Dopamine Effects on Striatal and Hippocampal Plasticity

描述（申请人提供）：基底神经节功能障碍患者表现出显著的认知障碍。然而，纹状体对学习的具体贡献尚不清楚：啮齿动物的病变研究表明，纹状体在刺激-反应或自我中心形式的学习中有选择性作用（将其与海马体进行的基于情境的学习分离开来），而灵长类动物的电生理证据支持纹状体在刺激-反应和情境依赖的学习中具有双重作用。然而，与海马体依赖性记忆的研究比较，支持了一个普遍的观点，即大脑中存在多个记忆系统。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。考虑到这种并行的神经表征，了解不同的记忆系统是如何协调的就变得很有趣了。有了这笔资金，我们提出了一个关于这个问题的新观点，即研究神经调节剂（如多巴胺）如何根据当前的环境需求影响不同神经系统对学习的相对贡献。目的1将确定在纹状体和海马体、腹侧被盖（VTA）和黑质（SNc）中已知的结构中神经元的神经表征的性质。目的2将在测试纹状体和海马神经元的上下文敏感性时，通过可逆地使VTA和/或SNc结构失活，确定纹状体和海马神经元的上下文敏感性是否归因于VTA和/或SNc输入。为了确定失活效应是否由于多巴胺破坏，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时早期基因cFos表达的情境敏感性，通过测试VTA或SNc失活对纹状体和海马中cFos表达的影响，通过药理学测试多巴胺在情境诱导的cFos表达中的作用，来确定单个纹状体和海马单位记录的情境敏感性是否反映了更大的群体反应。并直接将cfo的激活模式与同一动物记录的单个数据进行比较。这些研究应该为多巴胺功能调节纹状体和海马体对不同形式学习的相对贡献的假设提供有力的检验。

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.