The roles of functionally defined populations of lamina I projection neurons

功能明确的 I 层投射神经元群体的作用

• 批准号: MR/V033638/1
• 负责人: Junichi Hachisuka
• 金额: $ 110.2万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV033638%2F1
• 关键词: roles; functionally; defined; populations; lamina

Neuropathic pain is a distressing condition that commonly occurs following disease or injury to nerves, and affects nearly 10% of the population. Treatment is often inadequate, and a major reason for this is our limited understanding of the nerve circuits in the spinal cord that are involved in this condition. Previous studies have identified a group of nerve cells in the superficial part of the spinal cord, known as lamina I projection neurons, which carry sensory information related to pain and skin temperature directly to the brain. It has also been shown that these cells have a role in neuropathic pain. However, the projection neurons are functionally heterogeneous, and this has made it difficult to understand the nerve circuits with which they interact, and to define their roles in different types of pain. In a recent study, we showed that two largely separate populations, which account for ~85% of lamina I projection neurons, could be identified in the mouse based on the presence of two different proteins. These proteins are encoded by genes known as Tacr1 and Gpr83. We found that the Tacr1 and Gpr83 cells differed in their responses to painful or thermal stimuli applied to the skin, implying that they are responsible for different aspects of pain and temperature sensation. That study forms the starting point for the current project. We will initially identify specific populations of lamina I projection neurons by examining responses to skin stimulation not only for cells that express each of these receptors, but also for the smaller populations that express both receptors, or neither receptor. Previous studies in other species have suggested that different types of projection neuron have specific morphological features, and we will determine whether this is true for projection neurons in the mouse. We will then test the prediction that these different types of projection neuron are involved in different nerve circuits within the spinal cord. To do this, we will first investigate their inputs from another class of cell, known as excitatory interneurons. We will also test their responses to a class of drug known as opioids (which includes morphine) that can powerfully suppress pain. Blocking activity in a different group of spinal cord cells, known as inhibitory interneurons, leads to exaggerated sensations and this mechanism is thought to contribute to neuropathic pain. It has been shown that some lamina I projection neurons develop novel responses to brushing of hairs on the skin when this inhibition is blocked, and this is probably a correlate of the touch-evoked pain often seen in patients with nerve damage. We will test which classes of projection neuron show this type of response. We will then use an in vivo experimental approach that will allow us to silence the Tacr1 or Gpr83 cells individually, or to silence both populations simultaneously. We will initially test two different methods, involving either a cell-specific toxic protein, or a light-sensitive protein that will block activity in specific cells. We will determine which of these is more effective, and then apply it to a mouse model of nerve injury and test whether silencing each of these populations suppresses different aspects of neuropathic pain, such as spontaneous pain, or either mechanical or thermal hypersensitivity. Finally, we will examine a specific functional population of lamina I projection neurons that respond exclusively to cooling of the skin, rather than painful stimuli. We will test the prediction that these are the cells that lack both Tacr1 and Gpr83 receptors, and we will investigate the nerve circuits to which they contribute.The project will provide valuable information about how the spinal cord processes sensory information perceived as pain and temperature, as well as the cells and circuits that underlie neuropathic pain. This is vital for the development of new therapies for treating this distressing condition.

