症反应；我们发现白细胞介素1相关信号 在损伤后的第一周内，在pnd21的皮质和皮质下结构中表达上调。我会决定是否 这种上调同样发生在奖励通路中，这种可能性因脑损伤对 青春期大脑，皮质和NAC中IL-1细胞因子和因子上调。我 假设对发育中的大脑的创伤性损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对可卡因的成瘾倾向。为了测试这一点 假设，目标1将确定在pnd21的脑损伤是否导致奖赏通路的中断和增强 在随后的大脑发育中，利用可卡因的自我给药模型，可卡因的成瘾倾向 青春期和成年期的可卡因成瘾和体视学评估多巴胺能信号 奖励路径。目的2将评估急性损伤脑中奖赏通路中的炎症信号， 并确定IL-1信号是否有助于青少年对可卡因的成瘾倾向。生化 技术将被用来描述早期脑外伤后奖赏通路中的炎症情况。脑损伤动物 将使用IL-1R拮抗剂或载体进行急性治疗，以评估IL-1对成瘾易感性的影响 青春期。在这些目标中产生的数据将扩大我们对年龄相关性脆弱性的理解 包括对包括吸毒成瘾在内的长期适应不良行为的机械性见解。是这样的 这些发现将有助于优化脑损伤儿童的康复平台。

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.