From the spinal cord to the brain: Neurology of the pain and itch neurons

尽管我们对初级感觉神经元和脊髓的了解取得了巨大进展， 对疼痛和瘙痒刺激做出反应并传递的神经元间回路，这些刺激是如何 但是，大脑如何解释这些信号以产生疼痛和瘙痒的感觉仍然不清楚。在很大程度上，这种差距 反映了我们对投射神经元的有限信息， 将信息从脊髓传递到大脑。这一差距是至关重要的，因为它是信号所携带的 投射神经元被大脑“读取”，最终导致疼痛或瘙痒的感知， 它们的各种子模态（热、冷、机械等）。我们的研究计划是多学科的，使用 新的病毒，遗传和功能（电生理，行为和成像）的方法来表征 投射神经元的特性，参与它们的回路，它们的脊髓上靶点， 其活动的功能性后果。研究计划的一个重要焦点是 对疼痛或瘙痒刺激作出反应的回路的会聚或分离，以及 这些回路在受伤的情况下会发生改变。我们的计划包括几个高度创新的 这些实验不仅首次确定了投射神经元的分子异质性， 而且还将检查脑中神经元群体对投射神经元中的活动的响应。 定义投射神经元的分子亚型和基于Cre表达小鼠的发育 这些分子特征将允许大量的实验，包括基于病毒的逆行（狂犬病）， 顺行（HSV）追踪影响投射神经元子集的回路，以及行为神经元的行为。 选择性消融的结果，或DREADD介导的这些神经元的激活/抑制。最后利用 令人难以置信的强大的钙离子成像技术，信号的神经元群体的活动，在清醒，自由 移动小鼠，我们将获得新的信息，行为相关的algogen和促肾上腺素诱发的 脊髓上活动使用新的行为范式，我们的计划也将提供重要的见解， 通过这些过程，有害的，甚至无害的刺激（在受伤的情况下），被解释为 痛.这些新方法将提供有关动物疼痛的质量的信息， 经验，并提供了一个强有力的验证小鼠模型的慢性疼痛和瘙痒， 翻译到人类的状态。

Despite tremendous progress in our understanding of the primary sensory neurons and spinal cord interneuronal circuits that respond to and transmit pain and itch-provoking stimuli, how these stimuli are interpreted by the brain to produce the perceptions of pain and itch are still unclear. To a great extent, this gap in our knowledge reflects the much more limited information that we have about the projection neurons that carry the information from the spinal cord to the brain. That gap is critical as it is the signals carried by the projection neurons that are “read” by the brain and that ultimately lead to a perception of pain or itch, and to their various submodalities (heat, cold, mechanical, etc.). Our research program is multidisciplinary, using novel viral, genetic and functional (electrophysiological, behavioral and imaging) approaches to characterize the properties of the projection neurons, the circuits that engage them, their supraspinal targets and the functional consequence of their activity. An important focus of the research program is on the question of convergence or segregation of the circuits that respond to painful or itch-provoking stimuli and the extent to which these circuits are altered in the setting of injury. Our program includes several highly innovative experiments that for the first time will not only determine the molecular heterogeneity of the projection neurons, but will also examine the responses of populations of neurons in the brain to activity in the projection neurons. Defining molecular subtypes of projection neurons and the development of Cre-expressing mice based on these molecular features will permit a host of experiments, including viral-based retrograde (rabies) and anterograde (HSV) tracing of circuits that influence subsets of projection neurons, as well as the behavioral consequence of selective ablation, or DREADD-mediated activation/inhibition of these neurons. Finally, using incredibly powerful Ca2+ imaging techniques that signal the activity of populations of neurons in awake, freely moving mice, we will obtain new information on the behavioral correlates of algogen and pruritogen-evoked supraspinal activity. Using novel behavioral paradigms our program will also provide important insights into the processes through which noxious, and even innocuous stimuli (in the setting of injury), are interpreted as painful. These new approaches will provide information about the quality of the pain that the animal experiences and also offer a powerful validation of the mouse models of chronic pain and itch and their translatability to the human condition.