A Chronic Pain in the ACC
2019; Cell Press; Volume: 102; Issue: 5 Linguagem: Inglês
10.1016/j.neuron.2019.05.021
ISSN1097-4199
AutoresNur Zeynep Güngör, Joshua P. Johansen,
Tópico(s)Memory and Neural Mechanisms
ResumoIn this issue of Neuron, Meda et al., 2019Meda K.S. Patel T. Braz J.M. Malik R. Turner M.L. Seifikar H. Basbaum A.I. Sohal V.S. Microcircuit Mechanisms through which Mediodorsal Thalamic Input to Anterior Cingulate Cortex Exacerbates Pain-Related Aversion.Neuron. 2019; 102 (this issue): 944-959Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar provide novel insights into how chronic pain alters connectivity and excitatory-inhibitory balance in a mediodorsal thalamus to anterior cingulate cortex circuit to promote aversive learning. In this issue of Neuron, Meda et al., 2019Meda K.S. Patel T. Braz J.M. Malik R. Turner M.L. Seifikar H. Basbaum A.I. Sohal V.S. Microcircuit Mechanisms through which Mediodorsal Thalamic Input to Anterior Cingulate Cortex Exacerbates Pain-Related Aversion.Neuron. 2019; 102 (this issue): 944-959Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar provide novel insights into how chronic pain alters connectivity and excitatory-inhibitory balance in a mediodorsal thalamus to anterior cingulate cortex circuit to promote aversive learning. Without thinking, you grab a hot pot on the stove. It only takes a moment of singeing flesh to realize that this was a mistake. No one enjoys these types of painful experiences, but the pain system is indispensable for survival. For example, people with congenital pain insensitivity have shorter life expectancy because they cannot detect when they are injured and should seek help. By contrast, a sensitized pain system, such as in chronic pain conditions, can drastically reduce life quality by affecting patients' mood, motivation, and behavior. An underexplored area in pain research is how nociceptive information is transmitted to the cortex to build the pain experience and how these circuits are altered by chronic pain. The study by Meda and colleagues in this issue of Neuron (Meda et al., 2019Meda K.S. Patel T. Braz J.M. Malik R. Turner M.L. Seifikar H. Basbaum A.I. Sohal V.S. Microcircuit Mechanisms through which Mediodorsal Thalamic Input to Anterior Cingulate Cortex Exacerbates Pain-Related Aversion.Neuron. 2019; 102 (this issue): 944-959Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar) addresses these questions by revealing key pathways that convey aversive information during chronic pain to a cortical region important in processing the emotional aspects of pain, namely the anterior cingulate cortex (ACC), and determining how the synaptic and microcircuit connectivity in this region is altered in chronic pain models. In the hope of understanding pain transmission and developing novel treatments for chronic pain disorders, for over a century, animal researchers have focused intensively on studying the primary afferent, spinal, and brainstem mechanisms of nociception. In parallel, human studies have sought to identify cortical regions important for the subjective sensory or affective qualities of pain. The ACC has emerged as a brain region that is important in processing the emotional/motivational, but not the sensory, features of pain and for producing learned changes in behavior in response to noxious stimuli. Thus, ACC lesions selectively reduce the subjective affective pain experience in humans (Hurt and Ballantine, 1974Hurt R.W. Ballantine Jr., H.T. Stereotactic anterior cingulate lesions for persistent pain: a report on 68 cases.Clin. Neurosurg. 1974; 21: 334-351Crossref PubMed Google Scholar) and render animals unable to learn to avoid environments associated with noxious stimuli (Johansen and Fields, 2004Johansen J.P. Fields H.L. Glutamatergic activation of anterior cingulate cortex produces an aversive teaching signal.Nat. Neurosci. 2004; 7: 398-403Crossref PubMed Scopus (287) Google Scholar). There are many potential cortical, thalamic, and brainstem sources by which nociceptive information can reach the ACC. Prior anatomical and electrophysiological studies suggested that nociceptive signals come from the medial thalamus, including the mediodorsal nucleus (MD), which contains nociresponsive neurons and provides dense innervation of ACC and other medial prefrontal cortical regions (Vogt, 2005Vogt B.A. Pain and emotion interactions in subregions of the cingulate gyrus.Nat. Rev. Neurosci. 2005; 6: 533-544Crossref PubMed Scopus (1348) Google Scholar). In the present study, Meda et al., 2019Meda K.S. Patel T. Braz J.M. Malik R. Turner M.L. Seifikar H. Basbaum A.I. Sohal V.S. Microcircuit Mechanisms through which Mediodorsal Thalamic Input to Anterior Cingulate Cortex Exacerbates Pain-Related Aversion.Neuron. 