Dissection of a new spinal cord circuit in pain sensation

伤害感，或有害刺激的感觉，对我们的日常生活是必不可少的。正常的急性痛觉可防止 我们从潜在的损害或重复的伤害，而在病理条件下扭曲的神经电路更 吃慢性疼痛，这是一个巨大的人类健康问题。目前，我们对神经回路的理解 在正常和病理条件下，调节和调节痛觉是令人惊讶的不完整的。 我们建议研究一组表达该受体的抑制性脊髓背侧中间神经元。 酪氨酸激酶RET，约占III-V板层抑制性中间神经元的三分之一 (深层)。我们的初步研究表明，这些深层早期RET抑制中间神经元是独一无二的 它们在伤害性感受中的回路和功能以前还没有被定义过。 目的1.确定深层早期RET抑制的分子、生理和解剖学特性 中间神经元。为此，我们将对深层早期的RET抑制中间神经元进行基因标记，以研究它们的 大体解剖、抑制性神经递质的特性、生理特性和单个神经元的形态。 GY。我们的预期结果将揭示深层早期RET抑制中间神经元的独特特征和促RET活性。 深入了解它们之间的潜在联系和功能。 目的2.解剖与深层早期RET抑制中间神经元相关的神经回路。在这个目标中， 我们将同时使用光学/电子显微镜成像和脊髓切片记录，并结合电子和 光刺激以确定深层早期RET抑制中间神经元的输入和输出。在一起，我们的 这项工作将揭示与这种新的脱氢酶抑制中间神经元相关的功能联系。 目的3.测定急性疼痛和慢性疼痛中深层早期RET抑制中间神经元的功能 疼痛。在这一目标中，我们将要么用毒素消融深层早期RET抑制中间神经元，要么急性激活RET抑制中间神经元。 使用光遗传学和药理学方法激发它们，并测试小鼠的伤害性行为反应 在急性和慢性疼痛条件下。通过这些实验，我们预计将揭示重要的功能 深层早期RET抑制中间神经元在调节急、慢性疼痛中的作用。 简而言之，我们提出的研究将阐明一种新的脱氢酶抑制中枢神经元的电路和功能。 在管理伤害性信息的传递和调制方面。我们的工作会带来更好的 从而为慢性疼痛的治疗提供潜在的新思路。

Nociception, or the sense of noxious stimuli, is essential for our daily lives. Normal acute nociception prevents us from potential damage or repetitive injuries, while distorted neural circuits in pathological conditions gener- ate chronic pain, which is a huge human health problem. At present, our understanding of neural circuits in mediating and modulating pain sensation under normal and pathological conditions is surprisingly incomplete. We proposed to study a population of inhibitory dorsal spinal cord interneurons, which express the receptor tyrosine kinase RET neonatally and makes up about one third of inhibitory interneurons in laminae III to V (deep layer). Our preliminary study showed that these deep layer early RET+ inhibitory interneurons are unique and their circuits and functions in nociception have not been defined before. Aim 1. Define molecular, physiological, and anatomical properties of deep layer early RET+ inhibitory interneurons. In this aim, we will genetically label deep layer early RET+ inhibitory interneurons to study their gross anatomy, identities of inhibitory neural transmitter, physiological properties, and single neuron morpholo- gy. Our anticipated results will reveal unique features of deep layer early RET+ inhibitory interneurons and pro- vide an insight into their potential connections and functions. Aim 2. Dissect neural circuits associated with deep layer early RET+ inhibitory interneurons. In this aim, we will use both light/electronic microscopy imaging and spinal cord slice recording coupled with electric and optical stimuli to determine input and output of deep layer early RET+ inhibitory interneurons. Together, our work will reveal functional connections associated with this new population of DH inhibitory interneurons. Aim 3. Determine functions of deep layer early RET+ inhibitory interneurons in acute pain and chronic pain. In this aim, we will either ablate deep layer early RET+ inhibitory interneurons using toxin or acutely acti- vate them using optogenetic and pharmacological approach and test mouse nociceptive behavioral responses under acute and chronic pain conditions. With these experiments, we anticipate revealing important functions of deep layer early RET+ inhibitory interneurons in modulating acute and chronic pain. In short, our proposed study will elucidate circuits and function of a new population of DH inhibitory interneu- rons in governing the transmission and modulation of nociceptive information. Our work would lead to a better understanding about DH circuits and provide potential new thoughts for chronic pain treatment.