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Understanding the role of inhibition in the expiratory microcircuit

了解抑制在呼气微回路中的作用

基本信息

批准号：
BB/X008290/1
负责人：
Robert Huckstepp
金额：
$ 61.83万
依托单位：
University of Warwick
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2023
资助国家：
英国
起止时间：
2023 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FX008290%2F1
关键词：
Understanding role inhibition expiratory microcircuit

项目摘要

Breathing is our first act upon birth, and the last action we complete before death. The first to last breath taken, is in fact, how we define someone's life. We don't love our children from their 'first blink', we don't love our partners until our 'dying thought', soldiers do not fight until their last 'heart beat', and nobody at a surprise encounter has ever said 'as I live and walk'. However we risk taking breathing for granted. The respiratory pattern is generated by specialised nuclei -the preBötzinger complex (preBötC; controlling inspiration), a post-inspiratory oscillator, currently thought to be the post-inspiratory complex (PiCo), and the parafacial lateral region (pFL: controlling expiration)We know a significant amount about the inspiratory oscillator: It's subdivisions, as well as it's inputs and outputs; We even know it's human analogue, which consists of ~120,000 neurons. Much less is known about the other 2 oscillators. Of the remaining 2, the expiratory oscillator is the better studied but even then our knowledge is minimal: We know broadly which neurotransmitters these neurons produce, but not if they are sub-divided further; we know the function of the excitatory subtype, but not the inhibitory one, and; whilst we have a map of it's inputs, it's outputs remain largely unknown. Finally, the post-inspiratory oscillator remains largely uninvestigated: we know it's subdivisions but the function of them is mostly undetermined, other than they drive post-inspiratory motor output whilst reducing inspiratory period; we know little about it's outputs except that it does not appear to project directly to the expiratory oscillator.In this set of experiments we will manipulate different subpopulations of neurons in the rhythm generating network. The manipulations will focus on the role of the often overlooked inhibitory neurons, and the excitatory neurons that drive them. By changing their activity individually or in combination, we can begin to parse out how the different types of neurons in these oscillators work together to pattern motor output. Furthermore, will will make the neurons express fluorescent molecules to identify and quantify the neurons, whilst simultaneously allowing us to build an anatomical map of the outputs of these neurons, upon which our functional data will be added. By building such an in depth map we hope to build a model of respiration to help guide future experiments and therapeutic targeting.

呼吸是我们出生后的第一个动作，也是我们在死亡前完成的最后一个动作。从第一次呼吸到最后一次呼吸，实际上是我们如何定义一个人的生命。我们不爱我们的孩子从他们的“第一眼”，我们不爱我们的合作伙伴，直到我们的“死的想法”，士兵不战斗，直到他们最后的“心跳”，没有人在一个惊喜的遭遇曾经说“我活着和走”。然而，我们冒着呼吸是理所当然的风险。呼吸模式是由专门的核-前伯青格复合体产生的（preBötC;控制吸气），吸气后振荡器，目前被认为是吸气后复合体（皮科），以及面旁外侧区（pFL：控制呼气）我们对吸气振荡器了解很多：它的细分，以及它的输入和输出;我们甚至知道它是人类的类似物，由~ 120，000个神经元组成。对另外两个振荡器的了解要少得多。在剩下的两个中，呼气振荡器是研究得最好的，但即使这样，我们的知识也是最少的：我们大致知道这些神经元产生哪些神经递质，但如果它们被进一步细分就不知道了;我们知道兴奋亚型的功能，但不知道抑制亚型的功能;虽然我们有它的输入地图，但它的输出在很大程度上仍然是未知的。最后，吸气后振荡器在很大程度上还没有被研究：我们知道它的细分，但它们的功能大多是不确定的，除了它们驱动吸气后运动输出，同时减少吸气时间;我们对它的输出知之甚少，除了它似乎没有直接投射到呼气振荡器。在这组实验中，我们将在节律产生过程中操纵不同的神经元亚群。网络这些操作将集中在经常被忽视的抑制性神经元和驱动它们的兴奋性神经元的作用上。通过单独或组合地改变它们的活动，我们可以开始解析这些振荡器中不同类型的神经元如何共同工作以形成运动输出模式。此外，将使神经元表达荧光分子以识别和量化神经元，同时允许我们建立这些神经元输出的解剖图，在此基础上添加我们的功能数据。通过构建这样一个深度图，我们希望建立一个呼吸模型，以帮助指导未来的实验和治疗靶向。