Propofol Modulates Early Memory Consolidation in Humans

Abstract

Maintenance of memory across time is crucial for adaptive behavior. Current theories posit that the underlying consolidation process depends on stabilization of synapses and reorganization of interactions between hippocampus and neocortex. However, the temporal properties of hippocampal-neocortical network reconfiguration during consolidation are still a matter of debate. Translational research on this issue is challenged by the paucity of techniques to transiently interfere with memory in the healthy human brain. Here, we report a neuro-pharmacological approach with the GABA A -ergic anesthetic propofol and a memory task sensitive to hippocampal dysfunction. Patients undergoing minor surgery learned word lists before injection of an anesthetic dose of propofol. Results show that administration of the drug shortly after learning (~13 min) impairs recall after awakening but spares recognition. By contrast, later administration (~105 min) has no effect. These findings suggest significant changes in memory networks very early after learning that are decisive for later recall. Propofol general anesthesia provides an experimental tool to modulate the first steps of hippocampus-mediated memory consolidation in humans. 3 Significance statementConsolidation of memories depends both on mechanisms at the synaptic and the systems level. How and when these mechanisms interact is currently unclear. Here, we have used the anesthetic drug propofol to create a transient pharmacological 'lesion' of the neural substrates of memory consolidation in humans undergoing minor surgery. Our results show that there is a brief time window after learning where hippocampus-dependent memories are susceptible to GABA-ergic modulation with propofol. Later recall appears to depend significantly on integrity of these first steps of memory formation. We infer that there is significant rearrangement of memory networks during the first hours after learning. Propofol general anesthesia provides an experimental approach to interfere with early memory consolidation in humans.

Normal and Abnormal Sharp Wave Ripples in the Hippocampal-Entorhinal Cortex System: Implications for Memory Consolidation, Alzheimer's Disease, and Temporal Lobe Epilepsy

“…It is believed that ensemble formation is mediated in part by use-dependent synaptic plasticity, such as NMDA receptor (NMDAR)-dependent long-term potentiation (LTP), initiated by oscillatory brain activity (rhythms) and regulated by a variety of neuromodulators such as brain-derived neurotrophic factor (BDNF), dopamine, and acetylcholine (ACh). These oscillations effectively enable both the formation and consolidation of memories through repeated circuit activation in the days and nights following learning events (Norimoto et al, 2018 ; Malerba and Bazhenov, 2019 ; Eichenlaub et al, 2020 ; Moon et al, 2020 ; Nguyen et al, 2020 ; Patel et al, 2020 ).…”

Edaravone Alleviated Propofol-Induced Neurotoxicity in Developing Hippocampus by mBDNF/TrkB/PI3K Pathway

“…Propofol is widely used during invasive diagnostic and surgical procedures and for sedation, including in newborns and young children. 1,4,[6][7][8] Compared to other intravenous anesthetics, propofol-induced anesthesia is associated with fewer side effects and faster recovery. The benefits of propofol include the rapid onset of anesthesia and short recovery time, 4 as well as neuroprotective effects in pathogenic situations.…”

Post-encoding modulation of spatial memory by a GABAA-agonist

“…After encoding, synaptic consolidation is thought to occur within seconds to hours while systems consolidation may continue for months or even years (Kelleher et al, 2004;Smith and Squire, 2009;Takashima et al, 2009). Recently, the traditional view on memory consolidation has been challenged by research suggesting that significant hippocampal-neocortical rearrangement can occur within minutes after encoding (Lesburguères et al, 2011;Kitamura et al, 2017;Moon et al, 2020;Tambini and D'Esposito, 2020).…”

“…A potential pharmacological approach is the shortacting anaesthetic propofol (2,6-diisopropylphenol), which is commonly used in routine medical procedures (Sahinovic et al, 2018;Walsh, 2018). Propofol acts as an agonist on the g-aminobutyric-acid (GABA)-A-receptor and as a partial antagonist on (NMDA)-receptors, affecting long-term-potentiation and synaptic consolidation in hippocampal slices as well as hippocampus-dependent memory consolidation (Wei et al, 2002;Nagashima et al, 2005;Zhang et al, 2013;Moon et al, 2020). An fMRI study showed that even sub-hypnotic doses of propofol are sufficient to modulate hippocampal activity in humans (Pryor et al, 2015).…”

“…An fMRI study showed that even sub-hypnotic doses of propofol are sufficient to modulate hippocampal activity in humans (Pryor et al, 2015). Propofol, therefore, represents a promising tool to transiently interfere with hippocampus-dependent cognitive processes and to elucidate how the human brain processes, transforms, and stabilizes memories over time (Vallejo et al, 2019;Moon et al, 2020).…”