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.

Long-term memories are thought to depend upon the coordinated activation of a broad network of cortical and subcortical brain regions. However, the distributed nature of this representation has made it challenging to define the neural elements of the memory trace, and lesion and electrophysiological approaches provide only a narrow window into what is appreciated a much more global network. Here we used a global mapping approach to identify networks of brain regions activated following recall of long-term fear memories in mice. Analysis of Fos expression across 84 brain regions allowed us to identify regions that were co-active following memory recall. These analyses revealed that the functional organization of long-term fear memories depends on memory age and is altered in mutant mice that exhibit premature forgetting. Most importantly, these analyses indicate that long-term memory recall engages a network that has a distinct thalamic-hippocampal-cortical signature. This network is concurrently integrated and segregated and therefore has small-world properties, and contains hub-like regions in the prefrontal cortex and thalamus that may play privileged roles in memory expression.

In the hippocampus, the production of dentate granule cells (DGCs) persists into adulthood. As adult-generated neurons are thought to contribute to hippocampal memory processing, promoting adult neurogenesis therefore offers the potential for restoring mnemonic function in the aged or diseased brain. Within this regenerative context, one key issue is whether developmentally generated and adult-generated DGCs represent functionally equivalent or distinct neuronal populations. To address this, we labeled separate cohorts of developmentally generated and adult-generated DGCs and used immunohistochemical approaches to compare their integration into circuits supporting hippocampus-dependent memory in intact mice. First, in the water maze task, rates of integration of adult-generated DGCs were regulated by maturation, with maximal integration not occurring until DGCs were five or more weeks in age. Second, these rates of integration were equivalent for embryonically, postnatally, and adult-generated DGCs. Third, these findings generalized to another hippocampus-dependent task, contextual fear conditioning. Together, these experiments indicate that developmentally generated and adult-generated DGCs are integrated into hippocampal memory networks at similar rates, and suggest a functional equivalence between DGCs generated at different developmental stages.