Department of Neuroscience, University of Michigan, Ann Arbor, Michigan 48109.
Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425.
J Neurosci. 2019 Mar 13;39(11):2041-2051. doi: 10.1523/JNEUROSCI.2822-18.2018. Epub 2019 Jan 8.
Outputs from the nucleus accumbens (NAc) include projections to the ventral pallidum and the ventral tegmental area and subtantia nigra in the ventral mesencephalon. The medium spiny neurons (MSN) that give rise to these pathways are GABAergic and consist of two populations of equal number that are segregated by differentially expressed proteins, including D1- and D2-dopamine receptors. Afferents to the ventral pallidum arise from both D1- and D2-MSNs, whereas the ventral mesencephalon is selectively innervated by D1-MSN. To determine the extent of collateralization of D1-MSN to these axon terminal fields we used retrograde labeling in transgenic mice expressing tdTomato selectively in D1-MSN, and found that a large majority of D1-MSN in either the shell or core subcompartments of the accumbens collateralized to both output structures. Approximately 70% of D1-MSNs projecting to the ventral pallidum collateralized to the ventral mesencephalon, whereas >90% of mesencephalic D1-MSN afferents collateralized to the ventral pallidum. In contrast, <10% of dorsal striatal D1-MSNs collateralized to both the globus pallidus and ventral mesencephalon. D1-MSN activation is required for conditioned cues to induce cocaine seeking. To determine which D1-MSN projection mediates cued cocaine seeking, we selectively transfected D1-MSNs in transgenic rats with an inhibitory Gi-coupled DREADD. Activation of the transfected Gi-DREADD with clozapine-N-oxide administered into the ventral pallidum, but not into the ventral mesencephalon, blocked cue-induced cocaine seeking. These data show that, although accumbens D1-MSNs largely collateralize to both the ventral pallidum and ventral mesencephalon, only D1-MSN innervation of the ventral pallidum is necessary for cue-induced cocaine seeking. Activity in D1 dopamine receptor-expressing neurons in the NAc is required for rodents to respond to cocaine-conditioned cues and relapse to drug seeking behaviors. The D1-expressing neurons project to both the ventral pallidum and ventral mesencephalon, and we found that a majority of the neurons that innervate the ventral pallidum also collateralize to the ventral mesencephalon. However, despite innervating both structures, only D1 innervation of the ventral pallidum mediates cue-induced cocaine seeking.
伏隔核（NAc）的输出包括向腹侧苍白球和腹侧被盖区以及中脑腹侧的黑质的投射。产生这些途径的中等棘突神经元（MSN）是 GABA 能的，由两个数量相等的群体组成，这些群体通过差异表达的蛋白质（包括 D1-和 D2-多巴胺受体）分离。腹侧苍白球的传入纤维来自 D1-和 D2-MSN，而腹侧中脑则被 D1-MSN 选择性支配。为了确定 D1-MSN 对这些轴突末梢的分支程度，我们使用在转基因小鼠中转基因表达 tdTomato 选择性地在 D1-MSN 中表达的逆行标记，并发现 NAc 壳核或核部的大多数 D1-MSN 都向这两个输出结构分支。大约 70%的投射到腹侧苍白球的 D1-MSN 向腹侧中脑分支，而>90%的中脑 D1-MSN 传入纤维向腹侧苍白球分支。相比之下，<10%的背侧纹状体 D1-MSN 向苍白球和腹侧中脑都分支。D1-MSN 的激活是条件线索诱导可卡因寻求所必需的。为了确定哪种 D1-MSN 投射介导线索诱导的可卡因寻求，我们在转基因大鼠中转基因选择性转染 D1-MSN 与抑制性 Gi 偶联的 DREADD。用氯氮平-N-氧化物在腹侧苍白球中激活转染的 Gi-DREADD，但不在腹侧中脑，可阻断线索诱导的可卡因寻求。这些数据表明，尽管 NAc 的 D1-MSN 主要向腹侧苍白球和腹侧中脑分支，但只有 D1-MSN 对腹侧苍白球的支配对于线索诱导的可卡因寻求是必要的。伏隔核中 D1 多巴胺受体表达神经元的活动是啮齿动物对可卡因条件线索作出反应和重新寻求药物行为所必需的。表达 D1 的神经元投射到腹侧苍白球和腹侧中脑，我们发现，支配腹侧苍白球的大多数神经元也向腹侧中脑分支。然而，尽管支配着这两个结构，只有 D1 对腹侧苍白球的支配介导线索诱导的可卡因寻求。