神经性疼痛是一种令人痛苦的情况，通常发生在疾病或神经损伤之后，影响到近10%的人口。治疗往往是不够的，一个主要原因是我们对脊髓中与这种情况有关的神经回路的了解有限。此前的研究已经发现，脊髓浅层有一组神经细胞，被称为I层投射神经元，它们将与疼痛和皮肤温度相关的感觉信息直接传递到大脑。研究还表明，这些细胞在神经病理性疼痛中起着一定作用。然而，投射神经元在功能上是不同的，这使得理解它们相互作用的神经回路，以及确定它们在不同类型疼痛中的作用变得困难。在最近的一项研究中，我们表明，基于两种不同蛋白的存在，可以在小鼠中识别出两个基本独立的群体，这两个群体约占I层投射神经元的85%。这些蛋白质由被称为Tacr1和GPR83的基因编码。我们发现，Tacr1和GPR83细胞对施加在皮肤上的疼痛或热刺激的反应不同，这意味着它们对疼痛和温度感觉的不同方面负责。这项研究构成了当前项目的起点。我们最初将通过检测皮肤刺激的反应来鉴定I层投射神经元的特定群体，不仅检测表达这些受体中每一个的细胞，而且检测表达两种受体或不表达任何受体的较小群体。以前在其他物种中的研究表明，不同类型的投射神经元具有特定的形态特征，我们将确定这是否适用于小鼠的投射神经元。然后，我们将测试这些不同类型的投射神经元参与脊髓内不同神经回路的预测。为了做到这一点，我们将首先研究它们来自另一类细胞的输入，即兴奋性中间神经元。我们还将测试他们对一种被称为阿片类药物(包括吗啡)的反应，这种药物可以有效地抑制疼痛。另一组被称为抑制性中间神经元的脊髓细胞的阻断活动会导致夸张的感觉，这一机制被认为是神经病理性疼痛的原因之一。已有研究表明，当这种抑制被阻断时，一些板层I投射神经元对皮肤上的刷毛产生新的反应，这可能与神经损伤患者中常见的触摸诱发疼痛有关。我们将测试哪类投射神经元显示出这种类型的反应。然后，我们将使用体内实验方法，允许我们单独使Tacr1或GPR83细胞沉默，或同时使这两个群体沉默。我们最初将测试两种不同的方法，要么涉及细胞特异性有毒蛋白，要么涉及将阻断特定细胞活动的光敏蛋白。我们将确定其中哪一种更有效，然后将其应用于神经损伤的小鼠模型，并测试沉默这些群体中的每一种是否会抑制神经病理性疼痛的不同方面，如自发性疼痛，或者机械或热过敏。最后，我们将研究板层I投射神经元的特定功能群体，这些神经元只对皮肤的降温反应，而不是疼痛刺激。我们将验证这样的预测，即这些细胞同时缺乏Tacr1和GPR83受体，我们将研究它们参与的神经回路。该项目将提供有关脊髓如何处理感知到的疼痛和温度的感觉信息以及神经病理性疼痛背后的细胞和回路的有价值的信息。这对于开发治疗这种令人痛苦的疾病的新疗法至关重要。

项目成果

Neuropeptide Y-expressing dorsal horn inhibitory interneurons gate spinal pain and itch signalling.

• DOI: 10.7554/elife.86633
• 发表时间: 2023-07-25
• 期刊: eLife
• 影响因子: 7.7
• 作者: Boyle KA;Polgar E;Gutierrez-Mecinas M;Dickie AC;Cooper AH;Bell AM;Jumolea E;Casas-Benito A;Watanabe M;Hughes DI;Weir GA;Riddell JS;Todd AJ
• 通讯作者: Todd AJ

Sodium-calcium exchanger-3 regulates pain "wind-up": From human psychophysics to spinal mechanisms.

• DOI: 10.1016/j.neuron.2022.05.017
• 发表时间: 2022-08-17
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Trendafilova T;Adhikari K;Schmid AB;Patel R;Polgár E;Chisholm KI;Middleton SJ;Boyle K;Dickie AC;Semizoglou E;Perez-Sanchez J;Bell AM;Ramirez-Aristeguieta LM;Khoury S;Ivanov A;Wildner H;Ferris E;Chacón-Duque JC;Sokolow S;Saad Boghdady MA;Herchuelz A;Faux P;Poletti G;Gallo C;Rothhammer F;Bedoya G;Zeilhofer HU;Diatchenko L;McMahon SB;Todd AJ;Dickenson AH;Ruiz-Linares A;Bennett DL
• 通讯作者: Bennett DL

Grpr expression defines a population of superficial dorsal horn vertical cells that have a role in both itch and pain.

• DOI: 10.1097/j.pain.0000000000002677
• 发表时间: 2023-01-01
• 期刊: Pain
• 影响因子: 7.4

Calretinin-expressing islet cells are a source of pre- and post-synaptic inhibition of non-peptidergic nociceptor input to the mouse spinal cord.

• DOI: 10.1038/s41598-023-38605-9
• 发表时间: 2023-07-18
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Davis, Olivia C.;Dickie, Allen C.;Mustapa, Marami B.;Boyle, Kieran A.;Browne, Tyler J.;Gradwell, Mark A.;Smith, Kelly M.;Polgar, Erika;Bell, Andrew M.;Kokai, Eva;Watanabe, Masahiko;Wildner, Hendrik;Zeilhofer, Hanns Ulrich;Ginty, David D.;Callister, Robert J.;Graham, Brett A.;Todd, Andrew J.;Hughes, David I.
• 通讯作者: Hughes, David I.