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

描述(申请人提供)：虽然强有力的证据表明，内侧颞叶(MTL)对于学习和保持关于事实和事件的新信息是必不可少的，纹状体对于获得新的技能和习惯是重要的，但这两个大脑区域之间特定互动的性质仍然知之甚少。这个双PI方案的目标是利用动物模型系统中行为神经生理学研究(Suzuki)的精确空间和时间分辨率，以及BOLD人类fMRI研究(STARK)中广泛的激活监测和灵活的行为操作，来表征在已知依赖于这两个区域的条件性运动联想学习任务中，MTL和纹状体之间的特定贡献和相互作用。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在新的条件运动联想学习过程中MTL和纹状体神经活动的模式和时间动力学。神经生理学研究将包括单单位四极管记录、网络相关分析和跨MTL和纹状体的LFP分析。BOLD功能磁共振研究将包括描述这些区域之间的功能连接。我们将检验这样一种假设，即在新的条件运动联想学习过程中，MTL和纹状体信号学习都存在，但在学习过程中利用了不同的计算原理，即MTL将记忆中的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，以及在发出奖赏预测错误信号方面发挥突出作用。我们还将测试纹状体在发出奖赏预测错误信号中的作用与MTL直接交互作用的假设，该MTL定义了先前研究中描述的纹状体的一个“陈述性”部分。在目标2中，斯塔克将使用各种假设的任务操纵来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大脑区域对联想学习的独特贡献。在目标3中，斯塔克和铃木将对在动物身上测量的单个单位活动、LFP信号和棘波-场一致性的模式与在人类中测量的大胆功能磁共振信号和功能连接性的模式进行详细的比较，以确定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疾病状态的治疗也具有重要意义，这些疾病状态会影响这些大脑区域，包括阿尔茨海默病、注意力缺陷障碍、老年认知障碍、帕金森氏病和亨廷顿病。 与公共卫生相关：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，而帕金森氏病和亨廷顿病涉及纹状体损伤。在这里，我们建议在人类中结合使用BOLD fMRI方法和在非人类灵长类动物中使用单一单位神经生理记录技术来表征对新的联想学习重要的内侧颞叶区域和纹状体区域的个体贡献和相互作用。了解人类的BOLD fMRI信号和非人灵长类动物的单单位生理信号之间的详细关系将有助于我们认识到非人灵长类动物模型系统在理解人类认知方面的潜力。这些信息也将成为开发治疗影响内侧颞叶和纹状体的记忆、认知和运动功能障碍的重要基础。

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.