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Genetic dissection of neural pathways for appetitive associative learning

食欲联想学习神经通路的遗传解剖

基本信息

批准号：
8976537
负责人：
Xiaoxi Zhuang
金额：
$ 19.75万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8976537
关键词：
Adaptive Behaviors Address Adenylate Cyclase Adult Affect Agreement Alleles Animals Behavioral Brain region Cells Conditioned Stimulus Corpus striatum structure Coupled Cues Cyclic AMP Data Development Dissection Dopamine Dopamine D1 Receptor Dopamine D2 Receptor Financial compensation Foundations Gene Deletion Genetic Goals Incentives Knockout Mice Learning Link Literature Mediating Mental disorders Molecular Motivation Motor Mus Neural Pathways Neurons Nucleus Accumbens Obesity Operant Conditioning Outcome Pathway interactions Play Predictive Value Process Publishing Rewards Role Signal Pathway Signal Transduction Specificity Synaptic plasticity System Testing Virus addiction adenylyl cyclase type V approach behavior cell type classical conditioning dopamine system dopaminergic neuron in vivo public health relevance recombinase relating to nervous system response

项目摘要

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.

描述（由申请人提供）：多巴胺信号传导与奖励的许多方面有关。尽管关于这个重要主题的文献很多，但区域和细胞类型特异性多巴胺信号传导是否以及如何在奖励的特定方面发挥不同作用仍然存在激烈争论。多巴胺 D1 和 D2 受体主要与纹状体中棘神经元 (MSN) 中的 cAMP 通路偶联。我们近年来的研究表明，通过 cAMP 的多巴胺信号传导对于皮质纹状体的可塑性至关重要。此外，5 型腺苷酸环化酶 (AC5) 缺陷 (AC5KO) 小鼠的食欲联想学习严重受损。 AC5 是纹状体和伏隔核中用于多巴胺-cAMP 信号转导的主要腺苷酸环化酶。食欲联想学习中这样一个关键分子的识别提供了一个独特的机会来执行精确操作并严格测试食欲联想学习特定方面的区域和细胞类型特异性多巴胺信号传导的必要性和充分性。该领域最重要的问题之一是条件刺激（CS）同时获得预测价值和激励价值。多巴胺参与这两个过程。尚未解决的第二个重要问题是，与多巴胺信号传导缺陷相关的条件性接近反应的缺乏可能是由于真正缺乏 CS 奖励关联或由于动物无法参与动机和运动系统并促进接近行为。此应用程序的目标 1 将解决这些问题。对于目标 2，我们生成了条件 AC5 等位基因，这将使我们能够使用 Cre 重组酶介导的基因删除在特定区域和细胞类型中实现 AC5 基因删除。这些研究将使我们能够测试这些细胞中 AC5 支持特定行为过程的必要性。此外，我们将在 AC5KO 背景上进行病毒介导的区域和细胞类型特异性 AC5 重新表达。这将使我们能够测试充分性，即测试是否该大脑区域和该细胞类型中的 AC5 足以支持特定的行为过程。