Time-dependent reorganization of brain circuitry underlying long-term memory storage

Abstract

Retrograde amnesia observed following hippocampal lesions in humans and animals is typically temporally graded, with recent memory being impaired while remote memories remain intact, indicating that the hippocampal formation has a time-limited role in memory storage. However, this claim remains controversial because studies involving hippocampal lesions tell us nothing about the contribution of the hippocampus to memory storage if this region was present at the time of memory retrieval. We therefore used non-invasive functional brain imaging using (14C)2-deoxyglucose uptake to examine how the brain circuitry underlying long-term memory storage is reorganized over time in an intact brain. Regional metabolic activity in the brain was mapped in mice tested at different times for retention of a spatial discrimination task. Here we report that increasing the retention interval from 5 days to 25 days resulted in both decreased hippocampal metabolic activity during retention testing and a loss of correlation between hippocampal metabolic activity and memory performance. Concomitantly, a recruitment of certain cortical areas was observed. These results indicate that there is a time-dependent reorganization of the neuronal circuitry underlying long-term memory storage, in which a transitory interaction between the hippocampal formation and the neocortex would mediate the establishment of long-lived cortical memory representations.

Role of β-Adrenoceptors in Memory Consolidation: β3-Adrenoceptors Act on Glucose Uptake and β2-Adrenoceptors on Glycogenolysis

“…It is well documented that following learning, increases in glucose uptake occur in brain regions associated with memory (Bontempi et al, 1996(Bontempi et al, , 1999Rose and Csillag, 1985;McNay et al, 2000, Krebs andParent, 2005), and it is clear from our results that this effect is dependent on GLUTs b-ARs in central metabolism and memory ME Gibbs et al localized on different cell types. By comparing the temporal profile of different selective vs nonselective drugs, we provide evidence for a specific role for astrocytic/endothelial glucose transport 30 min after learning.…”

Dynamic histone marks in the hippocampus and cortex facilitate memory consolidation

“…While pH3S10 and AcH3K14 are associated with short-term and recent memory, 3MeH3K36 is primarily associated with short-term and AcH4K5 with recent memory. Importantly, the transience of these PTMs is consistent with the postulated time-limited engagement of the hippocampus in the processing of newly formed memory traces 1,2,7 . Further, the activation of PTMs is selectively associated with memory recall, as none of the PTMs was changed without memory testing ( Supplementary Fig.…”

“…These results indicate that the same histone PTMs induced in the hippocampus for short-term and recent memory are established in the cortex, but only after a delay, that is, only for recent and remote memory, and not for short-term memory. This suggests that PTMs in the PFC are more stable than in the hippocampus, and highlights a correlation between the spatiotemporal dynamics of their activation and memory consolidation 3,7,8 .…”

“…While the hippocampus is recruited for the formation and shortterm storage of new memory traces, the cortex, in particular the prefrontal cortex (PFC), is needed for long-term storage [3][4][5][6] . At a molecular level, several studies have demonstrated that recent (that is, day-old) memory primarily activates gene expression and metabolic changes in the hippocampus, whereas remote (that is, weekold) memory does so essentially in cortical areas 3,7,8 .…”

AAV vectors for RNA-based modulation of gene expression

“…Major insights into the molecular mechanisms of learning and memory have been obtained through experimental approaches using transgenic technologies in mouse, fly and worm. Yet, relevant quantitative behavioural assays are obtained only from larger mammals including rats 21 where homologous recombination-based transgenic technology is not readily available nor practical. AAVmediated knockdown of candidate genes has been demonstrated in the rat, and should be feasible in nonhuman primates.…”