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An amygdala-to-cingulate cortex circuit for conflicting choices in chronic pain.

ABSTRACT: Chronic pain is a complex experience with multifaceted behavioral manifestations, often leading to pain avoidance at the expense of reward approach. How pain facilitates avoidance in situations with mixed outcomes is unknown. The anterior cingulate cortex (ACC) plays a key role in pain processing and in value-based decision-making. Distinct ACC inputs inform about the sensory and emotional quality of pain. However, whether specific ACC circuits underlie pathological conflict assessment in pain remains underexplored. Here, we demonstrate that mice with chronic pain favor cold avoidance rather than reward approach in a conflicting task. This occurs along with selective strengthening of basolateral amygdala inputs onto ACC layer 2/3 pyramidal neurons. The amygdala-cingulate projection is necessary and sufficient for the conflicting cold avoidance. Further, low-frequency stimulation of this pathway restores AMPA receptor function and reduces avoidance in pain mice. Our findings provide insights into the circuits and mechanisms underlying cognitive aspects of pain and offer potential targets for treatment.

SUBMITTER: Valentinova K

PROVIDER: S-EPMC10636611 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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An amygdala-to-cingulate cortex circuit for conflicting choices in chronic pain.

Valentinova Kristina K Acuña Mario A MA Ntamati Niels R NR Nevian Natalie E NE Nevian Thomas T

Cell reports 20230920 10

Chronic pain is a complex experience with multifaceted behavioral manifestations, often leading to pain avoidance at the expense of reward approach. How pain facilitates avoidance in situations with mixed outcomes is unknown. The anterior cingulate cortex (ACC) plays a key role in pain processing and in value-based decision-making. Distinct ACC inputs inform about the sensory and emotional quality of pain. However, whether specific ACC circuits underlie pathological conflict assessment in pain r ...[more]

PMID: 37733589

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Project description:IntroductionResting state functional connectivity (FC) is widely used to assess functional brain alterations in patients with chronic pain. However, reports of FC accompanying tonic pain in pain-free persons are rare. A network we term the Descending Pain Modulatory Network (DPMN) is implicated in healthy and pathologic pain modulation. Here, we evaluate the effect of tonic pain on FC of specific nodes of this network: anterior cingulate cortex (ACC), amygdala (AMYG), periaqueductal gray (PAG), and parabrachial nuclei (PBN).MethodsIn 50 pain-free participants (30F), we induced tonic pain using a capsaicin-heat pain model. functional MRI measured resting BOLD signal during pain-free rest with a 32 °C thermode and then tonic pain where participants experienced a previously warm temperature combined with capsaicin. We evaluated FC from ACC, AMYG, PAG, and PBN with correlation of self-report pain intensity during both states. We hypothesized tonic pain would diminish FC dyads within the DPMN.ResultsOf all hypothesized FC dyads, only PAG and subgenual ACC was weakly altered during pain (F = 3.34; p = 0.074; pain-free>pain d = 0.25). After pain induction sACC-PAG FC became positively correlated with pain intensity (R = 0.38; t = 2.81; p = 0.007). Right PBN-PAG FC during pain-free rest positively correlated with subsequently experienced pain (R = 0.44; t = 3.43; p = 0.001). During pain, this connection's FC was diminished (paired t=-3.17; p = 0.0026). In whole-brain analyses, during pain-free rest, FC between left AMYG and right superior parietal lobule and caudate nucleus were positively correlated with subsequent pain. During pain, FC between left AMYG and right inferior temporal gyrus negatively correlated with pain. Subsequent pain positively correlated with right AMYG FC with right claustrum; right primary visual cortex and right temporo-occipitoparietal junction CONCLUSION: We demonstrate sACC-PAG tonic pain FC positively correlates with experienced pain and resting right PBN-PAG FC correlates with subsequent pain and is diminished during tonic pain. Finally, we reveal PAG- and right AMYG-anchored networks which correlate with subsequently experienced pain intensity. Our findings suggest specific connectivity patterns within the DPMN at rest are associated with subsequently experienced pain and modulated by tonic pain. These nodes and their functional modulation may reveal new therapeutic targets for neuromodulation or biomarkers to guide interventions.

Project description:AimsEpidemiological studies in patients with neuropathic pain have demonstrated a strong association between neuropathic pain and psychiatric conditions such as anxiety. Preclinical and clinical work has demonstrated that electroacupuncture (EA) effectively alleviates anxiety-like behaviors induced by chronic neuropathic pain. In this study, a potential neural circuitry underlying the therapeutic action of EA was investigated.MethodsThe effects of EA stimulation on mechanical allodynia and anxiety-like behaviors in animal models of spared nerve injury (SNI) were examined. EA plus chemogenetic manipulation of glutamatergic (Glu) neurons projecting from the rostral anterior cingulate cortex (rACCGlu ) to the dorsal raphe nucleus (DRN) was used to explore the changes of mechanical allodynia and anxiety-like behaviors in SNI mice.ResultsElectroacupuncture significantly alleviated both mechanical allodynia and anxiety-like behaviors with increased activities of glutamatergic neurons in the rACC and serotoninergic neurons in the DRN. Chemogenetic activation of the rACCGlu -DRN projections attenuated both mechanical allodynia and anxiety-like behaviors in mice at day 14 after SNI. Chemogenetic inhibition of the rACCGlu -DRN pathway did not induce mechanical allodynia and anxiety-like behaviors under physiological conditions, but inhibiting this pathway produced anxiety-like behaviors in mice at day 7 after SNI; this effect was reversed by EA. EA plus activation of the rACCGlu -DRN circuit did not produce a synergistic effect on mechanical allodynia and anxiety-like behaviors. The analgesic and anxiolytic effects of EA could be blocked by inhibiting the rACCGlu -DRN pathway.ConclusionsThe role of rACCGlu -DRN circuit may be different during the progression of chronic neuropathic pain and these changes may be related to the serotoninergic neurons in the DRN. These findings describe a novel rACCGlu -DRN pathway through which EA exerts analgesic and anxiolytic effects in SNI mice exhibiting anxiety-like behaviors.

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An amygdala-to-cingulate cortex circuit for conflicting choices in chronic pain.

Publications

An amygdala-to-cingulate cortex circuit for conflicting choices in chronic pain.

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