Genetic dissection of neural pathways for appetitive associative learning

 描述（由申请人提供）：多巴胺信号传导涉及奖励的许多方面。尽管关于这个重要主题的大量文献，但区域和细胞类型特异性多巴胺信号是否以及如何在奖励的特定方面发挥独特作用仍然存在很大争议。多巴胺D1和D2受体主要与纹状体中型棘神经元（MSN）中的cAMP通路偶联。我们近年来的研究表明，多巴胺信号通过cAMP是必不可少的皮质纹状体可塑性。此外，腺苷酸环化酶5型（AC 5）缺陷（AC 5 KO）小鼠的食欲联想学习严重受损。AC 5是纹状体和脑桥核中多巴胺-cAMP信号传导的主要腺苷酸环化酶。在食欲联想学习中识别这样的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异性多巴胺信号传导在食欲联想学习的特定方面的必要性和充分性。条件刺激具有预测价值和激励价值是该领域的重要问题之一。多巴胺参与了这两个过程。尚未解决的第二个重要问题是，缺乏条件性的方法反应与多巴胺信号传导缺陷可能是由于真正缺乏CS-奖励协会或由于动物的无法从事动机和运动系统，促进接近行为。本申请的目标1将解决这些问题。对于目标2，我们已经产生了条件AC 5等位基因，其将允许我们使用Cre重组酶介导的基因缺失在特定区域和细胞类型中实现AC 5基因缺失。这些研究将使我们能够测试AC 5在这些细胞中支持特定行为过程的必要性。此外，我们将在AC 5 KO背景下进行病毒介导的区域和细胞类型特异性AC 5再表达。这将使我们能够测试充分性，即，以测试是否 AC 5在这个大脑区域和这种细胞类型中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.