Dissection of a new spinal cord circuit in pain sensation

伤害性感受，或对有害刺激的感觉，对我们的日常生活至关重要。正常的急性伤害性感受 我们从潜在的损害或重复性损伤，而扭曲的神经回路在病理条件下， 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介导和调节痛觉是令人惊讶的不完全的。 我们建议研究一群抑制性脊髓背侧中间神经元，它们表达受体 酪氨酸激酶RET是一种重要的抑制性中间神经元，约占III至V层抑制性中间神经元的三分之一 (deep层）。我们的初步研究表明，这些深层早期RET+抑制性中间神经元是独特的， 并且它们在伤害感受中的回路和功能以前没有被定义。 目标1。定义深层早期RET+抑制的分子、生理和解剖学特性 中间神经元在这个目标中，我们将遗传标记深层早期RET+抑制性中间神经元，以研究它们的功能。 大体解剖，抑制性神经递质的身份，生理特性，和单个神经元形态， 戈伊。我们的预期结果将揭示深层早期RET+抑制性中间神经元和前 深入了解它们的潜在联系和功能。 目标2.解剖与深层早期RET+抑制性中间神经元相关的神经回路。在这一目标下， 我们将使用光学/电子显微镜成像和脊髓切片记录， 光学刺激以确定深层早期RET+抑制性中间神经元的输入和输出。我们一起， 这项工作将揭示与这种新的DH抑制性中间神经元群体相关的功能连接。 目标3：确定急性疼痛和慢性疼痛中深层早期RET+抑制性中间神经元的功能 痛苦在这个目标中，我们将使用毒素消融深层早期RET+抑制性中间神经元，或急性激活 利用光遗传学和药理学方法评估它们，并测试小鼠伤害性行为反应 在急性和慢性疼痛条件下。通过这些实验，我们预计会揭示重要的功能 深层早期RET+抑制性中间神经元在调节急性和慢性疼痛中的作用。 简而言之，我们的研究将阐明DH抑制性interneu的新群体的电路和功能。 神经元在控制伤害性信息的传递和调制中的作用。我们的工作会带来更好的 为慢性疼痛的治疗提供新的思路。

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.