What is memory?

The mechanism of memory remains one of the great unsolved problems of biology. Grappling with the question more than a hundred years ago, the German zoologist Richard Semon formulated the concept of the engram, lasting connections in the brain that result from simultaneous “excitations”, whose precise physical nature and consequences were out of reach of the biology of his day. Neuroscientists now have the knowledge and tools to tackle this question, however, and this Forum brings together leading contemporary views on the mechanisms of memory and what the engram means today.

Fig. 1

Synaptic connectivity between engram cells as a mechanism for memory storage. a Cellular connectivity in a feedforward excitatory circuit, b synaptic configuration, c dendritic spine density, and d protein synthesis state, shown in a naïve circuit, a circuit during encoding, a circuit after consolidation, or a circuit in an amnesic condition. Engram circuit, cells, and synapses are displayed in green, non-engram in gray. In the naïve state, the circuit displays a variety of synaptic patterns, including strong (thick gray lines) and weak synapses (thin gray lines) as well as silent synapses (dotted lines) exclusively expressing NMDA receptors. During encoding, a network of engram cells is recruited. The preferential connection between engram cells occurs either by potentiation of existing connections (blue dotted circles) or by unsilencing synapses (red dotted circles). A spine density increase supports the synaptic changes. During consolidation, the steady state synthesis of AMPA receptors is shifted to a higher level and the disruption of consolidation with protein synthesis inhibitors (PSI) results in retrograde amnesia. However, during PSI-induced amnesia, memory storage persists within an engram-specific set of weak synaptic connections