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Adrenergic signalling to astrocytes in anterior cingulate cortex contributes to pain-related aversive memory in rats.

ABSTRACT: Pain contains both sensory and affective dimensions. We identify the role of norepinephrine in colorectal distention (sub-threshold for acute pain) induced conditioned place avoidance and plasticity gene expression in the anterior cingulate cortex (ACC). Activating locus coeruleus (LC)-projecting ACC neurons facilitates pain-evoked aversive consolidation and memory, while inhibiting LC-projecting ACC neurons reversibly blocks it. Optogenetic activation of ACC astrocytes facilitates aversive behaviour. ACC astrocytic Gi manipulation suppressed aversive behaviour and early plasticity gene expression induced by opto-activation of LC neurons projecting to ACC. Evidences for the critical role of β2AR in ACC astrocytes were provided using AAV encoding β2AR miRNAi to knockdown β2AR in astrocytes. In contrast, opto-activation of ACC astrocytic β2ARs promotes aversion memory. Our findings suggest that projection-specific adrenergic astrocytic signalling in ACC is integral to system-wide neuromodulation in response to visceral stimuli, and plays a key role in mediating pain-related aversion consolidation and memory formation.

SUBMITTER: Iqbal Z

PROVIDER: S-EPMC9816175 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Adrenergic signalling to astrocytes in anterior cingulate cortex contributes to pain-related aversive memory in rats.

Iqbal Zafar Z Lei Zhuogui Z Ramkrishnan Aruna S AS Liu Shu S Hasan Mahadi M Akter Mastura M Lam Yuk Yan YY Li Ying Y

Communications biology 20230105 1

Pain contains both sensory and affective dimensions. We identify the role of norepinephrine in colorectal distention (sub-threshold for acute pain) induced conditioned place avoidance and plasticity gene expression in the anterior cingulate cortex (ACC). Activating locus coeruleus (LC)-projecting ACC neurons facilitates pain-evoked aversive consolidation and memory, while inhibiting LC-projecting ACC neurons reversibly blocks it. Optogenetic activation of ACC astrocytes facilitates aversive beha ...[more]

PMID: 36604595

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Project description:Central sensitization is essential in maintaining chronic pain induced by chronic pancreatitis (CP), but cortical modulation of painful CP remains elusive. Here, we examined the role of the anterior cingulate cortex (ACC) in the pathogenesis of abdominal hyperalgesia in a rat model of CP induced by intraductal administration of trinitrobenzene sulfonic acid (TNBS). TNBS treatment resulted in long-term abdominal hyperalgesia and anxiety in rats. Morphological data indicated that painful CP induced a significant increase in FOS-expressing neurons in the nucleus tractus solitarii (NTS) and ACC, and some FOS-expressing neurons in the NTS projected to the ACC. In addition, a larger portion of ascending fibers from the NTS innervated pyramidal neurons, the neural subpopulation primarily expressing FOS under the condition of painful CP, rather than GABAergic neurons within the ACC. CP rats showed increased expression of vesicular glutamate transporter 1, and increased membrane trafficking and phosphorylation of the N-methyl-D-aspartate receptor (NMDAR) subunit NR2B and the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunit GluR1 within the ACC. Microinjection of NMDAR and AMPAR antagonists into the ACC to block excitatory synaptic transmission significantly attenuated abdominal hyperalgesia in CP rats, which was similar to the analgesic effect of endomorphins injected into the ACC. Specifically inhibiting the excitability of ACC pyramidal cells via chemogenetics reduced both hyperalgesia and comorbid anxiety, whereas activating these neurons via optogenetics failed to aggravate hyperalgesia and anxiety in CP rats. Taken together, these findings provide neurocircuit, biochemical, and behavioral evidence for involvement of the ACC in hyperalgesia and anxiety in CP rats, as well as novel insights into the cortical modulation of painful CP, and highlights the ACC as a potential target for neuromodulatory interventions in the treatment of painful CP.

Dataset Information

Adrenergic signalling to astrocytes in anterior cingulate cortex contributes to pain-related aversive memory in rats.

Publications

Adrenergic signalling to astrocytes in anterior cingulate cortex contributes to pain-related aversive memory in rats.

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