Modulating cutaneous afferent input: Identifying a source of presynaptic (axo-axonic) inputs inthe mouse spinal dorsal horn

调节皮肤传入输入：识别小鼠脊髓背角突触前（轴突）输入的来源

• 批准号: BB/J000620/1
• 负责人: David Hughes
• 金额: $ 63.24万
• 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: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ000620%2F1
• 关键词: Modulating; cutaneous; afferent; input; Identifying

Each time we touch an object, feel the cold winter wind on our hands or the warmth from a cup of tea through our fingers, specific sensory nerve endings in the skin responding to mechanical and thermal stimuli have been activated. This sensory information is transmitted along specific types of nerve fibres that project from these peripheral endings and into our central nervous system where it can then be perceived as touch, cold or warmth sensations. Although our central nervous system receives a constant barrage of sensory information such as the pressure of clothes on our skin or the warmth of our feet in our shoes, we are able to subconsciously filter or prioritise this information, enabling us to mount contextually relevant responses to our environment and carry on with our daily business without overloading our sensory systems. However, in cases where people have damaged peripheral nerves in accidents or as a result of surgical treatment, the efficiency of this filtering system sometimes changes and the individual may as a consequence develop an altered state of sensory processing, where previously innocuous stimuli are now perceived as being painful (tactile allodynia). The aim of this project is to identify a population of cells that are responsible for controlling the flow sensory input entering the spinal cord directly, thereby allowing the central nervous system to filter incoming sensory information without the need for more complex processing. I propose that spinal dorsal horn cells that express the calcium-binding protein parvalbumin are a population likely to carry out this function and therefore constitute a very important (and easily identifiable) class of interneuron. I will aim to characterise these nerve cells in the rat and mouse using a series of immunohistological experiments to determine the morphological features of these cells and establish which class of sensory fibres (and consequently sensory modalities) they are likely to control. I will then determine the electrophysiological properties of these cells by carrying out targeted recording experiments in a transgenic mouse model where all cells containing parvalbumin have been genetically altered to emit an intrinsic green fluorescence. Having established both the electrophysiological and neuroanatomical characteristics of these cells, I then intend to see which, if any, of these properties change in mice that have developed tactile allodynia following surgically-induced peripheral nerve injury. I believe that this project is critical in helping us gain a better understanding of the basic circuitry of the spinal cord, how these cells filter sensory information entering the central nervous system and also what changes occur that contribute to the development of tactile allodynia. By determining these basic properties, it is hoped that specific pharmacological therapies can then be developed to manage or alleviate chronic pain conditions more effectively.

每次我们触摸物体时，都会在手指上感受到寒冷的冬季风或一杯茶中的温暖，皮肤中的特定感觉神经末端对机械和热刺激有反应。这些感官信息沿着从这些外围末端投射到我们的中枢神经系统的特定类型的神经纤维传播，然后可以将其视为触摸，冷或温暖的感觉。尽管我们的中枢神经系统会收到不断的感官信息，例如衣服在皮肤上的压力或鞋子中的脚部温暖，我们能够下意识地过滤或优先考虑这些信息，使我们能够对环境的上下文相关响应，并在不超载我们的感觉系统的情况下随着我们的日常业务而继续进行上下文。但是，如果人们在事故中损害周围神经或由于手术治疗而受损的情况下，这种过滤系统的效率有时会发生变化，因此，个人可能会形成改变的感觉处理状态，而以前无害的刺激现在被认为是痛苦的（触觉异常）。该项目的目的是确定负责控制流动感官输入的细胞群，直接进入脊髓，从而使中枢神经系统可以过滤传入的感觉信息，而无需进行更复杂的处理。我建议表达钙结合蛋白白蛋白的脊柱背角细胞是可能执行此功能的人群，因此构成了一个非常重要的（易于识别）的中间神经元类。我将使用一系列免疫组织学实验来表征大鼠和小鼠中的这些神经细胞，以确定这些细胞的形态特征，并确定它们可能可以控制的一种感觉纤维（以及因此是感觉纤维）。然后，我将通过在转基因小鼠模型中进行靶向记录实验来确定这些细胞的电生理特性，在该模型中，所有含有白细胞蛋白的细胞均已遗传改变以发出固有的绿色荧光。在建立了这些细胞的电生理和神经解剖学特征之后，我打算查看这些特性（如果有的话）在手术诱导的周围神经损伤后发生了触觉异常的小鼠中发生了哪些变化。我认为，这个项目对于帮助我们更好地了解脊髓的基本电路，这些细胞如何过滤进入中枢神经系统的感觉信息以及发生的变化有助于触觉异常的发展，这一点至关重要。通过确定这些基本特性，希望可以开发特定的药理疗法来更有效地管理或减轻慢性疼痛状况。

项目成果

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.

Spinoparabrachial projection neurons form distinct classes in the mouse dorsal horn.

• DOI: 10.1097/j.pain.0000000000002194
• 发表时间: 2021-07-01
• 期刊: Pain
• 影响因子: 7.4
• 作者: Browne TJ;Smith KM;Gradwell MA;Iredale JA;Dayas CV;Callister RJ;Hughes DI;Graham BA
• 通讯作者: Graham BA

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

表达钙结合蛋白的胰岛细胞是小鼠脊髓非肽能伤害感受器输入的突触前和突触后抑制的来源

• DOI: 10.5167/uzh-234968
• 发表时间: 2023
• 作者: Davis, Olivia C

Anatomical and Molecular Properties of Long Descending Propriospinal Neurons in Mice.

• DOI: 10.3389/fnana.2017.00005
• 发表时间: 2017
• 期刊: Frontiers in neuroanatomy
• 影响因子: 2.9
• 作者: Flynn JR;Conn VL;Boyle KA;Hughes DI;Watanabe M;Velasquez T;Goulding MD;Callister RJ;Graham BA
• 通讯作者: Graham BA

The Cellular and Synaptic Architecture of the Mechanosensory Dorsal Horn.

• DOI: 10.1016/j.cell.2016.12.010
• 发表时间: 2017-01-12
• 期刊: Cell
• 影响因子: 64.5
• 作者: Abraira VE;Kuehn ED;Chirila AM;Springel MW;Toliver AA;Zimmerman AL;Orefice LL;Boyle KA;Bai L;Song BJ;Bashista KA;O'Neill TG;Zhuo J;Tsan C;Hoynoski J;Rutlin M;Kus L;Niederkofler V;Watanabe M;Dymecki SM;Nelson SB;Heintz N;Hughes DI;Ginty DD
• 通讯作者: Ginty DD