PDF(Pubmed)
Abstract：
Systemic manipulations that enhance dopamine (DA) transmission around the time of fear extinction can strengthen fear extinction and reduce conditioned fear relapse. Prior studies investigating the brain regions where DA augments fear extinction focus on targets of mesolimbic and mesocortical DA systems originating in the ventral tegmental area, given the role of these DA neurons in prediction error. The dorsal striatum (DS), a primary target of the nigrostriatal DA system originating in the substantia nigra (SN), is implicated in behaviors beyond its canonical role in movement, such as reward and punishment, goal-directed action, and stimulus-response associations, but whether DS DA contributes to fear extinction is unknown. We have observed that chemogenetic stimulation of SN DA neurons during fear extinction prevents the return of fear in contexts different from the extinction context, a form of relapse called renewal. This effect of SN DA stimulation is mimicked by a DA D1 receptor (D1R) agonist injected into the DS, thus implicating DS DA in fear extinction. Different DS subregions subserve unique functions of the DS, but it is unclear where in the DS D1R agonist acts during fear extinction to reduce renewal. Furthermore, although fear extinction increases neural activity in DS subregions, whether neural activity in DS subregions is causally involved in fear extinction is unknown. To explore the role of DS subregions in fear extinction, adult, male Long-Evans rats received microinjections of either the D1R agonist SKF38393 or a cocktail consisting of GABAA/GABAB receptor agonists muscimol/baclofen selectively into either dorsomedial (DMS) or dorsolateral (DLS) DS subregions immediately prior to fear extinction, and extinction retention and renewal were subsequently assessed drug-free. While increasing D1R signaling in the DMS during fear extinction did not impact fear extinction retention or renewal, DMS inactivation reduced later renewal. In contrast, DLS inactivation had no effect on fear extinction retention or renewal but increasing D1R signaling in the DLS during extinction reduced fear renewal. These data suggest that DMS and DLS activity during fear extinction can have opposing effects on later fear renewal, with the DMS promoting renewal and the DLS opposing renewal. Mechanisms through which the DS could influence the contextual gating of fear extinction are discussed.
摘要：
在恐惧灭绝前后增强多巴胺（DA）传播的系统操作可以增强恐惧灭绝并减少条件性恐惧复发。先前的研究调查了DA增加恐惧灭绝的大脑区域，重点是起源于腹侧被盖区的中脑边缘和中皮层DA系统的目标。考虑到这些DA神经元在预测误差中的作用。背侧纹状体（DS），黑质纹状体DA系统起源于黑质（SN）的主要目标，牵涉到超出其在运动中的规范作用的行为，比如奖励和惩罚，以目标为导向的行动，和刺激-反应关联，但是DSDA是否有助于恐惧灭绝是未知的。我们已经观察到，在恐惧灭绝期间，化学遗传刺激SNDA神经元可以防止恐惧在与灭绝背景不同的背景下返回。一种称为更新的复发形式。SNDA刺激的这种作用被注射到DS中的DAD1受体（D1R）激动剂模拟，从而暗示DSDA在恐惧灭绝中。不同的DS子区域服务于DS的独特功能，但目前尚不清楚D1R激动剂在恐惧灭绝期间的作用位置，以减少更新。此外，尽管恐惧灭绝会增加DS子区域的神经活动，尚不清楚DS子区域的神经活动是否与恐惧灭绝有因果关系。为了探索DS子区域在恐惧灭绝中的作用，成人,雄性Long-Evans大鼠在恐惧消退前立即接受D1R激动剂SKF38393或由GABAA/GABAB受体激动剂麝香酚/巴氯芬组成的混合物的显微注射，和灭绝保留和更新随后被评估为无药物。虽然在恐惧灭绝期间DMS中增加D1R信号不会影响恐惧灭绝的保留或更新，DMS失活减少了后来的续订。相比之下,DLS失活对恐惧灭绝保留或更新没有影响，但是在灭绝期间DLS中D1R信号的增加会减少恐惧更新。这些数据表明，恐惧灭绝期间的DMS和DLS活动可能对以后的恐惧更新产生相反的影响，DMS促进更新，DLS反对更新。讨论了DS可能影响恐惧灭绝的上下文门控的机制。