2019; 102 (this issue): 944-959Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar used optogenetics to test the functional role of the MD-to-ACC pathway in normal and chronic pain treated animals in avoidance learning using the place conditioning assay. After expressing a light responsive excitatory opsin protein in MD cells, they optically stimulated MD cell terminals in the ACC when animals were in a specific experimental chamber. Then, they examined whether animals avoided this chamber when given a choice between multiple contexts to explore. Contrary to the hypothesis that MD inputs convey noxious information to the ACC in otherwise pain-free conditions, stimulation of the MD-to-ACC pathway did not produce avoidance of the stimulation paired chamber in normal animals. However, in chronic pain treated animals, stimulation of the same pathway invariably produced place avoidance. Next, to assess whether blocking this pathway was rewarding in chronic pain conditions, they expressed an opsin that inhibits neural activity in response to light. They found that blocking neurotransmitter release at MD synapses in ACC caused the opposite effect of stimulation; animals preferred the chamber in which this inhibition occurred in chronic pain treated animals as well as in pain-free animals. Thus, the MD-to-ACC pathway is modified to convey aversive information during chronic pain, although its role in pain-free animals is less clear. Meda et al., 2019Meda K.S. Patel T. Braz J.M. Malik R. Turner M.L. Seifikar H. Basbaum A.I. Sohal V.S. Microcircuit Mechanisms through which Mediodorsal Thalamic Input to Anterior Cingulate Cortex Exacerbates Pain-Related Aversion.Neuron. 2019; 102 (this issue): 944-959Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar then examined the mechanisms through which this circuit is altered by chronic pain. They began with the hypothesis that synaptic changes occurring in the ACC provide the MD inputs access to aversion circuits. In fact, many previous studies had reported a potentiation of excitatory synaptic transmission and an increase in excitability in ACC neurons in animal models of chronic pain (Bliss et al., 2016Bliss T.V. Collingridge G.L. Kaang B.K. Zhuo M. Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain.Nat. Rev. Neurosci. 2016; 17: 485-496Crossref PubMed Scopus (342) Google Scholar). Thus, one possibility was that an increase in the strength of MD-to-ACC synaptic connections would occur following chronic pain induction. To test this question, Meda et al., 2019Meda K.S. Patel T. Braz J.M. Malik R. Turner M.L. Seifikar H. Basbaum A.I. Sohal V.S. Microcircuit Mechanisms through which Mediodorsal Thalamic Input to Anterior Cingulate Cortex Exacerbates Pain-Related Aversion.Neuron. 2019; 102 (this issue): 944-959Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar used an optogenetically assisted, ex vivo circuit-mapping approach in which MD-to-ACC connectivity was assessed by the optogenetic stimulation of MD terminals in the ACC. Surprisingly, they found that the excitatory synaptic strength of MD inputs to ACC pyramidal cells was reduced in chronic pain (Figure 1). The reduction occurred in the ACC cells that project both to the contralateral medial prefrontal cortex (mPFC) and back to MD. By contrast, the ability of MD inputs to drive inhibition in cortically and subcortically projecting ACC pyramidal neurons was not affected. Consistent with their findings that excitatory transmission at ACC neurons was reduced while inhibition was unaffected by chronic pain, they found that the balance of excitation to inhibition (E/I balance) was shifted toward inhibition. Interestingly, the reduced E/I balance was only apparent in MD-projecting ACC neurons. This finding suggested a novel mechanism for chronic-pain-induced aversion: that a shift in E/I balance in ACC in chronic pain conditions allows MD inputs to produce aversion by inhibiting (rather than exciting) ACC neurons that project back to MD. Following on this model, Meda et al., 2019Meda K.S. Patel T. Braz J.M. Malik R. Turner M.L. Seifikar H. Basbaum A.I. Sohal V.S. Microcircuit Mechanisms through which Mediodorsal Thalamic Input to Anterior Cingulate Cortex Exacerbates Pain-Related Aversion.Neuron. 2019; 102 (this issue): 944-959Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar optogenetically inhibited mPFC or MD-projecting ACC neurons in vivo. This manipulation produced similar results to the optogenetic excitation of the MD-to-ACC pathway: conditioned place avoidance but only in chronic pain conditions. By contrast, inhibition of ACC cells that project to the contralateral mPFC had no effect on behavior. These findings supported the model that inhibition of MD-projecting ACC neurons by MD inputs produces aversion. Further supporting the specificity of the MD-ACC pathway, Meda et al., 2019Meda K.S. Patel T. Braz J.M. Malik R. Turner M.L. Seifikar H. Basbaum A.I. Sohal V.S. Microcircuit Mechanisms through which Mediodorsal Thalamic Input to Anterior Cingulate Cortex Exacerbates Pain-Related Aversion.Neuron. 