Dopamine Effects on Striatal and Hippocampal Plasticity

描述（由申请人提供）：基底神经节功能障碍患者表现出显著和显著的认知障碍。然而，纹状体对学习的具体贡献仍不清楚：啮齿动物损伤研究表明，纹状体在刺激反应或自我中心形式的学习中具有选择性作用（将其与海马体进行的基于上下文的学习分离），而灵长类动物的电生理证据支持纹状体在刺激反应和上下文依赖性学习中的双重作用。然而，通过与以往对大脑依赖记忆的研究的比较，我们发现大脑中存在着多个记忆系统。然而，我们过去的工作表明，无论任务是什么，在不同的大脑结构中都有显著的平行表征。有了这种平行的神经表征，了解不同的记忆系统是如何协调的就变得很有意义了。有了这笔赠款，我们提出了一个新的角度来看待这个问题，这是研究如何神经调节剂（如多巴胺）可能会偏向不同的神经系统的相对贡献学习取决于当前的环境需求。目的1将确定已知为纹状体和海马、腹侧被盖（VTA）和黑质（SNc）提供多巴胺的结构中的神经元的神经表征的性质。目的2将确定纹状体和海马神经元的上下文敏感性是否是由于VTA和/或SNc输入通过可逆地失活这些结构，同时测试纹状体和海马神经元的上下文敏感性。为了确定失活效应是否是由于多巴胺中断，我们将应用D1或D2受体拮抗剂，然后监测纹状体和海马神经元的上下文敏感性。目的3将通过评估纹状体和海马中即刻早期基因cFos表达的背景敏感性，通过测试VTA或SNc失活对纹状体和海马中cFos表达的影响，通过测试多巴胺在背景诱导的cFos表达中的作用，并通过直接比较cFos激活模式与从相同动物记录的单个单元数据。这些研究应该为多巴胺调节纹状体和海马对不同形式学习的相对贡献的假设提供强有力的检验。

DESCRIPTION (provided by applicant): Patients with basal ganglia dysfunction show significant and striking cognitive impairments. The specific contribution of striatum to learning, however, remains unclear: rodent lesion studies suggests a selective role in stimulus-response or egocentric forms of learning (dissociating it from context-based learning performed by hippocampus), while primate electrophysiological evidence supports a dual role for striatum in both stimulus-response and context-dependent learning. Nevertheless, comparison with studies of hippocampal-dependent memory supports a common view that multiple memory systems exist in brain. Our past work, however, shows that regardless of task, there is significant parallel representation in different brain structures. Given this parallel neural representation, it becomes of interest to know how different memory systems are coordinated. With this grant, we propose a novel perspective on this issue, which is to study how neuromodulators (e.g. dopamine) might bias the relative contributions of different neural systems to learning depending on current environmental demands. Aim 1 will determine the nature of neural representation by neurons in structures known to supply striatum and hippocampus with dopamine, the ventral tegmentum (VTA) and substantia nigra (SNc). Aim 2 will determine whether context-sensitivity of striatum and hippocampal neurons is due to VTA and/or SNc input by reversibly inactivating these structures while testing the context-sensitivity of striatal and hippocampal neurons. To determine whether the inactivation effects are due to dopamine disruption, we will apply D1 or D2 receptor antagonists, and then monitor the context-sensitivity of striatal and hippocampal neurons. Aim 3 will determine whether the context-sensitivity of single striatal and hippocampal unit records is reflective of a larger population response by evaluating the context sensitivity of the expression of the immediate-early gene cFos in striatum and hippocampus, by testing the effects of VTA or SNc inactivation on cFos expression in striatum and hippocampus, by testing pharmacologically a role for dopamine in context-induced cFos expression, and by directly comparing cFos activation patterns with single unit data recorded from the same animals. These studies should provide a strong test for the hypothesis that dopamine functions to regulate the relative contribution of striatum and hippocampus to different forms of learning.