Functional convergence of developmentally and adult‐generated granule cells in dentate gyrus circuits supporting hippocampus‐dependent memory

Abstract

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.

Stimulation of Entorhinal Cortex Promotes Adult Neurogenesis and Facilitates Spatial Memory

“…6m; r ϭ 0.04, p ϭ 0.89). These data are therefore consistent with the idea that 1-week-old adult-generated neurons are insufficiently mature to be integrated into hippocampal memory circuits (Kee et al, 2007b;Stone et al, 2010).…”

“…7a). This 6.5 week stimulation-training delay ensures that additional neurons, produced as a consequence of stimulation, are sufficiently mature (ϳ6 weeks old) to contribute to spatial learning [previous experiment (Kee et al, 2007b;Stone et al, 2010)]. During training, latency to find the platform declined similarly in both groups ( Fig.…”

“…To evaluate whether a similar proportion of cells differentiate into neurons after stimulation of the EC, mice were treated with equimolar doses of IdU and then CldU, two chemically related thymidine analogs. IdU and CldU are recognized by different antibodies and therefore may be used to label separate cohorts of cells in the same animal (Vega and Peterson, 2005;Stone et al, 2010;Tronel et al, 2010). In this experiment, IdU injections occurred 3-5 d after stimulation, a poststimulation time point corresponding to the peak in stimulation-induced changes in proliferation, and CldU injections occurred 7-9 d after stimulation, a poststimulation time point when proliferation rates have returned to baseline (Fig.…”

“…The integration of adult-generated neurons into hippocampal memory circuits is maturation dependent, with new neurons not contributing in maximal numbers until they are Ͼ5 weeks of age (Kee et al, 2007b;Stone et al, 2010). Therefore, stimulationinduced increases in the contribution of adult-generated neurons should not occur if there is only a brief delay between stimulation and training.…”

Interaction between Neurogenesis and Hippocampal Memory System: New Vistas

“…Some studies, indeed, highlighted a specific behavioral signature for neurons born in development ( pups or juvenile) versus adulthood (Wei et al 2011;Nakashiba et al 2012;Tronel et al 2014). However, others reported a functional equivalence between these different neuronal populations (Stone et al 2011b). In sum, as a result of these ambiguities, each study should include a clear time line of animal's age (ontogenetic stage) and cell's age.…”