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Papers of the Week

Papers: 11 May 2024 - 17 May 2024

2024 May 16

J Neurosci


Distinctive neurophysiological signatures of analgesia after inflammatory pain in the ACC of freely moving mice.


Kissinger ST, O'neil E, Li B, Johnson KW, Krajewski JL, Kato AS


Preclinical assessments of pain have often relied upon behavioral measurements and anesthetized neurophysiological recordings. Current technologies enabling large scale neural recordings, however, have the potential to unveil quantifiable pain signals in conscious animals for preclinical studies. Although pain processing is distributed across many brain regions, the anterior cingulate cortex (ACC) is of particular interest in isolating these signals given its suggested role in the affective (‘unpleasant’) component of pain. Here, we explored the utility of the ACC towards preclinical pain research using head-mounted miniaturized microscopes to record calcium transients in freely moving male mice expressing GCaMP6f under the Thy1 promoter. We verified the expression of GCaMP6f in excitatory neurons and found no intrinsic behavioral differences in this model. Using a multimodal stimulation paradigm across naive, pain, and analgesic conditions, we found that while ACC population activity roughly scaled with stimulus intensity, single cell representations were highly flexible. We found only low magnitude increases in population activity after CFA, and insufficient evidence for the existence of a robust nociceptive ensemble in the ACC. However, we found a temporal sharpening of response durations and generalized increases in pairwise neural correlations in the presence of the mechanistically distinct analgesics gabapentin or ibuprofen after (but not before) CFA induced inflammatory pain. This increase was not explainable by changes in locomotion alone. Taken together, these results highlight challenges in isolating distinct pain signals amongst flexible representations in the ACC but suggest a neurophysiological hallmark of analgesia after pain that generalizes to at least two analgesics. Our study measured neural activity in the anterior cingulate cortex (ACC) of transgenic mice to improve measures of pain and analgesia in preclinical models. We found that although ACC population activity scaled with stimulus intensity and could be decoded, single cell representations of sensory stimuli were flexible. Low magnitude increases in ACC population activity were observed after pain, but subpopulations with specific activity changes driven by pain/analgesia were difficult to disambiguate from intrinsic variability. Interestingly, responses were temporally sharpened and exhibited increased cell to cell correlations in the presence of two distinct analgesics after CFA but not before. These distinct neural signatures of analgesia occurring only after pain may broaden our understanding of central mechanisms of pain and analgesia.