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很重要，但这两个大脑区域之间具体相互作用的性质仍然知之甚少。这项双pi提案的目标是利用动物模型系统中行为神经生理学研究的精确空间和时间分辨率（Suzuki），以及在人类BOLD fMRI研究中可用的广泛激活监测和灵活的行为操作（Stark），来表征MTL和纹状体在已知依赖于这两个区域的条件运动联想学习任务中的具体贡献和相互作用。在目的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条件运动联想学习期间MTL和纹状体的神经活动模式和时间动态。神经生理学研究将包括跨MTL和纹状体的单单元四极体记录、网络相关分析和LFP分析。BOLD fMRI研究将包括表征这些区域之间的功能连接。我们将测试在新的条件运动联想学习过程中MTL和纹状体信号学习的假设，但在学习过程中使用不同的计算原理，使得MTL在记忆中将随机元素联系在一起，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，以及在信号奖励预测错误中发挥突出作用。我们还将验证纹状体在奖励预测错误信号传递中的作用与MTL直接相互作用的假设，MTL定义了纹状体的“声明性”部分，在之前的研究中描述过。在Aim 2中，Stark将使用假设的各种任务操作，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元活动模式、LFP信号和峰场相干性与人类中测量的BOLD fMRI信号模式和功能连通性进行详细比较，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单细胞实验结果转化为我们对人类大脑功能的理解至关重要。了解MTL和纹状体之间的功能相互作用，对于开发各种影响这些脑区域的疾病状态的治疗方法也具有重要意义，这些疾病包括阿尔茨海默病、注意力缺陷障碍、衰老中的认知障碍、帕金森病和亨廷顿病。

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.