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

Abstract

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. Emerging evidence from mouse models suggests that adult-born neurons exert an inhibitory influence on the dentate gyrus, which may be important for maintaining the sparse code that is needed to form precise memories. However, since the dentate gyrus is composed of a heterogeneous population of cells that are born throughout life, it is unclear if newborn neurons inhibit 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 quantifying experience-induced Fos expression in BrdU+ cells. Consistent with an inhibitory role, enhancing neurogenesis blocked experience-dependent Fos expression in developmentally-born neurons and also in the broader granule cell population. In contrast, blocking neurogenesis did not significantly impact activity patterns. These results confirm previous work in mice and identify the developmentally-born population of neurons as a major target of neurogenesis-mediated inhibition. Treatments that target neurogenesis may therefore benefit disorders that are characterized by excitation-inhibition imbalance in the hippocampus, such as age-related memory impairments, fear and anxiety, and epilepsy.