Dissecting active neural circuits regulating sensory and affective pain

项目摘要 阿片类药物作为一种止痛药一直是最受欢迎的止痛疗法，以提供快速缓解 剧烈的疼痛。几十年的阿片类药物滥用给疼痛治疗带来了负面影响。对神经学的认识 为了开发更有效和更安全的疼痛治疗方法，实际驱动疼痛的电路是必不可少的。 神经解剖学研究使我们能够定义神经元的重要区域和亚群 疼痛。然而，对每种疼痛模式激活的神经回路的了解非常有限； 所有痛依赖激活的神经元亚群是如何传递伤害性信号的 通过不同的疼痛情况以及区分急性和慢性疼痛的过渡。此外，最近 注意力也调谐到了疼痛的情感维度的潜在机制，如抑郁、焦虑、 和认知丧失，特别是与慢性疼痛有关。前扣带回皮质(ACC)是一个大脑 已知的结构会驱使与慢性疼痛相关的厌恶。肾上腺皮质神经元的功能变化 由慢性疼痛引起的疼痛尚未在分子和神经电路水平上得到明确解释。我们的预赛 研究表明，更多的神经元是疼痛在同侧被特异性激活。 与假手术组相比，SNL组小鼠脊髓损伤明显减少。类似地，对侧脑皮质中的神经元 在慢性疼痛条件下，ACC也被选择性地激活，这也与以前的 描述由于ACC神经元的过度兴奋而导致的慢性疼痛相关的厌恶反应的研究。 因此，在这里，我们将重点放在疼痛相关行为的两个代表性区域：作为关键大脑的ACC 结构中的情感疼痛；和脊髓的感觉使用小鼠遗传学结合 神经解剖学、化学遗传学和神经记录，以便更好地了解 通过揭示特定疼痛下活跃的神经回路来揭示疼痛相关行为的机制 条件。在特定的目标1中，我们将确定由不同的疼痛刺激(急性高温)激活的神经元亚群 和机械性疼痛，以及慢性疼痛)，并通过化学遗传学控制疼痛的活动 为了验证这些神经元是否直接调节特定的疼痛 医疗模式。在特定的目标2中，我们将研究慢性疼痛依赖激活的ACC神经元在 为了更好地了解ACC区分情感和情感障碍的机制 与慢性疼痛相关的感官疼痛行为。我们将使用神经解剖示踪来识别ACC 神经元亚群及其与其他疼痛相关脑区的投射神经元。我们的 拟议的研究将使我们能够为未来有针对性的大脑电路项目R01收集可行性数据 研究建议，这将有助于进一步了解调节神经递质传递的活跃神经回路 不同疼痛方式在脊髓诱发的痛觉信号及其情感表达 以及在慢性疼痛中由ACC环路介导的感觉性疼痛行为。

Project Summary Opioids as a pain medication has been the most preferred pain treatments in order to provide quick relief from severe pain. Decades of opioid abuse have triggered negative impact on pain therapies. Understanding of neural circuits that are actually driving pain is essential in order to develop more effective and safer pain therapies. Neuroanatomical studies have allowed us to define the regions and subsets of neurons that are important for pain. However, there is very limited understanding of neural circuits that are activated by each pain modality; i.e. how all of the pain-dependently activated neuronal subsets communicate to transmit nociceptive signals derived by distinct pain conditions as well as to distinguish the transition of acute and chronic pain. In addition, recent attention has also tuned into mechanisms underlying emotional dimension of pain such as depression, anxiety, and loss of cognition, especially associated with chronic pain. The anterior cingulate cortex (ACC) is a brain structure known to drive aversion associated with chronic pain. The functional changes in the ACC neurons caused by chronic pain have yet to be clearly explained at the molecular and neural circuit levels. Our preliminary studies have demonstrated that a larger number of neurons are pain specifically activated in the ipsilateral side of the spinal cord in SNL mice compared to those of sham. Similarly, neurons in the contralateral side of the ACC are also selectively activated under a chronic pain condition, which is also consistent with the previous studies describing aversive response associated with chronic pain due to the hyperexcitability of ACC neurons. Here, we therefore focus on two representative regions for pain-related behaviors: the ACC as a key brain structure in the affective pain; and the spinal cord for sensory using mouse genetics combined with neuroanatomy, chemogenetics, and neural recording in order to obtain a better understanding of the mechanisms underlying pain-related behaviors by shedding light on active neural circuits under specific pain conditions. In Specific Aim 1, we will identify the neuronal subsets activated by distinct pain stimuli (acute heat and mechanical pain, and chronic pain) in the spinal cord, and chemogenetically manipulate the activity of pain specifically-activated neurons in order to validate that these neurons are directly regulating the specific pain modalities. In Specific Aim 2, we will investigate the role of chronic pain dependently activated ACC neurons in order to obtain a better understanding of the mechanism by which the ACC discriminates the affective and sensory pain behavior associated with chronic pain. We will use neuroanatomical tracing to identify the ACC neuronal subsets and their projection neurons communicating with other pain-related brain regions. Our proposed studies will enable us to collect feasibility data for a future Targeted BRAIN Circuits Projects R01 research proposal, which will help to further understand the active neural circuits regulating the transmission of pain sensory signals elicited by different pain modalities at the spinal cord and also the expression of affective and sensory pain behavior mediated by the ACC circuits in chronic pain.