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

每当我们触摸物体，感受我们手上的寒风，或者通过我们的手指感受一杯茶的温暖时，皮肤上对机械和热刺激做出反应的特定感觉神经末梢都会被激活。这种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外周末端投射到我们的中枢神经系统，在那里它可以被感知为触摸、冷感或暖感。尽管我们的中枢神经系统不断地收到一连串的感觉信息，比如衣服对我们皮肤的压力或我们脚穿鞋子的温度，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环境相关的反应，并在不使我们的感觉系统超载的情况下继续我们的日常事务。然而，如果人们在事故中或由于手术治疗而损害了周围神经，这种过滤系统的效率有时会改变，因此个人可能会产生感觉处理的改变状态，在这种状态下，以前无害的刺激现在被认为是疼痛的(触觉异常痛症)。这个项目的目的是识别一组负责控制感觉输入直接进入脊髓的流量的细胞，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，因此构成了一类非常重要的(且容易识别的)中间神经元。我的目标是通过一系列免疫组织学实验来确定这些细胞的形态特征，并确定它们可能控制哪一类感觉纤维(以及随后的感觉方式)，以确定这些神经细胞的特征。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，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，我打算看看这些属性中的哪些，如果有的话，在手术诱导的周围神经损伤后出现触觉过敏的小鼠身上发生变化。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，这些细胞如何过滤进入中枢神经系统的感觉信息，以及发生了哪些有助于触觉异常痛的发展的变化是至关重要的。通过确定这些基本特性，人们希望能够开发出特定的药物疗法，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.