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）：该提案的目的是研究前额叶锥体神经元（PPN）中的树突状事件及其对单胺多巴胺（DA）和5-羟色胺（5-HT）的调节。长期以来人们认为，在抑郁症和精神分裂症等多种神经系统疾病中看到的症状是，前额叶皮层（PFC）中DA和5-HT信号的异常。 PPN的顶端树突富含由抗精神病药靶向的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，而是用赋予具有复杂综合性能的树突的离子渠道进行了丰富的投资。通过向SOMA注入电流而产生的后传播作用电位（BPAP）可以沿主要顶端树突轴传播数百微米，从而提供了一种用于探测树突兴奋性的工具。该提案中描述的实验结合了两光子激发激光扫描显微镜（2p LSM）和全细胞贴片夹电生理学方法，以实现三个特定目标。具体目的1是确定BPAP侵入PPN的远端根尖树突的程度以及电压门控离子通道对树突状兴奋性的贡献。神经元将通过斑块移液管加载Ca2+敏感的染料，与BPAP相关的树突中的Ca2+瞬变将使用2P LSM测量。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AIM 1中概述的范式来实现，同时焦化DA和5-HT受体激动剂。具体目的3是确定5-HT2A激动剂是否影响与通过用NMDA直接去极化PPN树突产生的动作电位相关的Ca2+信号。评估潜在的树突状现象，这些现象可能是单胺与神经调节有关的最突出的内在细胞机制，这将有助于为患有精神分裂症患者的人开发理性疗法。该职业发展奖（K01）将支持这项研究，并让我进行新的强化培训系列，使我能够发展和完善技能，从而极大地增强了我在脑部疾病领域进行有意义研究的能力，并促进我向独立调查员的过渡。