Dopaminergic Regulation of Pyramidal Cells

锥体细胞的多巴胺能调节

基本信息

批准号：
7208450
负责人：
ARIEL Y DEUTCH
金额：
$ 32.2万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-15 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7208450
关键词：
Affinity Agonist Animals Antipsychotic Agents Architecture Autopsy Axon Behavioral Body Size Brain Cell Count Chronic Corpus striatum structure Data Deafferentation procedure Dendrites Dendritic Spines Denervation Dopamine Dopamine Agonists Dopamine Antagonists Dopamine Receptor Elements Evaluation Functional disorder Image Impaired cognition Knockout Mice Lead Length Lesion Mutant Strains Mice Neurons Neuropil Output Population Prefrontal Cortex Pyramidal Cells Regulation Reporting Research Personnel Rodent Role Schizophrenia Secondary to Signal Transduction Structure Synapses Techniques Testing Thinking Trees Vertebral column adrenergic receptor alpha(2C)atypical antipsychotic base density dopamine D4 receptor extracellular gray matter human DRD4 protein in vivo insight nerve supply neuron loss neuronal cell body neuropathology novel strategies presynaptic prevent programs receptor response size

项目摘要

DESCRIPTION (provided by applicant): Behavioral data suggest the presence of a decrease in dopamine (DA) tone in the RFC in schizophrenia, consistent with morphological evidence of a decrease in the RFC DA innervation. Postmortem studies of schizophrenia have noted a decrease in PFC volume that is not due to a loss of neurons, but rather a decrease in neuropil, suggesting changes in the size of cell bodies, a decrease in presynaptic elements, or a pruning of the dendritic trees of neurons. Several groups have reported that the basal dendrites of PFC pyramidal cells are truncated and have a decreased density of dendritic spines. In striatal medium spiny neurons, which have the same synaptic architecture of DA axons and dendritic spines in PFC pyramidal cells, DA denervation causes a decrease in dendritic spine density and length. Our preliminary data indicate that cortical DA depletion also causes a reduction in dendritic length and spine density in the basal dendrites of layer V pyramidal cells in the PFC. We hypothesize that a decrease in PFC DA results in remodeling of pyramidal cell dendrites. We propose to determine if DA denervation of the PFC in rodents results in dendritic remodeling of PFC pyramidal cells, and assess if pyramidal cells differ in their response to DA denervation based on their projection targets. In order to determine which DA receptor(s) is involved in DA denervation-induced dendritic remodeling, we will examine the effects of DA receptor antagonists and use DA receptor knockout mice. We will also determine if loss of signaling through the alpha 2c adrenergic receptor, for which DA has low nanomolar affinity, is involved. Finally, we will determine if DA denervation- induced morphological alterations in PFC pyramidal cells can be reversed by chronic treatment with dopamine agonists or atypical antipsychotic drugs, which increase extracellular DA levels in the PFC. These studies will reveal the mechanisms underlying the dendritic reorganization of prefrontal cortical neurons, and may offer insights into new approaches for slowing cortical loss and the treatment of cognitive dysfunction in schizophrenia.

描述（由申请人提供）：行为数据表明，精神分裂症中RFC中多巴胺（DA）张力的降低，这与RFC DA神经支配降低的形态学证据一致。对精神分裂症的验尸研究已经注意到，PFC体积的减少不是由于神经元的丧失，而是神经元的降低，表明细胞体大小的变化，突触前元素的减少或神经元树突树的修剪。几个组报告说，PFC锥体细胞的基础树突被截短，树突状棘的密度降低。在纹状体培养基神经元中，在PFC锥体细胞中具有相同的DA轴突和树突状刺的突触结构，DA的神经膜会导致树突状脊柱密度和长度降低。我们的初步数据表明，皮质DA耗竭还会导致PFC中V层V锥体细胞的基底树突中的树突长度和脊柱密度降低。我们假设PFC DA的减少会导致锥体细胞树突的重塑。我们建议确定啮齿动物中PFC的DA去神经是否导致对PFC锥体细胞的树突重塑，并根据其投影靶标评估其对DA神经的反应的锥体细胞是否有所不同。为了确定哪个DA受体参与DA神经神经化引起的树突重塑，我们将检查DA受体拮抗剂的作用并使用DA受体敲除小鼠。我们还将确定是否涉及DA具有低纳摩尔亲和力的Alpha 2C肾上腺素能受体的信号丢失。最后，我们将通过多巴胺激动剂或非典型抗精神病药的慢性治疗来逆转DA神经诱导的PFC锥体细胞中DA诱导的形态改变，从而增加了PFC的细胞外DA水平。这些研究将揭示前额叶皮质神经元的树突状重组的基础机制，并可能提供有关减缓皮质损失和精神分裂症认知功能障碍的新方法的见解。