In the past five years or so, it has become accepted that the brain continues to produce new neurons throughout adulthood [31
]. The vast majority of these are produced in the hippocampus, and their numbers are significant and estimated to be > 5000 per day [36
]. The neurons arise from progenitor cells in the subgranular zone of the dentate gyrus and, as they mature, they migrate to the granule cell layer. Over the course of a week, the new neurons establish axonal projections and connections to CA3 pyramidal cells [38
]. They are capable of generating action potentials and thus appear as functional neurons [39
]. Because these new neurons are experientially na
ve yet can establish connections with cells that are not, they possess properties that would be useful for detecting novelty and perhaps encoding new information, as suggested for nonmammalian species [40
To evaluate the role of these new neurons in memory formation, we reduced their production to ~ 20% of normal using an anti-mitotic agent [41
] ). Animals were then trained on several different learning tasks, some requiring the hippocampus and others not, some including a trace interval and others not. Animals in which neurogenesis was greatly reduced did not acquire the trace eyeblink conditioning task, although they readily learned the same task using a delay-type paradigm (). Similarly, animals in which neurogenesis was greatly reduced had impaired ability to learn a trace fear conditioning task [42
] ). These animals expressed minimal conditioned responses during the trace interval or even when the footshock US would have occurred, suggesting that they had very little memory for the aversive event or at least could not remember when it would occur. Depletion of the population of new neurons did not disrupt other types of hippocampus-dependent learning, such as that evident in a spatial navigation task using the Morris water maze () or in contextual fear conditioning [42
]. Thus, the reduction in neurogenesis was not associated with a general decrement in learning or even a preferential decrement in hippocampus-dependent learning. Rather, it appears that the presence of new neurons in the adult hippocampus is preferentially associated with the formation of trace memories.
Figure 3 Formation of trace memories is impaired when the population of newly generated neurons is depleted. (a) (i) New cells in the hippocampus were labeled with bromodeoxyuridine (BrdU), a thymidine analog that labels into dividing cells . Animals received (more ...)
Many adult-generated neurons in the hippocampus, indeed the majority, die within weeks of their birth and do not survive to establish connections with other cells or brain regions [36
]. What might be their function during this short window of time? Perhaps they are used to process novel stimuli, and if the neurons are not used or exposed to stimuli in a temporally related manner, they die. If this general scenario were true, then cells exposed to trace conditioning stimuli as they establish themselves in the granule cell layer should survive longer. To test this hypothesis, cells born on a particular day were treated with bromodeoxyuridine (BrdU; ), which labels cells in the S phase of mitosis [36
]. After one week, groups of animals were trained on trace or delay eyeblink conditioning. Other groups were exposed to the same number of stimuli but presented in an explicitly unpaired manner (). Once the animals learned the association, the number of new cells that remained was counted and the percentage of cells with neuron-specific markers was determined. Many more neurons – over twice as many – remained in animals that had acquired the trace memory (). These data indicate that exposure to the trace conditioning procedure can rescue newly generated neurons from death. Learning the delay conditioning task did not alter cell survival and, thus, learning in and of itself is not sufficient to rescue newly generated neurons from death. Exposure to explicitly unpaired stimuli also did not enhance their survival (). Again, these findings suggest that newly generated neurons in the hippocampus are sensitive to the formation of trace memories.
Figure 4 The formation of trace memories increases the survival of adult-generated neurons. (a) The dentate gyrus of the hippocampal formation (i) and new cells within the granule cell layer (ii) that were labeled with bromodeoxyuridine (BrdU). (b) Animals were (more ...)