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.

项目摘要小脑功能障碍已在各种认知障碍中隐含（例如自闭症谱系障碍，精神分裂症以及注意力不足和多动症障碍）与无法自适应改变以前学过的行为。几项独立研究指出疾病相关的小脑功能障碍是由于小脑的实验破坏，因果关系或至少促成了这种行为不足面对变化，降低小鼠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Purkinje神经元）始终如一发现行为僵化是突出特征的认知障碍中受损。字段工作假设是“认知小脑”（例如Crus I和Lobule VI）的功能障碍导致异常小脑和前脑区域之间涉及灵活行为的沟通状态（例如前额叶皮质）。然而，我们对小脑在柔性和僵化中的作用的理解仍然存在主要差距行为，其中包括：1）哪种类型的小脑活性可能会导致僵化的行为； 2）哪个小脑皮层的特定解剖/功能子区域涉及； 3）哪些信息有什么小脑编码与行为灵活性有关的； 4）下游前脑区域与什么交流小脑在柔性行为过程中，这些区域是由小脑功能障碍影响的相同区域；和 5）绝对交流对下游前脑区域和网络活动有什么影响它与与精神障碍有关的异常大脑状态匹配。在AIM 1中，我们将通过破坏小脑定义的子区域来解决问题1和2（Crus I，Crus II和 LOBULE VI）使用Dreadd技术，然后在2-Cue奖励联系中测量灵活行为小鼠范式。我们还将使用密集电极从小脑记录来解决问题3 灵活行为过程中的阵列，以建立小脑编码哪些信息以支持自适应逆转以前学习的刺激奖励联想。在AIM 2中，我们将通过组合解决问题4和5 与全脑神经影像学的小脑相同定义的子区域的化学遗传破坏，小鼠中的特殊静止状态功能磁共振成像（RS-FMRI）。在这里，我们提出了两种不同的方法，这些方法将使我们能够建立与问题1-5将为多次跟进研究奠定基础。我们的总体目标是确定不同大脑区域合作影响正常和异常的认知行为，提供有关如何神经认知功能障碍发生，并探讨疾病发展如何影响或受到影响异常的大脑神经通路。