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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结小脑功能障碍与各种认知障碍(如自闭症谱系障碍、精神分裂症、注意力缺陷和多动障碍)与无法适应性改变有关以前学过的行为。几项独立研究指出，与疾病相关的小脑功能障碍是这种行为缺陷的原因或至少是促成因素是实验性的小脑破坏降低小鼠在面对变化时自适应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) 在认知障碍中被发现受到损害，其中行为不灵活是一个突出的特征。田野工作假说是“认知小脑”(如小腿I和小叶VI)的功能障碍导致异常参与灵活行为(如前额叶)的小脑和前脑区域之间的通信状态大脑皮层)。然而，在我们对小脑在灵活和僵硬中的作用的理解上仍然存在重大差距行为，这包括：1)什么类型的小脑异常活动会导致僵硬的行为；2)哪种小脑皮质特定的解剖/功能亚区受累；3)什么信息小脑编码与行为灵活性有关；4)前脑下游区域与什么联系在灵活行为中的小脑，这些区域是否也受到小脑功能障碍的影响；以及 5)通讯异常对下游前脑区域和网络活动有何影响它与精神障碍相关的异常大脑状态相匹配。在目标1中，我们将通过破坏小脑已定义的亚区(CRU I、CRU II和CRU II)来解决问题1和2 小叶VI)使用DREADD技术，然后在两个线索的奖励关联中测量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，以确定小脑编码什么信息来支持适应性逆转以前学过的刺激-奖赏关联。在目标2中，我们将通过组合来解决问题4和5 用全脑神经成像技术破坏小脑相同亚区的化学遗传学，特别是小鼠的静息状态功能磁共振成像(rs-fMRI)。在这里，我们提出两种不同的方法，这将使我们能够建立与以下相关的机械论假设问题1-5将为多项后续研究奠定基础。我们的总体目标是确定有多不同大脑区域相互协作，影响正常和异常的认知行为，为如何神经认知功能障碍的出现，并探索疾病的发展如何影响-或被影响- 脑神经回路异常。