Genetic Dissection of Catecholaminergic Innervation of the Cognitive Cerebellum

认知小脑儿茶酚胺能神经支配的基因解剖

基本信息

批准号：
10424496
负责人：
Erik Sean Carlson
金额：
$ 32.69万
依托单位：
SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10424496
关键词：
Address Anatomy Animals Area Attention Behavior Behavioral Brain Catecholamines Cell Nucleus Cells Cerebellar Cortex Cerebellar Nuclei Cerebellum Chronic Clinical Cognitive Cognitive deficits Complex Cre driver Cues Decision Making Dentate nucleus Discrimination Dissection Dopamine Dopamine D1 Receptor Electrodes Electrophysiology (science)Enzymes Etiology Fright Frontotemporal Dementia Genetic Human Impaired cognition Implant Impulsive Behavior Impulsivity Infusion procedures Involuntary Movements Knockout Mice Lateral Learning Maps Measures Mental disorders Motor Mus Nature Neurons Norepinephrine Outcome Output Parietal Lobe Pathway interactions Patients Pattern Performance Periodicity Pharmacology Phase Play Population Precision therapeutics Prefrontal Cortex Production Receptor Cell Regulation Research Rodent Role Scanning Schizophrenia Sensory Short-Term Memory Source Spatial Distribution Stimulus Structure Symptoms System Techniques Testing Time Tyrosine 3-Monooxygenase Viral Work autism spectrum disorder base behavior influence carbon fiber cerebellar lesion cognitive function cognitive performance cognitive task cognitive testing conditioned fear design experimental study eyeblink conditioning in vivo insight memory recognition nerve supply neuropsychiatric disorder neurotransmission nonhuman primate novel optogenetics response sensory discrimination social vestibulo-ocular reflex virtual

项目摘要

Studies in humans and non-human primates have identified a region of the dentate nucleus of the cerebellum (DCN), or lateral nucleus in rodents (LCN), which is activated during performance of cognitive tasks involving complex spatial and sequential planning. We have previously shown that the dopamine D1 receptor marks a population of neurons in the LCN with similar spatial distribution and regulates cognitive performance on several tasks related to attention and working memory, and has connections with other parts of the brain that are classically involved in these functions. The DCN is implicated in cognitive function in humans with psychiatric illnesses, but virtually nothing is known about its basic anatomical and functional organization. Unraveling this will set the stage for precision therapeutics in the cognitive domain, an area where we have few options to offer patients. We hypothesized that the locus ceruleus is the principal source of both dopamine and norepinephrine release in LCN, catecholamines are required for cerebellar enhancement of attention and working memory tasks, and locus ceruleus neurons release catecholamines in a phasic manner. We have mapped projections of the LC to DCN, and have found that when we electrically stimulate the LC, we can observe catecholamine release in the LCN with fast scan cyclic voltammetry in anesthetized animals. We have also found that when we turn off tyrosine hydroxylase expression in the LCN, we get abnormal performance on sensory discrimination, working memory, and impulsive behaviors. Here we propose to establish the basic electrophysiological, anatomical, and behavioral function of these pathways using Cre driver mouse lines in combination with advanced techniques in viral-based circuit dissection. Successful completion of our proposed aims will provide novel insight into the basic organization of the LCN and establish a framework for novel, precision therapeutics to assist patients with cognitive dysfunction.

对人类和非人类灵长类动物的研究已经确定了齿状核的一个区域小脑 (DCN) 或啮齿类动物的侧核 (LCN)，在涉及复杂空间和顺序规划的认知任务的执行。我们有先前表明，多巴胺 D1 受体通过以下方式标记 LCN 中的一群神经元：相似的空间分布并调节与以下相关的几个任务的认知表现注意力和工作记忆，并与大脑的其他部分有联系经典地参与这些功能。 DCN 与人类的认知功能有关患有精神疾病，但实际上对其基本解剖学和功能一无所知组织。阐明这一点将为认知领域的精准治疗奠定基础，我们为患者提供的选择很少。我们假设蓝斑是儿茶酚胺是 LCN 中多巴胺和去甲肾上腺素释放的主要来源，小脑增强注意力和工作记忆任务以及蓝斑所需的神经元以阶段性方式释放儿茶酚胺。我们已经将 LC 的投影映射到 DCN，并发现当我们电刺激LC时，我们可以观察到儿茶酚胺在麻醉动物中通过快速扫描循环伏安法在 LCN 中释放。我们还有发现当我们关闭 LCN 中酪氨酸羟化酶的表达时，我们会变得异常感觉辨别、工作记忆和冲动行为的表现。在这里我们提议建立这些的基本电生理学、解剖学和行为功能使用 Cre 驱动小鼠系与基于病毒的先进技术相结合的途径电路剖析。成功完成我们提出的目标将为我们提供新的见解 LCN 的基本组织，并建立新颖、精准治疗的框架帮助患有认知功能障碍的患者。