2019; 102 (this issue): 944-959Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar found that manipulating another afferent input to ACC from the lateral and basal nuclei of the amygdala (BLA) resulted in different behavioral effects and that BLA-to-ACC pathway exhibits distinct synaptic changes after chronic pain. Specifically, their findings suggest that chronic pain induced strengthening of excitatory BLA-to-ACC synapses opposes aversive aspects of chronic pain. Thus, different inputs to ACC exhibit distinct synaptic changes and control opposing aspects of behavior. Prior studies have shown that unidentified ACC synapses are strengthened under chronic pain conditions and that the mechanisms that mediate this potentiation are required for chronic-pain-induced enhancement of behavioral anxiety (Bliss et al., 2016Bliss T.V. Collingridge G.L. Kaang B.K. Zhuo M. Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain.Nat. Rev. Neurosci. 2016; 17: 485-496Crossref PubMed Scopus (342) Google Scholar). Furthermore, previous work has demonstrated that excitation of ACC neurons produces aversive learning (Bliss et al., 2016Bliss T.V. Collingridge G.L. Kaang B.K. Zhuo M. Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain.Nat. Rev. Neurosci. 2016; 17: 485-496Crossref PubMed Scopus (342) Google Scholar, Johansen and Fields, 2004Johansen J.P. Fields H.L. Glutamatergic activation of anterior cingulate cortex produces an aversive teaching signal.Nat. Neurosci. 2004; 7: 398-403Crossref PubMed Scopus (287) Google Scholar). The present findings support a different model in which inhibition of MD-projecting ACC neurons produces aversion in conditions of chronic pain. While future studies will need to resolve these discrepant models, one possibility is that different projections of ACC and afferent inputs other than MD and BLA are responsible for aversive aspects of excitation of ACC neurons in normal pain conditions. Synaptic strengthening of the excitatory connectivity in these other circuits following chronic pain may be responsible for the enhancement of anxiety apparent in these dysregulated conditions. Another outstanding question is how inhibition of MD-projecting ACC neurons produces aversion specifically in chronic pain conditions. One possibility is that during chronic pain, compensatory descending antinociceptive systems are engaged. Inhibition of MD-projecting ACC neurons may reduce these compensatory mechanisms by disinhibiting nociceptive processing at the level of the spinal cord, ultimately leading to aversion. Although optogenetic or electrical stimulation of ACC pyramidal neurons generally produces enhancement of pain (hyperalgesia) and stimulation of ACC GABAergic interneurons or inhibition of pyramidal neurons produces antinociception (Bliss et al., 2016Bliss T.V. Collingridge G.L. Kaang B.K. Zhuo M. Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain.Nat. Rev. Neurosci. 2016; 17: 485-496Crossref PubMed Scopus (342) Google Scholar), the possibility remains that MD-projecting subpopulations uniquely may generate compensatory analgesia during chronic pain. Alternative to the possibility that MD-projecting ACC cells participate in inhibiting nociceptive processing in the spinal cord, these cells might play an important role in the computation of aversive instructive signals. Previous studies have shown that activity in the ACC serves as an instructive signal for driving aversive associative learning, suggesting that it is necessary for inducing plasticity in brain circuits that store the place aversion memories (Bliss et al., 2016Bliss T.V. Collingridge G.L. Kaang B.K. Zhuo M. Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain.Nat. Rev. Neurosci. 2016; 17: 485-496Crossref PubMed Scopus (342) Google Scholar, Johansen and Fields, 2004Johansen J.P. Fields H.L. Glutamatergic activation of anterior cingulate cortex produces an aversive teaching signal.Nat. Neurosci. 