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      An amygdalar neural ensemble that encodes the unpleasantness of pain

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          Abstract

          Pain is an unpleasant experience. How the brain’s affective neural circuits attribute this aversive quality to nociceptive information remains unknown. By means of time-lapse in vivo calcium imaging and neural activity manipulation in freely behaving mice encountering noxious stimuli, we identified a distinct neural ensemble in the basolateral amygdala that encodes the negative affective valence of pain. Silencing this nociceptive ensemble alleviated pain affective-motivational behaviors without altering the detection of noxious stimuli, withdrawal reflexes, anxiety, or reward. Following peripheral nerve injury, innocuous stimuli activated this nociceptive ensemble to drive dysfunctional perceptual changes associated with neuropathic pain, including pain aversion to light touch (allodynia). These results identify the amygdalar representations of noxious stimuli that are functionally required for the negative affective qualities of acute and chronic pain perception.

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          Most cited references55

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          DREADDs for Neuroscientists.

          Bryan Roth (2016)
          To understand brain function, it is essential that we discover how cellular signaling specifies normal and pathological brain function. In this regard, chemogenetic technologies represent valuable platforms for manipulating neuronal and non-neuronal signal transduction in a cell-type-specific fashion in freely moving animals. Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic tools are now commonly used by neuroscientists to identify the circuitry and cellular signals that specify behavior, perceptions, emotions, innate drives, and motor functions in species ranging from flies to nonhuman primates. Here I provide a primer on DREADDs highlighting key technical and conceptual considerations and identify challenges for chemogenetics going forward.
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            Long-term dynamics of CA1 hippocampal place codes

            Via Ca2+-imaging in freely behaving mice that repeatedly explored a familiar environment, we tracked thousands of CA1 pyramidal cells' place fields over weeks. Place coding was dynamic, for each day the ensemble representation of this environment involved a unique subset of cells. Yet, cells within the ∼15–25% overlap between any two of these subsets retained the same place fields, which sufficed to preserve an accurate spatial representation across weeks.
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              Shape shifting pain: chronification of back pain shifts brain representation from nociceptive to emotional circuits.

              Chronic pain conditions are associated with abnormalities in brain structure and function. Moreover, some studies indicate that brain activity related to the subjective perception of chronic pain may be distinct from activity for acute pain. However, the latter are based on observations from cross-sectional studies. How brain activity reorganizes with transition from acute to chronic pain has remained unexplored. Here we study this transition by examining brain activity for rating fluctuations of back pain magnitude. First we compared back pain-related brain activity between subjects who have had the condition for ∼2 months with no prior history of back pain for 1 year (early, acute/subacute back pain group, n = 94), to subjects who have lived with back pain for >10 years (chronic back pain group, n = 59). In a subset of subacute back pain patients, we followed brain activity for back pain longitudinally over a 1-year period, and compared brain activity between those who recover (recovered acute/sub-acute back pain group, n = 19) and those in which the back pain persists (persistent acute/sub-acute back pain group, n = 20; based on a 20% decrease in intensity of back pain in 1 year). We report results in relation to meta-analytic probabilistic maps related to the terms pain, emotion, and reward (each map is based on >200 brain imaging studies, derived from neurosynth.org). We observed that brain activity for back pain in the early, acute/subacute back pain group is limited to regions involved in acute pain, whereas in the chronic back pain group, activity is confined to emotion-related circuitry. Reward circuitry was equally represented in both groups. In the recovered acute/subacute back pain group, brain activity diminished in time, whereas in the persistent acute/subacute back pain group, activity diminished in acute pain regions, increased in emotion-related circuitry, and remained unchanged in reward circuitry. The results demonstrate that brain representation for a constant percept, back pain, can undergo large-scale shifts in brain activity with the transition to chronic pain. These observations challenge long-standing theoretical concepts regarding brain and mind relationships, as well as provide important novel insights regarding definitions and mechanisms of chronic pain.
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                Author and article information

                Journal
                Science
                Science
                Science
                Science (New York, N.y.)
                American Association for the Advancement of Science
                0036-8075
                1095-9203
                18 January 2018
                2019
                : 363
                : 6424
                : 276-281
                Affiliations
                [1 ]Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
                [2 ]Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA
                [3 ]Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA
                [4 ]Stanford Neurosciences Institute, Stanford University, Stanford, CA 94305, USA
                [5 ]Department of Biology, Stanford University, Stanford, CA 94305, USA
                [6 ]Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305,USA
                [7 ]CNC Program, Stanford University, Stanford, CA 94305, USA
                [8 ]Department of Applied Physics, Stanford University, Stanford, CA 94305, USA
                [9 ]New York Stem Cell Foundation—Robertson Investigator, Stanford University, Stanford, CA 94305, USA
                [* ]These authors contributed equally to this work
                []Present address: Department of Psychiatry and Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
                []Present address: Institute of Neuroinformatics, ETH and University of Zurich, Zurich 8057, Switzerland
                Author notes
                [§ ] Corresponding author. Email: mschnitz@ 123456stanford.edu (M.J.S.); gs25@ 123456stanford.edu (G.S.)
                Article
                Science-363-276
                10.1126/science.aap8586
                6450685
                30655440
                476b1708-4551-4eb8-966e-f83ae5e054ff
                © 2019, American Association for the Advancement of Science

                This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 19 November 2017
                : 13 December 2018
                Categories
                Neuroscience

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