Glial glucose fuels the neuronal pentose phosphate pathway for long-term memory

Abstract

Brain function relies almost solely on glucose as an energy substrate. The main model of brain metabolism proposes that glucose is taken up and converted into lactate by astrocytes to fuel the energy-demanding neuronal activity underlying plasticity and memory. Whether direct neuronal glucose uptake is required for memory formation remains elusive. We uncover, in Drosophila, a mechanism of glucose shuttling to neurons from cortex glia, an exclusively perisomatic glial subtype, upon formation of olfactory long-term memory (LTM). In vivo imaging reveals that, downstream of cholinergic activation of cortex glia, autocrine insulin signaling increases glucose concentration in glia. Glucose is then transferred from glia to the neuronal somata in the olfactory memory center to fuel the pentose phosphate pathway and allow LTM formation. In contrast, our results indicate that the increase in neuronal glucose metabolism, although crucial for LTM formation, is not routed to glycolysis.

Glia fuel neurons with locally synthesized ketone bodies to sustain memory under starvation

“…2a ). To test our hypothesis, we targeted a key enzyme from each of these three steps in adult cortex glia using specific RNAi under the control of an inducible cortex glia driver 15 , 36 ( R54H02-Gal4 in combination with Tub-Gal80 ts ) and then examined the K-AM of starved flies (Fig. 2a–d ).…”

“…The following inducible driver lines were constructed in the laboratory and have already been described: Tub-Gal80 ts ; VT30559-Gal4 (ref. 14 ) and Tub-Gal80 ts ; R54H02-Gal4 15 and Tub -Gal80 ts ; Alrm-Gal4 15 . Lines that were constructed for this study include Tub -Gal80 ts ; Repo-Gal4 and Tub -Gal80 ts ; Mz0709-Gal4 .…”

“…In the fed condition, experiments were conducted similarly to other studies from our research group 14 , 15 . Briefly, to achieve RNAi induction, 1- to 2-day-old flies were kept at 30 °C for 2 d until conditioning.…”

“…Olfactory avoidance and shock avoidance tests were conducted similarly to previous studies from our research group as in work by ref. 15 except that flies were kept at 30 °C for 2 d and food deprived for 16 h before testing.…”

“…This association is stored as a memory trace in the mushroom body (MB) 12 , the major integrative brain centre for learning and memory in insects 13 . We showed in flies fed ad libitum that the formation of protein synthesis-dependent long-term memory (LTM) after multiple spaced olfactory trainings crucially relies on the regulation of both pyruvate (a glucose derivative) metabolism in MB neurons 14 and glucose metabolism in glial cells 15 . When flies are starved, LTM formation is blocked, which is beneficial for surviving food restriction 16 .…”