Behavioral and brain network effects of dysfunction in the cognitive cerebellum

项目摘要 小脑功能障碍与各种认知障碍有关（例如，自闭症谱系障碍， 精神分裂症，注意力缺陷和多动症）与无法适应性改变 以前学过的行为。几项独立的研究指出，疾病相关的小脑功能障碍是一种 小脑的实验性破坏是这种行为缺陷的原因或至少是促成因素 降低了小鼠适应性地改变先前学习的行为的能力， 环境此外，认知小脑中的某些神经元（即，浦肯野神经元）始终 发现在认知障碍中受损，其中行为不稳定性是突出特征。领域 工作假设是“认知小脑”的功能障碍（例如，小叶I和小叶VI）引起异常 小脑和前脑区域之间的交流状态，涉及灵活的行为（例如，前额叶 皮质）。然而，我们对小脑在灵活和不灵活的大脑活动中的作用的理解仍然存在重大差距。 行为，这包括：1）什么类型的异常小脑活动会导致不灵活的行为; 2） 小脑皮质的特定解剖/功能子区域参与; 3）什么信息， 小脑编码有关的行为灵活性; 4）下游前脑区域与 小脑在灵活的行为，以及这些相同的区域受到小脑功能障碍; 5)异常交流对下游前脑区域和网络活动的影响是什么， 它与精神失常相关异常大脑状态相吻合 在AIM 1中，我们将通过破坏小脑的定义的亚区（小脑I，小脑II和小脑III）来解决问题1和2。 小叶VI）使用DREADD技术，然后在2线索奖励关联中测量灵活行为 在小鼠中的范例。我们还将通过使用致密电极从小脑记录来解决问题3 灵活行为期间的阵列，以确定小脑编码哪些信息来支持适应性逆转 先前习得的刺激-奖励关联的结果。在目标2中，我们将结合以下内容来解决问题4和5： 用全脑神经成像对小脑的这些相同的限定亚区域进行化学遗传学破坏， 特别是小鼠的静息状态功能性磁共振成像（rs-fMRI）。 在这里，我们提出了两种不同的方法，使我们能够建立有关的机制假说， 问题1 - 5将为多项后续研究奠定基础。我们的总体目标是确定 大脑区域合作影响正常和异常的认知行为，提供线索， 神经认知功能障碍的出现，并探讨疾病的发展如何影响-或受到- 异常的大脑神经回路

PROJECT SUMMARY Cerebellar dysfunction has been implicated in various cognitive disorders (e.g., autism spectrum disorder, schizophrenia, and attention deficit and hyperactivity disorder) associated with the inability to adaptively alter previously learned behaviors. Several independent studies point to disease related cerebellar dysfunction as a causal or at least contributing factor in this behavioral deficit as experimental disruption of the cerebellum decreases the ability of mice to adaptively change previously learned behaviors in the face of a changing environment. Moreover, certain neurons in the cognitive cerebellum (i.e., Purkinje neurons) are consistently found to be damaged in cognitive disorders where behavioral inflexibility is a prominent feature. The fields working hypothesis is that dysfunction of the “cognitive cerebellum” (e.g., crus I and lobule VI) causes abnormal states of communication between the cerebellum and forebrain areas involved in flexible behavior (e.g. prefrontal cortex). There remains however major gaps in our understanding of the cerebellum's role in flexible and inflexible behavior, this includes: 1) what types of abnormal cerebellar activity can cause inflexible behavior; 2) which specific anatomical/functional sub-regions of the cerebellar cortex are involved; 3) what information does the cerebellum encode pertinent to behavioral flexibility; 4) what downstream forebrain regions communicate with the cerebellum during flexible behavior, and are these the same regions impacted by cerebellar dysfunction; and 5) what is the effect of abnormal communication on downstream forebrain regions and network activity and does it match abnormal brain states associated with mental disorder. In AIM 1 we will address questions 1 & 2 by disrupting defined subregions of the cerebellum (crus I, crus II, and lobule VI) using DREADD technology and then measuring flexible behavior in a 2-cue reward-association paradigm in mice. We will also address question 3 by recording from the cerebellum using dense-electrode arrays during flexible behavior to establish what information the cerebellum encodes to support adaptive reversal of previously learned stimulus-reward associations. In Aim 2, we will address questions 4 & 5 by combining chemo-genetic disruption of those same defined subregions of the cerebellum with whole-brain neuroimaging, specifically resting-state functional Magnetic Resonance Imaging (rs-fMRI) in mice. Here, we propose two distinct approaches that will allow us to establish mechanistic hypotheses related to questions 1 - 5 that will set the stage for multiple follow-on studies. Our overall goal is to determine how disparate brain regions collaborate to influence normal and abnormal cognitive behaviors, provide clues as to how neurocognitive dysfunction arises, and explore how disease development impacts—or is impacted by— abnormal brain neurocircuitry.