Amygdala mechanisms of pain aversion

疼痛是一种具有感觉和情感成分的多维体验。疼痛的厌恶性（即， 疼痛厌恶/不愉快）引起大多数慢性疼痛患者的痛苦，并且经常导致 共病障碍（焦虑/抑郁）。然而，我们的大脑分配否定的机制 情感效价对伤害性信息产生疼痛厌恶仍然没有解决。中的这一空白 知识阻止靶向疼痛厌恶机制以恢复慢性疼痛患者的健康。伤害性信息只有在经过情绪效价回路处理后，才会获得令人厌恶的品质。几个皮质和边缘系统结构有助于这个过程，包括前扣带/前额叶/岛皮质和杏仁核。我们在小鼠中获得的初步数据表明，疼痛厌恶编码在基底外侧杏仁核（BLA）的神经活动模式。首先，我们发现BLA活动模式在慢性神经病理性疼痛过程中发生演变，因此，诸如轻触和冷等无害刺激会异常地参与BLA伤害性神经集合。这一结果表明，BLA错误编码了躯体感觉信息，可能解释了这些无害的刺激如何在慢性疼痛期间变得疼痛（即厌恶）。第二，抑制标记的伤害性BLA神经元与化学遗传学没有改变爪子从伤害性刺激，但几乎消除疼痛情感动机行为和避免伤害性刺激。这一发现表明，疼痛刺激被检测到，但不再被视为厌恶。建立在这些初步的数据，我们建议阐明的机制，形成疼痛厌恶的BLA。在经历疼痛的自由移动小鼠中的钙动力学的荧光显微内窥镜检查将确定急性和慢性疼痛期间BLA效价神经集合中有害刺激是如何编码的（目的1）。特定BLA神经元输入的病毒追踪和化学遗传学/光遗传学抑制将揭示产生疼痛厌恶的回路（目的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神经元活性的递质和突触机制，以及与慢性疼痛出现相关的病理改变（目的3）。这项研究将通过解剖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预防共病心理障碍（如焦虑和抑郁）来发现治疗慢性疼痛的新方法。

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.