2004; 7: 398-403Crossref PubMed Scopus (287) Google Scholar). Thus, it is possible that in chronic pain conditions, inhibition of the MD-projecting ACC cells might organize the instructive signal computation network in ACC into a configuration that promotes aversive place conditioning or facilitates instructive signaling in brain regions that store the aversive memories. A final explanatory framework could be that the MD-to-ACC pathway serves a modulatory role by enhancing state-specific coding of noxious information in ACC neurons during chronic pain, leading to augmented aversive processing at the network level in ACC. This modulation of cortical-state hypothesis for MD function is supported by a recent study that found that MD stimulation increased putative interneuron firing rates and functional connectivity between pyramidal neurons in mPFC as well as enhancing state-specific neural coding during decision making (Schmitt et al., 2017Schmitt L.I. Wimmer R.D. Nakajima M. Happ M. Mofakham S. Halassa M.M. Thalamic amplification of cortical connectivity sustains attentional control.Nature. 2017; 545: 219-223Crossref PubMed Scopus (308) Google Scholar). Our interpretations about the role of the MD-ACC pathway are not mutually exclusive, and going forward, it will be important to determine the function of specific ACC output circuits to refine our understanding of how pain is encoded in ACC and how this information is integrated in other brain systems to guide behavior. Traditionally, the pain research field has taken a phenomenological approach to identify distributed brain networks that give rise to the multi-component pain experience. However, pain is not only a sensory and emotional quality that gives rise to psychophysical experience. Its most important role is as a motivational system that works in a coordinated way with other systems in the body to optimize animals' behaviors (Fields, 2006Fields H.L. A motivation-decision model of pain: the role of opioids.in: Flor H. Kalso E. Dostrovsky J.O. Proceedings of the 11th World Congress on Pain. IASP Press, 2006: 449-459Google Scholar, Seymour, 2019Seymour B. Pain: a precision signal for reinforcement learning and control.Neuron. 2019; 101: 1029-1041Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). In this context, it is interesting to note that the ACC participates in many aspects of cognition and behavior aside from pain (Kolling et al., 2016Kolling N. Behrens T. Wittmann M.K. Rushworth M. Multiple signals in anterior cingulate cortex.Curr. Opin. Neurobiol. 2016; 37: 36-43Crossref PubMed Scopus (136) Google Scholar). Thus, whether there are pain-specific subcircuits in ACC or whether pain is integrated with other information in this brain region to serve larger adaptive demands is an important question. Suggesting the latter, even at lower levels of the neuraxis, which receive direct spinal cord lamina I input, such as in the parabrachial nucleus (PB), neurons are not nociception specific. Nociresponsive PB neurons also respond to multiple types of stimuli, including illness-inducing chemicals, novel foods, and objects (Campos et al., 2018Campos C.A. Bowen A.J. Roman C.W. Palmiter R.D. Encoding of danger by parabrachial CGRP neurons.Nature. 2018; 555: 617-622Crossref PubMed Scopus (135) Google Scholar). Thus PB neurons do not encode pain per se, but more generally inform the animal about an actual or impending threat to promote adaptive behavioral changes. Similarly, the fact that ACC participates in many higher-order brain functions including social distress, error signaling, and forming internal models of the environment (Bliss et al., 2016Bliss T.V. Collingridge G.L. Kaang B.K. Zhuo M. Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain.Nat. Rev. Neurosci. 2016; 17: 485-496Crossref PubMed Scopus (342) Google Scholar, Kolling et al., 2016Kolling N. Behrens T. Wittmann M.K. Rushworth M. Multiple signals in anterior cingulate cortex.Curr. Opin. Neurobiol. 2016; 37: 36-43Crossref PubMed Scopus (136) Google Scholar, Vogt, 2005Vogt B.A. Pain and emotion interactions in subregions of the cingulate gyrus.Nat. Rev. Neurosci. 2005; 6: 533-544Crossref PubMed Scopus (1348) Google Scholar) suggests that nociceptive signals may be combined with other types of information to facilitate broader behavioral goals. Thus, shifting our perspective from one that defines pain solely as a sensory and emotional experience to a view of pain as an instrument for causing adaptive behavioral changes may provide a more useful framework for studying and understanding normal and aberrant pain mechanisms in ACC circuits and other pain-processing systems. Microcircuit Mechanisms through which Mediodorsal Thalamic Input to Anterior Cingulate Cortex Exacerbates Pain-Related AversionMeda et al.NeuronApril 25, 2019In BriefMeda et al. show that in chronic pain states, mediodorsal thalamic (MD) inputs to the anterior cingulate cortex (ACC) undergo pathway-specific changes. As a result, MD-ACC inputs suppress the activity of many subcortically projecting ACC neurons, thereby driving negative pain-related affect. Full-Text PDF Open Archive
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