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

每次我们触摸到一个物体，感觉到手上寒冷的冬天的风，或者从我们的手指上感受到一杯茶的温暖，皮肤上对机械和热刺激做出反应的特定感觉神经末梢都被激活了。这些感觉信息沿着特定类型的神经纤维传递，这些神经纤维从这些末梢投射到我们的中枢神经系统，然后它可以被感知为触觉、冷或温暖的感觉。尽管我们的中枢神经系统不断接收大量的感官信息，比如衣服对皮肤的压力，或者穿着鞋子的脚的温度，但我们能够下意识地过滤或优先处理这些信息，使我们能够对环境做出与上下文相关的反应，并在不使感官系统过载的情况下继续我们的日常事务。然而，当人们在意外事故中或由于手术治疗而损坏周围神经时，这种过滤系统的效率有时会发生变化，个体可能因此发展出一种改变的感觉处理状态，在这种状态下，以前无害的刺激现在被认为是痛苦的（触觉异常性痛）。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，从而允许中枢神经系统过滤传入的感觉信息，而不需要更复杂的处理。我认为，表达钙结合蛋白小白蛋白的脊髓背角细胞是一个可能执行这一功能的群体，因此构成了一个非常重要（且易于识别）的中间神经元类别。我将利用一系列的免疫组织学实验来描述大鼠和小鼠的这些神经细胞，以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（以及由此产生的感觉模式）。然后，我将通过在转基因小鼠模型中进行有针对性的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，所有含有小白蛋白的细胞都经过基因改造，可以发出固有的绿色荧光。在确定了这些细胞的电生理和神经解剖学特征后，我打算看看在手术诱导的周围神经损伤后发生触觉异常性疼痛的小鼠中，如果有的话，这些特性中的哪些会发生变化。我相信这个项目对于帮助我们更好地理解脊髓的基本电路至关重要，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导致了触觉异常性疼痛的发展。通过确定这些基本特性，希望能够开发出更有效地管理或缓解慢性疼痛的特定药理疗法。

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.