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)导致大多数慢性疼痛患者痛苦，并经常导致 共病障碍(焦虑/抑郁)。然而，我们大脑分配负面信息的机制 产生痛觉厌恶的伤害性信息的情感价值仍未解决。这一差距在 知识阻止有针对性的疼痛厌恶机制来恢复慢性疼痛患者的福祉。伤害性信息只有在通过情绪配价回路处理后才会获得其厌恶的性质。一些皮质和边缘结构参与了这一过程，包括前扣带回/前额叶/岛叶皮质和杏仁核。我们在小鼠身上获得的初步数据表明，痛觉厌恶编码在杏仁基底外侧核(BLA)的神经活动模式中。首先，我们发现BLA的活动模式在慢性神经病理性疼痛过程中发生演变，因此，光接触和寒冷等无害刺激异常地参与了BLA伤害性神经丛的活动。这一结果表明，BLA对躯体感觉信息进行了错误编码，这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)。第二，用化学遗传学药物抑制标记的伤害性BLA神经元并不改变从伤害性刺激中撤出爪子，但几乎消除了痛的情感-动机行为和对伤害性刺激的回避。这一发现表明，痛苦的刺激可以被检测到，但不再被认为是令人厌恶的。在这些初步数据的基础上，我们建议阐明在BLA中形成疼痛厌恶的机制。对经历疼痛的自由活动小鼠的钙动力学进行荧光显微内窥镜检查，将确定在急性和慢性疼痛期间，有害刺激是如何在BLA价神经丛中编码的(目标1)。病毒追踪和对特定BLA神经元输入的化学发生/光遗传抑制将揭示产生疼痛厌恶的电路(目标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神经元活动的递质和突触机制，以及与慢性疼痛出现相关的病理变化(目标3)。这项研究将通过剖析疼痛影响的潜在机制来改变我们对疼痛神经生物学的理解，并从长远来看，将通过削弱相关的厌恶情绪和预防焦虑和抑郁等共病心理障碍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.