Differential Effects of Extended Exercise and Memantine Treatment on Adult Neurogenesis in Male and Female Rats

Adult neurogenesis has potential to ameliorate a number of disorders that negatively impact the hippocampus, including age-related cognitive decline, depression, and schizophrenia. A number of treatments enhance adult neurogenesis including exercise, NMDA receptor antagonism, antidepressant drugs and environmental enrichment. Despite the chronic nature of many disorders, most animal studies have only examined the efficacy of neurogenic treatments over short timescales (≤1 month). Also, studies of neurogenesis typically include only 1 sex, even though many disorders differentially impact males and females. We tested whether two known neurogenic treatments, running and the NMDA receptor antagonist, memantine, could cause sustained increases in neurogenesis in male and female rats. We found that continuous access to a running wheel (cRUN) initially increased neurogenesis, but effects were minimal after 1 month and completely absent after 5 months. Similarly, a single injection of memantine (sMEM) transiently increased neurogenesis before returning to baseline at 1 month. To determine whether neurogenesis could be increased over a 2-month timeframe, we next subjected rats to interval running (iRUN), multiple memantine injections (mMEM), or alternating blocks of iRUN and mMEM. Two months of iRUN increased DCX+ cells in females and iRUN followed by mMEM increased DCX+ cells in males, indicating that neurogenesis was increased in the later stages of the treatments. However, thymidine analogs revealed that neurogenesis was minimally increased during the initial stages of the treatments. These findings highlight temporal limitations and sex differences in the efficacy of neurogenic manipulations, which may be relevant for designing plasticity-promoting treatments.