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

每当我们触摸到一个物体，感觉到冬天的寒风吹过我们的手，或者通过手指感受到一杯茶的温暖时，皮肤中对机械和热刺激做出反应的特定感觉神经末梢就会被激活。这种感觉信息是沿着特定类型的神经纤维传递的，这些神经纤维从这些外周末梢投射到我们的中枢神经系统，在那里它可以被感知为触觉、冷或热的感觉。虽然我们的中枢神经系统会不断接收到大量的感官信息，比如衣服对皮肤的压力或脚在鞋子里的温度，但我们能够下意识地过滤或优先考虑这些信息，使我们能够对环境做出与环境相关的反应，并在不使我们的感官系统过载的情况下继续我们的日常事务。然而，在人们在事故中或由于手术治疗而损伤外周神经的情况下，这种过滤系统的效率有时会改变，并且个体可能因此发展出感觉处理的改变状态，其中先前无害的刺激现在被感知为疼痛（触觉异常性疼痛）。该项目的目的是确定负责控制直接进入脊髓的感觉输入流的细胞群，从而使中枢神经系统能够过滤传入的感觉信息，而无需进行更复杂的处理。我建议，脊髓背角细胞表达的钙结合蛋白parvalbumin是一个人口可能进行这一功能，因此构成了一个非常重要的（和容易识别）类interneuron。我的目标是使用一系列免疫组织学实验来确定这些细胞的形态学特征，并确定它们可能控制哪一类感觉纤维（以及因此的感觉方式）。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，在转基因小鼠模型中，所有含有小清蛋白的细胞都被遗传改变以发射内在绿色荧光。在建立了这些细胞的电生理和神经解剖学特征之后，我打算看看这些特性中的哪一个（如果有的话）在小鼠中发生了触觉异常性疼痛，这些小鼠在神经损伤诱导的外周神经损伤之后发生了触觉异常性疼痛。我相信这个项目对于帮助我们更好地了解脊髓的基本回路至关重要，这些细胞如何过滤进入中枢神经系统的感觉信息，以及发生了什么变化有助于触觉异常性疼痛的发展。通过确定这些基本性质，希望可以开发特定的药理学疗法，以更有效地管理或缓解慢性疼痛状况。

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.