Astrocyte Adrenergic Signaling in the Anterior Cingulate Cortex Contributes to Visceral Pain-Evoked Aversion in Rats

Project: Research

View graph of relations


Pain contains both sensory and affective dimensions. In pathological chronic pain condition, anterior cingulate cortex (ACC) plays a critical role in the mediation of visceral pain sensation, where a desynchronized ACC neural network is associated with emotional and cognitive dysfunctions. Using a rodent pain-related aversion assay that combines the colorectal distention(CRD) with conditioned place avoidance (CPA) we showed that ACC mediates the pain-evoked aversive memory in rats in normal physiological condition. However, the mechanisms responsible for this process are unknown. Given the key role of locus coeruleus (LC) noradrenergic neurons in stimulating behavioral arousal, alertness and maintaining cognitive performance we hypothesize that LC-derived norepinephrine (NE) is causally linked to the encoding, aversive consolidation and retrieval of pain affective memory. We manipulate the role of NE in CRD induced CPA rat model by using selective depletion of LC adrenergic neurons. The pathway of LC-ACC circuits was further clarified by activating LC-projecting ACC neurons which facilitates pain-evoked aversive consolidation and memory, and by inhibiting LC-projecting ACC neurons which reversibly blocks it. Glial cells, particularly astrocytes, contribute to synaptic transmission and working memory. Our recent study provided evidences that optogenetic activation of astrocytes in the ACC facilitated lactate release, improved decision making and cortical network synchronization in rodents. We show that optogenetic activating ACC astrocytes facilitates aversive learning and memory. In contrast, chemogenetic activation of Gi pathway in ACC astrocytes by hM4Di designer receptors diminished the acquisition and expression of aversion memory. Manipulating astrocytes Gi pathway significantly suppressed aversive behavior induced by ontogenetic activation of LC neurons projecting to ACC. These data suggest that ACC astrocytes contribute to pain-related aversion by modulating LC-ACC bottom-up communication during aversive learning and memory. To characterize ACC astrocytic response to LC-NE signal we monitor astrocyte Ca2+ levels by a fiber-photometry system in freely behaving rats. We show that opto-stimulation of ACC projecting LC neurons would reliably evoked Ca2+ elevations in ACC astrocytes in a frequency dependent manner, while these responses were absent in animal injected with AAV5- GFAP –GFP. In the last phase of our experiment, we will focus on multiple-channel electrophysiological recordings to elucidate LC–ACC network plasticity and synchronization in pain aversive learning and memory retrieval. Conclusion: coordinated adrenergic astrocytic signaling in the ACC is integral to system-wide neuromodulation in response to behaviorally visceral stimuli, and plays a key role in mediating pain-evoked aversion consolidation and memory formation. 


Project number9043121
Grant typeGRF
StatusNot started
Effective start/end date1/01/22 → …