Amygdala mechanisms of pain aversion

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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.