Experimental Traumatic Brain Injury during Adolescence Enhances Cocaine Rewarding Efficacy and Dysregulates Dopamine and Neuroimmune Systems in Brain Reward Substrates
Experimental Traumatic Brain Injury during Adolescence Enhances Cocaine Rewarding Efficacy and Dysregulates Dopamine and Neuroimmune Systems in Brain Reward Substrates
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DOI：
10.1089/neu.2019.6472
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发表时间：
2019-08-21
影响因子：
4.2
通讯作者：
Ramirez, Servio H.
中科院分区：
文献类型：
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作者：
Cannella, Lee Anne;Andrews, Allison M.;Ramirez, Servio H.
虽然临床研究确认创伤性脑损伤(TBI)是物质使用障碍的危险因素，但其可能的潜在发病机制和特定年龄的影响仍不清楚。因此，这项研究的目的是检验这一假设，即在不断成熟的年龄，青春期脑外伤会改变奖赏途径的元素，导致对阈值以下剂量的可卡因的奖赏效应更敏感，该剂量的可卡因不会在幼稚、未受伤害的小鼠中引起显著的行为变化。具体地说，这些结果来自于对青春期(6周)或青壮年(8周)小鼠进行的受控脑损伤皮质撞击模型的组合，然后在2周后进行可卡因诱导的条件性位置偏爱试验。通过三维等值面绘制和体积图像分析，研究人员发现，脑外伤可以引起神经形态的变化，例如，在奖赏知觉和药物兴奋的处理过程中，大脑区域的树突复杂性降低和脊椎密度降低。此外，我们证明这些神经元的变化可能影响多巴胺相关基因的差异表达。我们的分析还提供了与年龄相关的免疫反应差异以及增强的小胶质细胞吞噬活性明显参与青少年脑外伤后神经元结构重建的证据。我们的研究表明，青春期的脑外伤，与多巴胺能系统的持续成熟相关，可能随后会增加成年后滥用可卡因的可能性。
Although clinical studies identify traumatic brain injury (TBI) as a risk factor for the development of substance use disorder, much remains unknown about the possible underlying pathogenesis and age-specific effects. Thus, the aim of this study is to test the hypothesis that at an age of ongoing maturation, adolescent TBI alters elements of the reward pathway, resulting in increased sensitivity to the rewarding effects of a subthreshold dose of cocaine that does not induce significant behavioral changes in naive, non-injured mice. Specifically, these results were derived from the combination of the controlled cortical impact model of TBI, performed on either adolescent (6 weeks) or young adult (8 weeks) mice, followed by the cocaine-induced conditioned place preference assay 2 weeks later. Using three-dimensional isosurface rendering and volumetric image analysis, TBI was found to induce neuromorphological changes such as decreased dendritic complexity and reduced spine density in brain regions essential for reward perception and processing of drug-induced euphoria. Further, we demonstrated that these neuronal changes may affect the differential expression of dopamine-associated genes. Our analysis also provided evidence for age-related differences in immune response and the distinct involvement of augmented microglial phagocytic activity in the remodeling of neuronal structures in the adolescent TBI brain. Our studies suggest that TBI during adolescence, a period associated with ongoing maturation of dopaminergic systems, may subsequently enhance the abuse liability of cocaine in adulthood.