Amygdala mechanisms of pain aversion

杏仁核的疼痛厌恶机制

• 批准号: 10163274
• 负责人: Gregory Scherrer
• 金额: $ 30.34万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163274
• 关键词: Acute; Acute Pain; Address; Affect; Affective; American; Amygdaloid structure; Anterior; Anxiety; Behavior; Brain; Brain Stem; Brain region; Calcium; Calcium Spikes; Cell Nucleus; Cells; Code; Data; Dependovirus; Desire for food; Detection; Development; Disease; Electrophysiology (science); Emotional; Enterobacteria phage P1 Cre recombinase; Female; Fluorescent in Situ Hybridization; Fostering; Fright; Functional disorder; Future; Image; In Situ Hybridization; Intralaminar Nuclear Group; Knowledge; Lead; Learning; Light; Mental Depression; Mental disorders; Methods; Mission; Motivation; Mus; National Institute of Neurological Disorders and Stroke; Negative Valence; Neurobiology; Neurons; Nociception; Output; Pain; Pain Research; Pain quality; Pathologic; Pattern; Personal Satisfaction; Play; Process; Public Health; Research; Role; Sensory; Shapes; Signal Transduction; Slice; Spinal Cord; Stimulus; Structure; Sucrose; Synapses; Synaptic Transmission; System; Testing; Thalamic structure; Touch sensation; United States National Institutes of Health; Viral; Water; Withdrawal; base; cell type; chronic neuropathic pain; chronic pain; chronic pain patient; comorbidity; experience; experimental study; innovation; male; microendoscopy; nerve injury; neurotransmission; novel; novel strategies; novel therapeutic intervention; optogenetics; presynaptic neurons; prevent; rabies viral tracing; relating to nervous system; somatosensory; tool

Pain is a multidimensional experience with sensory and affective components. The aversive quality of pain (i.e. pain aversion/unpleasantness) causes the majority of chronic pain patients' suffering, and often results in comorbid disorders (anxiety/depression). However, the mechanisms by which our brain assigns a negative emotional valence to nociceptive information to generate pain aversion remain unresolved. This gap in knowledge prevents targeting pain aversion mechanisms to restore the wellbeing of chronic pain patients. Nociceptive information only acquires its aversive quality once processed through emotional valence circuits. Several cortical and limbic structures contribute to this process, including the anterior cingulate/prefrontal/insular cortices, and the amygdala. We obtained preliminary data in mice suggesting that pain aversion is encoded in neural activity patterns in the basolateral amygdala (BLA). First, we found that BLA activity patterns evolve during chronic neuropathic pain, so that innocuous stimuli such as light touch and cold aberrantly engage BLA nociceptive neural ensembles. This result suggests that the BLA miscodes somatosensory information, possibly explaining how these innocuous stimuli become painful (i.e. aversive) during chronic pain. Second, inhibition of tagged nociceptive BLA neurons with chemogenetics did not alter paw withdrawal from noxious stimuli, but nearly eliminated pain affective-motivational behaviors and avoidance of noxious stimuli. This finding suggests that painful stimuli are detected, but are no longer perceived as aversive. Building on these preliminary data, we propose to elucidate the mechanisms that shape pain aversion in the BLA. Fluorescent microendoscopy of calcium dynamics in freely moving mice experiencing pain will determine how noxious stimuli are encoded in BLA valence neural ensembles, acutely and during chronic pain (Aim 1). Viral tracing and chemogenetic/optogenetic inhibition of specific BLA neuron inputs will uncover the circuits that generate pain aversion (Aim 2). Finally, multilabeling in situ hybridization and slice electrophysiology studies will identify the transmitters and synaptic mechanisms that regulate activity of BLA neurons, and the pathological alterations associated with the emergence of chronic pain (Aim 3). This research will transform our understanding of pain neurobiology by dissecting the mechanisms underlying pain affect and, in the long-term, will uncover new approaches to treat chronic pain by weakening the associated aversion and preventing comorbid psychological disorders, such as anxiety and depression.

疼痛是一种具有感官和情感成分的多维体验。痛苦的厌恶质量（即 疼痛厌恶/不愉快）会导致大多数慢性疼痛患者的痛苦，并且经常导致 合并症（焦虑/抑郁症）。但是，我们的大脑分配负面的机制 情绪化对伤害性信息产生痛苦厌恶的信息仍未解决。这个差距 知识阻止靶向厌恶机制恢复慢性疼痛患者的健康。一旦通过情感价电路处理，伤害性信息才能获得其厌恶质量。几种皮质和边缘结构有助于这一过程，包括前扣带回/前额叶/岛状皮质和杏仁核。我们在小鼠中获得了初步数据，表明疼痛厌恶是在基底外侧杏仁核（BLA）中的神经活动模式中编码的。首先，我们发现BLA活性模式在慢性神经性疼痛期间演变，因此无害的刺激（如轻触摸和冷dbrerrerrer）会使BLA伤害性神经结合物吸引。该结果表明，BLA错误编码体验信息，可能解释了这些无害的刺激如何在慢性疼痛期间变得痛苦（即厌恶）。其次，用化学遗传学抑制标记的伤害性BLA神经元不会改变有害刺激的爪子，而是几乎消除了疼痛情感动机行为和避免有害刺激的疼痛。这一发现表明检测到痛苦的刺激，但不再被视为厌恶。在这些初步数据的基础上，我们建议阐明在BLA中塑造疼痛厌恶的机制。自由移动的小鼠钙动力学的荧光显微镜检查会决定如何在Bla Valence神经集合中编码有害刺激，并在慢性疼痛期间（AIM 1）急性化。病毒追踪和化学遗传/光遗传学抑制特定的BLA神经元输入将发现产生疼痛厌恶的电路（AIM 2）。最后，多标记原位杂交和切片电生理学研究将确定调节BLA神经元活性的发射器和突触机制，以及与慢性疼痛出现有关的病理改变（AIM 3）。这项研究将通过剖析疼痛影响的机制来改变我们对疼痛神经生物学的理解，从长远来看，将通过削弱相关的厌恶和防止合并症的心理疾病（例如焦虑和抑郁）来揭示治疗慢性疼痛的新方法。