刺激反应行为策略（习惯化）是药物成瘾的主要行为表现，由于习惯化策略长期主导行为，存在目标导向策略和习惯化策略间转换失灵活。背侧纹状体Dorsal striatum DS ）被认为是调节行为策略的关键脑区。 D S 的两个关键亚区，背内侧纹状体（ D orsomedial Striatum D MS ）和背外侧纹状体 Dor solateralStriatum DLS ）分别参与调控目标导向和习惯化行为策略。但是，许多证据表明，单一亚区（ D LS 或 D MS ）对行为策略的调控作用存在明显的不一致性即研究发现 DMS 同样参与到习惯化行为的调控中，而 DLS 则可以调节训练早期目标导向行为表现。 DS 主要神经元为 GABA 能中型棘突神经元（ Medium Spine Neurons MSNs ），根据表达的多巴胺受体不同可以进一步分为特异性表达多巴胺 I 型 受体（ Dopamine D1 Receptor D1 ）的 D1 MSNs 和特异性表达多巴胺 II 型受体（ Dopamine D2 Receptor D2 ）的 D2 MSNs 。两类神经元常以相反的方式参与到奖赏、运动行为的调节中。最新研究提示， D S 内不同类型的神经元可能选择性调节行为策略。因此，结合上述 DS 亚区在行为策略中调控功能的不一致。我们推测， DS 的 DLS 和 DMS 的 D1 MSNs 和 D2 MSNs 活性改变可能是调控目标导向和习惯化行为策略的关键。为了验证这一假设，在创建基于行为策略检测的可卡因成瘾习惯化模型基础上 ，明确调控习惯化觅药行为表达的 DS 关键亚区；并利用转基因动物进一步探讨特异神经元亚型对行为策略的选择性调控作用。结果显示， DMS ，而不是 DLS ，在习惯化觅药行为表达时显著激活；此外，抑制 DMS 内 D2 MSNs 的活性阻断了习惯化觅药行为的表达，对目标导向行为无影响；而抑制 D1 MSNs 则对目标导向行为和习惯化觅药行为均没有影响。提示， DMS 脑区的 D2 MSNs 神经元特异性的在成瘾习惯化行为表达过程中可能发挥更关键的作用。该研究结果可在临床上干预药物线索驱动的自动化、强迫性觅药行为提供新的思路。
其他摘要
Drug addiction has long been taken as a maladaptive habit, which represents the imbalance between goal directed and stimulus response (habitual) behavior. The dorsal striatum (DS) plays a key role in mediating th e two action strategies, which is further divided into two distinct subregions: The dorsomedial striatum ( DMS and the dorsolateral striatum ( DLS )). The two regions regulate goal directed and habitual behavior respectively. However, evidence shows that there is an inconsistency in the roles of the DLS and DMS in regulating action strategies, suggesting that different types of neurons (D1 MSNs and D2 MSNs) in the DS may selectively involve in action strategies. Therefore, we hypothesize that D1 MSNs and D2 MS Ns in the specific subregions of the DS regulate goal directed and habitual behavior strategies, respectively. To test this hypothesis, we first established the cocaine seeking habit behavioral model, and based on that, we unraveled which DS subregions involved in cocaine seeking habits. Then we used transgenic rats to further explore the certain functions of D1 MSNs and D2 MSNs in behavioral strategies. The results showed that DMS, but not DLS, was significantly activated during the cue induced cocaine see king habits; In addition, inhibition of D2 MSNs in the DMS dampened the expression of cue induced cocaine seeking, while the same manipulation of D1 MSNs did not affect cocaine seeking habit. It is suggested that the D2 MSNs neurons in the DMS may play a m ore critical role in the cue induced cocaine seeking habit, thereby providing insights into clinical treatments in cue induced craving or even compulsive drug seeking behavior.
修改评论