Experience-Dependent Regulation of Dentate Gyrus Excitability by Adult-Born Granule Cells

Abstract

Behavioral studies have established a role for adult-born dentate granule cells in discriminating between similar memories. However, it is unclear how these cells mediate memory discrimination. Excitability is enhanced in maturing adult-born neurons, spurring the hypothesis that the activity of these cells "directly" encodes and stores memories. An alternative hypothesis posits that maturing neurons "indirectly" contribute to memory encoding by regulating excitation-inhibition balance. We evaluated these alternatives by using dentate-sensitive active place avoidance tasks to assess experience-dependent changes in dentate field potentials in the presence and absence of neurogenesis. Before training, X-ray ablation of adult neurogenesis-reduced dentate responses to perforant-path stimulation and shifted EPSP-spike coupling leftward. These differences were unchanged after place avoidance training with the shock zone in the initial location, which both groups learned to avoid equally well. In contrast, sham-treated mice decreased dentate responses and shifted EPSP-spike coupling leftward after the shock zone was relocated, whereas X-irradiated mice failed to show these changes in dentate function and were impaired on this test of memory discrimination. During place avoidance, excitation-inhibition coupled neural synchrony in dentate local field potentials was reduced in X-irradiated mice, especially in the θ band. The difference was most prominent during conflict learning, which is impaired in the X-irradiated mice. These findings indicate that maturing adult-born neurons regulate both functional network plasticity in response to memory discrimination and dentate excitation-inhibition coordination. The most parsimonious interpretation of these results is that adult neurogenesis indirectly regulates hippocampal information processing. SIGNIFICANCE STATEMENT: Adult-born neurons in the hippocampal dentate gyrus are important for flexibly using memories, but the mechanism is controversial. Using tests of hippocampus-dependent place avoidance learning and dentate electrophysiology in mice with normal or ablated neurogenesis, we find that maturing adult-born neurons are crucial only when memory must be used flexibly, and that these neurons regulate dentate gyrus synaptic and spiking responses to neocortical input rather than directly storing information, as has been proposed. A day after learning to avoid the initial or changed locations of shock, the dentate synaptic responses are enhanced or suppressed, respectively, unlike mice lacking adult neurogenesis, which did not change. The contribution of adult neurogenesis to memory is indirect, by regulating dentate excitation-inhibition coupling.