Dissecting active neural circuits regulating sensory and affective pain

剖析调节感觉和情感疼痛的活跃神经回路

• 批准号: 10206401
• 负责人: Akihiko Ozawa
• 金额: $ 67.28万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10206401
• 关键词: Acute; Acute Pain; Address; Affective; Analgesics; Animals; Anterior; Anxiety; Applications Grants; Attention; Automobile Driving; Behavior; Brain; Brain region; Cells; Clinical; Cognition; Cognitive; Communication; Contralateral; DNA; Data; Development; Dimensions; Emotional; Emotions; Empathy; Enterobacteria phage P1 Cre recombinase; FOS gene; Fiber; Future; Genetic; Genetic Recombination; Genetically Engineered Mouse; Goals; Immediate-Early Genes; Individual; Ipsilateral; Knowledge; Light; Link; Mechanics; Mediating; Mental Depression; Modality; Molecular; Motor; Mus; Neuraxis; Neuroanatomy; Neurons; Neurosciences; Nociception; Nociceptive Stimulus; Opioid; Pain; Pain management; Painless; Patients; Peripheral; Pharmacology Study; Photometry; Process; Quality of life; Research Proposals; Role; Sensory; Side; Signal Transduction; Spinal; Spinal Cord; Spinal nerve structure; Stimulus; Structure; System; Tamoxifen; Technology; Tissues; Touch sensation; addiction; chronic neuropathic pain; chronic pain; chronic painful condition; cingulate cortex; expectation; genetic approach; in vivo imaging; injured; mouse genetics; neural circuit; novel; opioid abuse; opioid misuse; optimal treatments; optogenetics; pain behavior; pain sensation; pain signal; psychologic; recombinase; relating to nervous system; response; side effect; somatosensory; tool; transmission process

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.

项目概要 阿片类药物作为止痛药一直是最受欢迎的疼痛治疗方法，可以快速缓解疼痛 剧烈疼痛。数十年的阿片类药物滥用对疼痛治疗产生了负面影响。对神经的理解 为了开发更有效、更安全的疼痛疗法，真正驱动疼痛的回路至关重要。 神经解剖学研究使我们能够定义对神经元至关重要的区域和子集。 疼痛。然而，对于每种疼痛方式激活的神经回路的了解非常有限。 IE。 所有疼痛依赖性激活的神经元亚群如何进行通信以传输衍生的伤害性信号 通过不同的疼痛状况以及区分急性和慢性疼痛的转变。此外，最近 注意力也转向了疼痛情绪维度的机制，例如抑郁、焦虑、 以及认知能力丧失，尤其是与慢性疼痛相关的认知能力丧失。前扣带皮层 (ACC) 是大脑 已知会驱动与慢性疼痛相关的厌恶的结构。 ACC神经元的功能变化 慢性疼痛引起的疼痛尚未在分子和神经回路水平上得到明确解释。我们的初步 研究表明，同侧有大量的神经元被疼痛特异性激活 SNL 小鼠的脊髓与假手术小鼠相比。同样，对侧神经元 ACC在慢性疼痛情况下也会选择性激活，这也与之前的研究一致 研究描述了由于 ACC 神经元过度兴奋而与慢性疼痛相关的厌恶反应。 因此，在这里，我们重点关注与疼痛相关行为的两个代表性区域：ACC 作为关键大脑 情感疼痛的结构；和脊髓使用小鼠遗传学结合感觉 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的活跃神经回路来研究疼痛相关行为的机制 状况。在具体目标 1 中，我们将识别由不同疼痛刺激（急性热刺激）激活的神经元亚群 和机械性疼痛，以及慢性疼痛）在脊髓中，并通过化学遗传学手段操纵疼痛的活动 专门激活的神经元，以验证这些神经元直接调节特定的疼痛 方式。在具体目标 2 中，我们将研究慢性疼痛依赖性激活的 ACC 神经元在 为了更好地理解 ACC 区分情感和情感的机制 与慢性疼痛相关的感觉疼痛行为。我们将使用神经解剖学追踪来识别 ACC 神经元亚群及其投射神经元与其他与疼痛相关的大脑区域进行通信。我们的 拟议的研究将使我们能够为未来的目标大脑电路项目 R01 收集可行性数据 研究提案，这将有助于进一步了解调节信号传输的主动神经回路 脊髓的不同疼痛方式引起的疼痛感觉信号以及情感的表达 慢性疼痛中 ACC 回路介导的感觉疼痛行为。

项目成果

Functional and anatomical analyses of active spinal circuits in a mouse model of chronic pain.

• DOI: 10.1097/j.pain.0000000000003068
• 发表时间: 2023-10
• 期刊: Pain
• 影响因子: 7.4
• 作者: Katarzyna M Targowska-Duda;Darian Peters;Jason L. Marcus;Gilles Zribi;L. Toll;Akihiko Ozawa