The brain is exceptionally complex, and thus the ways in which it changes in response to the damage and dysfunction of aging are also exceptionally complex. Memory is no exception, as illustrated here. This is one of the many reasons why the best hope for extending healthy life span significantly in the near future is to reverse the underlying damage, a comparatively simple set of processes, though not without its challenges. This should at the very least enable prevention of the deterioration and change of the aging brain, even if some of those downstream consequences of damage turn out to be irreversible via normal maintenance processes once the causative damage is repaired.
Long-lasting changes at synapses enable memory storage in the brain. Although aging is associated with impaired memory formation, it is not known whether the synaptic underpinnings of memory storage differ with age. Using a training schedule that results in the same behavioral memory formation in young and aged mice, we examined synapse ultrastructure and molecular signaling in the hippocampus after contextual fear conditioning.
Only in young, but not old mice, contextual fear memory formation was associated with synaptic changes that characterize well-known, long-term potentiation, a strengthening of existing synapses with one input. Instead, old-age memory was correlated with generation of multi-innervated dendritic spines (MISs), which are predominantly two-input synapses formed by the attraction of an additional excitatory, presynaptic terminal onto an existing synapse. Accordingly, a blocker used to inhibit MIS generation impaired contextual fear memory only in old mice.
Memory reconsolidation has been suggested to update memory storage. Reconsolidation involves initial destabilization followed by protein-synthesis-dependent restabilization. Destabilization can be analyzed when restabilization is blocked. To our knowledge, destabilization has only been studied at a young age. An earlier study suggested that reconsolidation is impaired in aged rats and humans. However, this study did not block protein synthesis to assess memory destabilization.
Here, we show that memory destabilization is impaired in aged mice. We detected this impairment using a re-exposure protocol that induces destabilization of strong contextual fear memory in young mice. Thus, in old age, memory destabilization may not only be impaired, it may be completely blocked. It is conceivable that impaired memory destabilization in aging is due to the involvement of MISs, as the reversal of these multi-input synapses into one-input synapses might not be induced by retrieval. An MIS-based memory-storing mechanism may explain why memory updating, a fundamental cognitive process, is impaired in old age.