Behavioral and brain network effects of dysfunction in the cognitive cerebellum

认知小脑功能障碍对行为和大脑网络的影响

• 批准号: 10651608
• 负责人: Paul James Mathews
• 金额: $ 22.2万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651608
• 关键词: Adaptive Behaviors; Address; Adult; Anatomy; Anterior; Applications Grants; Area; Attention deficit hyperactivity disorder; Basal Ganglia; Basic Science; Behavior; Behavior Disorders; Behavioral; Brain; Brain region; Cerebellar Cortex; Cerebellar Diseases; Cerebellum; Child; Clinical Sciences; Cognition Disorders; Cognitive; Collaborations; Communication; Coupling; Cues; Data; Development; Developmental Delay Disorders; Disease; Disparate; Dominant-Negative Mutation; Electrodes; Electrophysiology (science); Environment; Functional Magnetic Resonance Imaging; Functional disorder; Genetic; Genetic Enhancement; Genetic Suppression; Goals; Hippocampus; Human; Hyperactivity; Impaired cognition; Individual; Knowledge; Learning; Link; Lobule; Measures; Mental disorders; Methods; Mus; Neurocognitive; Neurons; Output; Parietal Lobe; Prefrontal Cortex; Prosencephalon; Psyche structure; Research; Rest; Reversal Learning; Rewards; Rodent; Role; Schizophrenia; Shapes; Signal Transduction; Statistical Methods; Stimulus; Technology; Testing; Thalamic structure; Training; Well in self; analytical method; animal imaging; autism spectrum disorder; behavioral response; brain abnormalities; cingulate cortex; designer receptors exclusively activated by designer drugs; experimental study; flexibility; independent component analysis; innovation; learned behavior; neural; neural circuit; neural network; neuroimaging; neuropsychiatric disorder; neurotransmission; novel; research study; suicidal

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.

项目概要 小脑功能障碍与各种认知障碍（例如自闭症谱系障碍、 精神分裂症、注意力缺陷和多动症）与无法适应性改变相关 以前习得的行为。几项独立研究指出，疾病相关的小脑功能障碍是一种 这种行为缺陷的因果因素或至少是促成因素，即小脑的实验性破坏 降低小鼠在面对不断变化的情况时适应性改变先前习得行为的能力 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到损害，其中行为僵化是一个显着特征。田野 工作假设是“认知小脑”（例如小腿 I 和小叶 VI）的功能障碍导致异常 涉及灵活行为的小脑和前脑区域之间的通信状态（例如前额叶） 皮层）。然而，我们对小脑在灵活和非灵活方面的作用的理解仍然存在重大差距。 行为，这包括：1）哪些类型的异常小脑活动会导致行为不灵活； 2）哪个 涉及小脑皮质的特定解剖/功能子区域； 3）什么信息 小脑编码与行为灵活性相关； 4）下游前脑区域与什么进行通信 灵活行为期间的小脑，这些区域是否受到小脑功能障碍的影响？和 5）异常通讯对下游前脑区域和网络活动有何影响？ 它匹配与精神障碍相关的异常大脑状态。 在 AIM 1 中，我们将通过破坏小脑的特定分区（小腿 I、小腿 II 和小腿 II）来解决问题 1 和 2。 小叶 VI) 使用 DREADD 技术，然后测量 2 线索奖励关联中的灵活行为 小鼠的范例。我们还将通过使用致密电极从小脑进行记录来解决问题 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 先前学到的刺激-奖励关联。在目标 2 中，我们将结合解决问题 4 和 5 通过全脑神经影像对小脑的那些相同定义的亚区域进行化学遗传学破坏， 特别是小鼠静息态功能磁共振成像（rs-fMRI）。 在这里，我们提出了两种不同的方法，使我们能够建立与 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差异有多大 大脑区域协作影响正常和异常的认知行为，提供关于如何影响正常和异常认知行为的线索 神经认知功能障碍的出现，并探讨疾病的发展如何影响——或被影响—— 大脑神经回路异常。