A combination of running and memantine increases neurogenesis and reduces activation of developmentally-born dentate granule neurons in rats

During hippocampal-dependent memory formation, sensory signals from the neocortex converge in the dentate gyrus. It is generally believed that the dentate gyrus decorrelates inputs in order to minimize interference between codes for similar experiences, often referred to as pattern separation. The proportion of dentate neurons that are activated by experience is therefore likely to impact how memories are stored and separated. Emerging evidence from mouse models suggests that adult-born neurons can both increase and decrease activity levels in the dentate gyrus. However, the precise conditions that determine the direction of this modulation, and whether it occurs in other species, remains unclear. Furthermore, since the dentate gyrus is composed of a heterogeneous population of cells that are born throughout life, it is unclear if newborn neurons modulate all cells equally. We therefore investigated whether adult neurogenesis in rats modulates activity in dentate gyrus neurons that are born at the peak of early postnatal development. Adult neurogenesis was increased by subjecting rats to an alternating running and memantine treatment schedule, and it was decreased with a transgenic GFAP-TK rat model. Activity was measured by Fos expression in BrdU+ cells after rats explored a novel environment. Consistent with an inhibitory role, running+memantine treatment prevented experience-dependent Fos expression in developmentally-born neurons and also in the broader granule cell population. In contrast, blocking neurogenesis did not alter activity patterns. These results suggest that the developmentally-born population of neurons may be a major target of neurogenesis-mediated inhibition. Treatments that promote neurogenesis may therefore benefit disorders where there is elevated activity in the dentate gyrus, such as anxiety and age-related memory impairments.