A fundamental question in memory research is how our brains can form enduring memories. In humans, memories of everyday life depend initially on the medial temporal lobe system, including the hippocampus. As these memories mature, they are thought to become increasingly dependent on other brain regions such as the cortex. Little is understood about how new memories in the hippocampus are transformed into remote memories in cortical networks. However, recent studies have begun to shed light on how remote memories are organized in the cortex, and the molecular and cellular events that underlie their consolidation.

Memory retrieval is not a passive phenomenon. Instead, it triggers a number of processes that either reinforce or alter stored information. Retrieval is thought to activate a second memory consolidation cascade (reconsolidation) that requires protein synthesis. Here, we show that the temporal dynamics of memory reconsolidation are dependent on the strength and age of the memory, such that younger and weaker memories are more easily reconsolidated than older and stronger memories. We also report that reconsolidation and extinction, two opposing processes triggered by memory retrieval, have distinct biochemical signatures: pharmacological antagonism of either cannabinoid receptor 1 or L-type voltage-gated calcium channels blocks extinction but not reconsolidation. These studies demonstrate the dynamic nature of memory processing after retrieval and represent a first step toward a molecular dissection of underlying mechanisms.

The cAMP responsive element binding protein (CREB) is a nuclear protein that modulates the transcription of genes with cAMP responsive elements in their promoters. Increases in the concentration of either calcium or cAMP can trigger the phosphorylation and activation of CREB. This transcription factor is a component of intracellular signaling events that regulate a wide range of biological functions, from spermatogenesis to circadian rhythms and memory. Here we review the key features of CREB-dependent transcription, as well as the involvement of CREB in memory formation. Evidence from Aplysia, Drosophila, mice, and rats shows that CREB-dependent transcription is required for the cellular events underlying long-term but not short-term memory. While the work in Aplysia and Drosophila only involved CREB function in very simple forms of conditioning, genetic and pharmacological studies in mice and rats demonstrate that CREB is required for a variety of complex forms of memory, including spatial and social learning, thus indicating that CREB may be a universal modulator of processes required for memory formation.

Although the molecular, cellular, and systems mechanisms required for initial memory processing have been intensively investigated, those underlying permanent memory storage remain elusive. We present neuroanatomical, pharmacological, and genetic results demonstrating that the anterior cingulate cortex plays a critical role in remote memory for contextual fear conditioning. Imaging of activity-dependent genes shows that the anterior cingulate is activated by remote memory and that this activation is impaired by a null alpha-CaMKII mutation that blocks remote memory. Accordingly, reversible inactivation of this structure in normal mice disrupts remote memory without affecting recent memory.

Throughout adulthood, new neurons are continuously added to the dentate gyrus, a hippocampal subregion that is important in spatial learning. Whether these adult-generated granule cells become functionally integrated into memory networks is not known. We used immunohistochemical approaches to visualize the recruitment of new neurons into circuits supporting water maze memory in intact mice. We show that as new granule cells mature, they are increasingly likely to be incorporated into circuits supporting spatial memory. By the time the cells are 4 or more weeks of age, they are more likely than existing granule cells to be recruited into circuits supporting spatial memory. This preferential recruitment supports the idea that new neurons make a unique contribution to memory processing in the dentate gyrus.

Throughout life, new neurons are continuously added to the dentate gyrus. As this continuous addition remodels hippocampal circuits, computational models predict that neurogenesis leads to degradation or forgetting of established memories. Consistent with this, increasing neurogenesis after the formation of a memory was sufficient to induce forgetting in adult mice. By contrast, during infancy, when hippocampal neurogenesis levels are high and freshly generated memories tend to be rapidly forgotten (infantile amnesia), decreasing neurogenesis after memory formation mitigated forgetting. In precocial species, including guinea pigs and degus, most granule cells are generated prenatally. Consistent with reduced levels of postnatal hippocampal neurogenesis, infant guinea pigs and degus did not exhibit forgetting. However, increasing neurogenesis after memory formation induced infantile amnesia in these species.

Renewed discussion about whether or not adult neurogenesis exists in the human hippocampus, and the nature and strength of the supporting evidence, has been reignited by two prominently published reports with opposite conclusions. Here, we summarize the state of the field and argue that there is currently no reason to abandon the idea that adult-generated neurons make important functional contributions to neural plasticity and cognition across the human lifespan.

Many attempts have been made to localize the physical trace of a memory, or engram, in the brain. However, until recently, engrams have remained largely elusive. In this Review, we develop four defining criteria that enable us to critically assess the recent progress that has been made towards finding the engram. Recent 'capture' studies use novel approaches to tag populations of neurons that are active during memory encoding, thereby allowing these engram-associated neurons to be manipulated at later times. We propose that findings from these capture studies represent considerable progress in allowing us to observe, erase and express the engram.