Monoaminergic regulation of dendritic excitability in prefrontal cortex

前额皮质树突兴奋性的单胺能调节

• 批准号: 7147619
• 负责人: MICHELLE DAY
• 金额: $ 15万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7147619
• 关键词: action potentials; calcium ion; confocal scanning microscopy; dendrites; dopamine receptor; electrophysiology; excitatory aminoacid; genetically modified animals; histology; laboratory mouse; neural transmission; neuroregulation; prefrontal lobe /cortex; pyramidal cells; serotonin receptor; stimulant /agonist; voltage /patch clamp; voltage gated channel

DESCRIPTION (provided by applicant): The objective of this proposal is to study dendritic events in prefrontal pyramidal neurons (PPNs) and their modulation by the monoamines dopamine (DA) and serotonin (5-HT). Abnormalities in DA and 5-HT signaling in the prefrontal cortex (PFC) have long been thought to underlie the symptoms seen in a variety of neurological illnesses such as depression and schizophrenia. The apical dendrites of PPNs are enriched with DA and 5-HT receptors that are targeted by antipsychotic drugs. The dendrites of PPNs are also the recipients of the vast majority of excitatory input. These dendrites are not passive, but are richly invested with ion channels that endow dendrites with complex integrative properties. Back-propagating action potentials (BPAPs) generated by injecting current to the soma can propagate hundreds of microns along the main apical dendritic shaft providing a tool for probing dendritic excitability. The experiments described in this proposal combine two-photon excitation laser scanning microscopy (2P LSM) and whole-cell patch clamp electrophysiology methodologies to accomplish three specific aims. Specific aim 1 is to determine the extent to which BPAPs invade the distal apical dendrites of PPNs and the contribution of the voltage-gated ion channels to dendritic excitability. The neurons will be loaded with Ca2+-sensitive dyes through the patch pipette, and Ca2+ transients in the dendrites associated with the BPAPs will be measured using 2P LSM. Specific aim 2 is to identify the impact of DA and 5-HT receptor activation on dendritic excitability. This will be accomplished using the paradigm outlined in specific aim 1 while focally applying DA and 5-HT-receptor agonists. Specific aim 3 is to determine if 5-HT2A agonists affect Ca2+ signals associated with action potentials generated by directly depolarizing the PPN dendrites with NMDA. Assessing the dendritic phenomena that potentially underlie the most prominent intrinsic cellular mechanisms involved in neuromodulation by monoamines will aid in the development of rational therapies for people suffering from schizophrenia. This Career Development Award (K01) will support this research and allow me to undertake a new line of intensive training that will enable me to develop and refine skills that will greatly enhance my ability to conduct meaningful research in the area of brain disorders, and facilitate my transition into an independent investigator.

描述（由申请人提供）：本提案的目的是研究前额锥体神经元（PPN）中的树突事件及其通过单胺多巴胺（DA）和血清素（5-HT）的调节。长期以来，人们一直认为前额皮质 (PFC) 中 DA 和 5-HT 信号传导异常是抑郁症和精神分裂症等多种神经系统疾病症状的根源。 PPN 的顶端树突富含抗精神病药物靶向的 DA 和 5-HT 受体。 PPN 的树突也是绝大多数兴奋性输入的接受者。这些树突不是被动的，而是富含离子通道，赋予树突复杂的综合特性。通过向体细胞注入电流产生的反向传播动作电位（BPAP）可以沿着主顶端树突轴传播数百微米，为探测树突兴奋性提供了工具。该提案中描述的实验结合了双光子激发激光扫描显微镜（2P LSM）和全细胞膜片钳电生理学方法来实现三个特定目标。具体目标 1 是确定 BPAP 侵入 PPN 远端顶端树突的程度以及电压门控离子通道对树突兴奋性的贡献。将通过贴片移液管向神经元加载 Ca2+ 敏感染料，并使用 2P LSM 测量与 BPAP 相关的树突中的 Ca2+ 瞬变。具体目标 2 是确定 DA 和 5-HT 受体激活对树突兴奋性的影响。这将使用特定目标 1 中概述的范例来实现，同时集中应用 DA 和 5-HT 受体激动剂。具体目标 3 是确定 5-HT2A 激动剂是否影响与用 NMDA 直接去极化 PPN 树突产生的动作电位相关的 Ca2+ 信号。评估可能是单胺神经调节所涉及的最突出的内在细胞机制的树突现象将有助于为精神分裂症患者开发合理的疗法。该职业发展奖（K01）将支持这项研究，并使我能够接受一系列新的强化培训，这将使我能够发展和完善技能，从而大大增强我在脑部疾病领域进行有意义的研究的能力，并促进我向独立调查员的转变。