Genetic dissection of neural pathways for appetitive associative learning

 描述(由申请人提供)：多巴胺信号与奖赏的许多方面有关。尽管在这个重要的主题上有大量的文献，但区域和细胞类型特定的多巴胺信号是否以及如何在奖赏的特定方面发挥不同的作用仍然存在高度的争论。在纹状体中棘神经元(MSN)中，多巴胺D1和D2受体主要与cAMP通路偶联。我们近年来的研究表明，多巴胺通过cAMP的信号对皮质纹状体的可塑性是必不可少的。此外，腺酰环化酶5(AC5)缺陷(AC5KO)小鼠在食欲联想学习中受到严重损害。AC5是纹状体和伏隔核中传递多巴胺-cAMP信号的主要腺酰环化酶。在食欲联想学习中识别这样一个关键分子提供了一个独特的机会来执行精确的操作，并严格测试区域和细胞类型特定的多巴胺信号在食欲联想学习的特定方面的必要性和充分性。该领域最重要的问题之一是条件刺激(CS)既具有预测价值又具有激励价值。多巴胺参与了这两个过程。第二个尚未解决的重要问题是，缺乏与多巴胺信号缺乏有关的条件性接近反应可能是由于CS-奖赏联系的真正缺乏，或者是由于动物无法参与动机和运动系统并促进接近行为。本应用程序的目标1将解决这些问题。对于目标2，我们已经产生了一个条件AC5等位基因，它将允许我们使用Cre重组酶介导的基因缺失来实现特定区域和细胞类型的AC5基因缺失。这些研究将使我们能够测试AC5在支持特定行为过程中在这些细胞中的必要性。此外，我们还将在AC5KO背景上进行病毒介导的区域和细胞类型特异性AC5的重新表达。这将允许我们测试充分性，即测试 AC5在这个脑区，这种细胞类型足以支持特定的行为过程。

 DESCRIPTION (provided by applicant): Dopamine signaling has been implicated in many aspects of reward. Despite the vast literature on this important subject, it is still highly debate if and how regional and cell-type-specific dopamine signaling plays distinct roles in specific aspects of reward. Both dopamine D1 and D2 receptors are mainly coupled to the cAMP pathway in striatal medium spiny neurons (MSNs). Our studies in recent years indicate that dopamine signaling through cAMP is essential for corticostriatal plasticity. Moreover, the adenylyl cyclase type 5 (AC5) deficient (AC5KO) mice are severely impaired in appetitive associative learning. AC5 is the main adenylyl cyclase in the striatum and nucleus accumbens for dopamine-cAMP signaling. Identification of such a key molecule in appetitive associative learning provides a unique opportunity to perform precise manipulations and to rigorously test the necessity and sufficiency of regional and cell type specific dopamine signaling in specific aspects of appetitive associative learning. One of the most important issues in the field is that the conditioned stimulus (CS) acquires both predictive value and incentive value. Dopamine is implicated in both processes. A second important issue that has not been resolved is that the lack of conditioned approach responses linked to dopamine signaling deficiency could be due to a true lack of CS-reward association or due to the animal's inability to engage motivational and motor systems and promote the approach behavior. Aim 1 of this application will address these issues. For Aim 2, we have generated a condition AC5 allele that will allow us to achieve AC5 gene deletion in specific regions and cell types using the Cre recombinase mediated gene deletion. These studies will allow us to test necessity of AC5 in these cells in supporting specifi behavioral processes. In addition, we will perform virus mediated regional and cell type specific AC5 re-expression on the AC5KO background. This will allow us to test sufficiency, i.e., to test if AC5 in this brain region and this cell type is sufficient in supporting specific behavioral processes.