Astrocyte L-Lactate Signaling in the ACC Regulates Visceral Pain Aversive Memory in Rats

Abstract

Pain involves both sensory and affective elements. An aspect of the affective dimension of pain is its sustained unpleasantness, characterized by emotional feelings. Pain results from interactions between memory, attentional, and affective brain circuitry, and it has attracted enormous interest in pain research. However, the brain targets and signaling mechanism involved in pain remain elusive. Using a conditioned place avoidance (CPA) paradigm, we show that colorectal distention (CRD magnitude ≤ 35 mmHg, a subthreshold for pain) paired with a distinct environment can cause significant aversion to a location associated with pain-related insults in rats. We show a substantial increase in the L-lactate concentration in the anterior cingulate cortex (ACC) following CPA training. Local exogenous infusion of lactate into the ACC enhances aversive memory and induces the expression of the memory-related plasticity genes pCREB, CREB, and Erk1/2. The pharmacological experiments revealed that the glycogen phosphorylation inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) impairs memory consolidation. Furthermore, short-term Gi pathway activation of ACC astrocytes before CPA training significantly decreases the lactate level and suppresses pain-related aversive learning. The effects were reversed by the local infusion of lactate into the ACC. Our study demonstrates that lactate is released from astrocytes in vivo following visceral pain-related aversive learning and memory retrieval and induces the expression of the plasticity-related immediate early genes CREB, pCREB, and Erk1/2 in the ACC. Chronic visceral pain is an important factor in the pathophysiology of irritable bowel syndrome (IBS). The current study provides evidence that astrocytic activity in the ACC is required for visceral pain-related aversive learning and memory.

Chemogenetic activation of astrocytes promotes remyelination and restores cognitive deficits in visceral hypersensitive rats

“…It is clear that astrocytes play a crucial role in the modulation of neuronal activity and synaptic plasticity. Astrocytes regulate the release of neurotransmitters, and energy substrates such as lactate, 19 , 76 which are considered to be involved in learning and memory. 35 Increasing neuronal activity has been shown to enhance the generation of oligodendrocytes and thickness of individual myelin segments.…”

Review on the neuron damage parameters in patients with end-stage renal disease

“…Further support was found for an association with others renal function [64]. GFAP levels could reflect neuronal damage in obese of ESRD [65]. GFAP circulating levels have been described in the context of traumatic brain injury [66].…”

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

“…Astrocytes are the main sites of glycogen storage in the CNS, and can rapidly metabolize glycogen to lactate 76 and transport it to neurons during periods of neuronal activity. Recently, we have demonstrated that astrocyte-lactate signalling in the ACC is required in regulating visceral aversive memory 77 .…”