Glycogen-derived Lactate In Astrocytes Regulates Long-term Memory Forgetting

[Backgroug and Objective] Forgetting is one of the important components of the memory system.Clarifing the neural mechanism of forgetting will provide new targets and new ideas for the prevention and treatment of memory-related disorders.Astrocytic glycogen-derived lactate plays an important role in the process of memory formation,but its role in forgetting is still unclear.This study tested the scientific hypothesis "the down-regulation of astrocytic glycogen-derived lactate promotes forgetting of long-term memory",revealing a critical role of astrocytic glycogen-derived lactate in forgetting of long-term memory.[Method] Using long-term object location recognition(OLR)memory paradigm to evaluate the memory performance in rats;Using colorimetric method to detect hippocampal lactate levels;Using Western Blot to examine hippocampal astrocyte activation marker glial fibrillary acidity protein(GFAP)and glycogen phosphorylase(GP)protein expression levels;Using immunofluorescence to observe the number of astrocytes and neurons;Using fluorocitrate(FC)to selectively inhibit the activation of astrocytes;Using L-alpha-aminoadipic acid(L-AAA)to selectively ablate astrocytes;Using GP selective inhibitor 1,4-Dideoxy-1,4-imino-D-arabinitol(DAB)to inhibit the production of astrocytic glycogen-derived lactate.[Results](1)The temporal characteristics of long-term OLR memory forgetting: OLR memory shows a stable persistence for about 3 days,and then it shows a stable forgetting.(2)Forgetting of long-term OLR memory is accompanied by the down-regulation of hippocampal GFAP,GP and lactate levels.(3)After long-term OLR memory is consolidated,FC inhibits the activation of astrocytes to promote forgetting;inhibiting astrocytes before long-term OLR memory training does not affect memory formation and retrieval.(4)After long-term OLR memory is consolidated,astrocytes are ablated by L-AAA to promote forgetting;Ablation of astrocytes before long-term OLR memory training does not affect memory formation and retrieval;astrocytes are recovered by ablation does not affect the formation,retrieval and retention of memory after being normal.(5)After the long-term OLR memory is consolidated,DAB inhibits the production of glycogen-derived lactate in astrocytes and promotes the forgetting.(6)After the long-term OLR memory is consolidated,the administration of exogenous lactate does not enhance the OLR memory but delays the forgetting in a dose-dependent manner.(7)Exogenous lactate reverses the promoting effect of FC,L-AAA and DAB on long-term OLR memory forgetting.[Conclusion] Astrocytes are involved in the regulation of long-term memory forgetting,and the down-regulation of its glycogen-derived lactate promotes forgetting.