Neurophysiological And Fmri Studies Of Associative Learning In The Mtl And Striat

描述（由申请人提供）：虽然强有力的证据表明内侧颞叶（MTL）对于学习和保留事实和事件的新信息至关重要，纹状体对于获得新技能和习惯非常重要，但这两个大脑区域之间特定相互作用的性质仍然知之甚少。该双PI建议的目标是利用动物模型系统（Suzuki）中行为神经生理学研究的精确空间和时间分辨率，以及BOLD fMRI研究（Stark）中可用的广泛激活监测和灵活的行为操纵。在已知的条件运动联想学习任务中，取决于这两个领域。在目标1中，我们将在实验动物和人类中使用相同的任务来评估新的条件性运动联想学习期间MTL和纹状体中神经活动的模式和时间动态。神经生理学研究将包括跨MTL和纹状体的单个单元四极记录、网络相关性分析和LFP分析。BOLD fMRI研究将包括这些区域之间功能连接的表征。我们将测试以下假设：MTL和纹状体在新的条件运动联想学习期间都发出学习信号，但在学习过程中利用不同的计算原理，使得MTL在记忆中将随机元素关联在一起，而纹状体的作用包括基于运动或基于方向的刺激-反应学习以及在发出奖励预测错误信号中的突出作用。我们还将测试的假设，纹状体的信号奖励预测错误的作用直接与MTL定义的“声明”部分的纹状体在以前的研究中描述的相互作用。在目标2中，斯塔克将使用各种任务操作假设，使联想学习任务更依赖于MTL或纹状体，以更好地表征这两个不同的大脑区域对联想学习的独特贡献。在Aim 3中，Stark和Suzuki将对动物中测量的单个单位活动、LFP信号和尖峰场相干性的模式与人类中测量的BOLD fMRI信号和功能连接的模式进行详细比较，以定义这些不同分析水平之间的关系。了解这种关系的细节对于最终将动物实验中的单细胞发现转化为我们对人类大脑功能的理解至关重要。理解MTL和纹状体之间的功能相互作用对于开发影响这些脑区域的各种疾病状态的治疗也具有重要意义，所述疾病状态包括阿尔茨海默病、注意力缺陷障碍、衰老中存在的认知障碍、帕金森病和亨廷顿病。 公共卫生相关性：阿尔茨海默病、精神分裂症、发育障碍和衰老都涉及与内侧颞叶损伤相关的学习和记忆障碍，而帕金森病和亨廷顿病涉及纹状体损伤。在这里，我们建议使用BOLD功能磁共振成像方法在人类和非人类灵长类动物的单单位神经生理记录技术相结合，以表征新的联想学习的重要的内侧颞叶区和纹状体区的个人贡献和相互作用。了解BOLD功能磁共振成像信号在人类和非人类灵长类动物的单一单位生理信号之间的详细关系，将有助于我们实现非人类灵长类动物模型系统的潜力，了解人类的认知。这一信息也将作为开发影响内侧颞叶和纹状体的记忆、认知和运动功能障碍的治疗方法的重要基础。

DESCRIPTION (provided by applicant): While strong evidence suggests that the medial temporal lobe (MTL) is essential for learning and retaining new information for facts and events and the striatum is important for acquiring new skills and habits, the nature of the specific interactions between these two brain regions remains poorly understood. The goal of this dual-PI proposal is to take advantage of the precise spatial and temporal resolution of behavioral neurophysiology studies in animal model systems (Suzuki) together with the broad activation monitoring and flexible behavioral manipulation available in BOLD fMRI studies in humans (Stark) to characterize the specific contributions and interactions between the MTL and the striatum during a conditional motor associative learning task known to be dependent on both areas. In Aim 1, we will use the same task in both experimental animals and humans to assess the patterns and temporal dynamics of neural activity in the MTL and striatum during new conditional motor associative learning. Neurophysiology studies will include single unit tetrode recording, network correlation analyses and LFP analyses across both the MTL and the striatum. The BOLD fMRI studies will include characterization of functional connectivity between these areas. We will test the hypothesis that both the MTL and striatum signal learning during new conditional motor associative learning, but utilize distinct computational principles during the learning process such that the MTL associates random element together in memory while the role of the striatum includes motor- based or direction-based stimulus-response learning as well as a prominent role in signaling reward prediction error. We will also test the hypothesis that the role of the striatum in signaling reward prediction error interacts directly with the MTL defining a "declarative" portion of the striatum described in previous studies. In Aim 2, Stark will use various task manipulations hypothesized to make the associative learning task more dependent on either the MTL or the striatum to better characterize the unique contributions of these two different brain areas to associative learning. In Aim 3 Stark and Suzuki will conduct a detailed comparison of the pattern of single unit activity, LFP signals and spike-field coherence measured in animals to the pattern of BOLD fMRI signals and functional connectivity measured in humans to define the relationship between these different levels of analysis. Understanding the details of this relationship will be essential for ultimately translating experimental single cell findings in animals to our understanding of human brain function. Understanding the functional interactions between the MTL and striatum also has important implications for the development of treatments of a wide variety of disease states that affect these brain areas including Alzheimer's disease, attention deficit disorders, cognitive impairments present in aging, Parkinson's disease and Huntington's disease. PUBLIC HEALTH RELEVANCE: Alzheimer's disease, schizophrenia, developmental disorders and aging all involve impairments in learning and memory associated with damage to the medial temporal lobe while Parkinson's disease and Huntinton's disease involve damage to the striatum. Here we propose to use a combination of BOLD fMRI approaches in humans and single unit neurophysiological recording techniques in non-human primates to characterize the individual contributions and interactions of both medial temporal lobe areas and striatal areas important for new associative learning. Understanding the detailed relationship between BOLD fMRI signals in humans and single unit physiology signals in non-human primates will help us realize the potential of non-human primate model systems for understanding human cognition. This information will also serve as an important foundation for the development of treatments for disorders of memory, cognition and motor function that affect the medial temporal lobe and striatum.