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:
- 金额:$ 22.2万
- 依托单位:
- 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:
- 关键词:Adaptive BehaviorsAddressAdultAnatomyAnteriorApplications GrantsAreaAttention deficit hyperactivity disorderBasal GangliaBasic ScienceBehaviorBehavior DisordersBehavioralBrainBrain regionCerebellar CortexCerebellar DiseasesCerebellumChildClinical SciencesCognition DisordersCognitiveCollaborationsCommunicationCouplingCuesDataDevelopmentDevelopmental Delay DisordersDiseaseDisparateDominant-Negative MutationElectrodesElectrophysiology (science)EnvironmentFunctional Magnetic Resonance ImagingFunctional disorderGeneticGenetic EnhancementGenetic SuppressionGoalsHippocampusHumanHyperactivityImpaired cognitionIndividualKnowledgeLearningLinkLobuleMeasuresMental disordersMethodsMusNeurocognitiveNeuronsOutputParietal LobePrefrontal CortexProsencephalonPsyche structureResearchRestReversal LearningRewardsRodentRoleSchizophreniaShapesSignal TransductionStatistical MethodsStimulusTechnologyTestingThalamic structureTrainingWell in selfanalytical methodanimal imagingautism spectrum disorderbehavioral responsebrain abnormalitiescingulate cortexdesigner receptors exclusively activated by designer drugsexperimental studyflexibilityindependent component analysisinnovationlearned behaviorneuralneural circuitneural networkneuroimagingneuropsychiatric disorderneurotransmissionnovelresearch studysuicidal
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Paul James Mathews其他文献
Paul James Mathews的其他文献
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{{ truncateString('Paul James Mathews', 18)}}的其他基金
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:
10373891 - 财政年份:2022
- 资助金额:
$ 22.2万 - 项目类别:
Optimizing Small Molecule Read-Through Compounds for Treating AtaxiaTelangiectasia
优化小分子通读化合物治疗共济失调毛细血管扩张症
- 批准号:
10434554 - 财政年份:2022
- 资助金额:
$ 22.2万 - 项目类别:
An optogenetic approach to exploring climbing fiber connections in the cerebellum
探索小脑攀爬纤维连接的光遗传学方法
- 批准号:
8520408 - 财政年份:2011
- 资助金额:
$ 22.2万 - 项目类别:
An optogenetic approach to exploring climbing fiber connections in the cerebellum
探索小脑攀爬纤维连接的光遗传学方法
- 批准号:
8125240 - 财政年份:2011
- 资助金额:
$ 22.2万 - 项目类别:
An optogenetic approach to exploring climbing fiber connections in the cerebellum
探索小脑攀爬纤维连接的光遗传学方法
- 批准号:
8332962 - 财政年份:2011
- 资助金额:
$ 22.2万 - 项目类别:
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