Pain contains both sensory and affective dimensions. In 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. In physiological condition a variety of studies have implicated ACC in aversion and fear. 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 colorectal distention (CRD) induced conditioned place avoidance (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. Cumulative evidences have suggested that LC-NE modulated cortical synaptic activities are derived from activation of astrocytes. 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 optogenetic 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.

βARs play a vital role in memory function by exerting effects on neurons. However, β2ARs are also found in astrocytes. The evidences for the critical role of β2AR in ACC astrocytes was further provided using AAV encoding β2AR shRNA with the astrocytic promoter-glial fibrillary acidic protein (GFAP) to knockdown β2AR in astrocytes, in contrast, optogenetic activation of astrocytic β2ARs in ACC promotes condition place aversion learning and memory. In 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.