Differential effects of extended exercise and memantine treatment on adult neurogenesis in male and female rats

Abstract

The creation of new neurons in adulthood has potential for treating a number of disorders that are characterized by neurodegeneration or impaired plasticity. Animal models of reduced neurogenesis, and studies of the volume and structural integrity of the hippocampus in humans, suggest a possible therapeutic role for adult neurogenesis in age-related cognitive decline, depression, and schizophrenia. Research over the past 20 years has identified a number of approaches for enhancing adult neurogenesis, such as exercise, NMDA receptor antagonists, antidepressant drugs and environmental enrichment. However, despite the chronic nature of many disorders that impact the human hippocampus, most animal studies have only examined the efficacy of neurogenic treatments over relatively short timescales ([~]1 month or less). Additionally, investigations into the regulation of neurogenesis typically include only 1 sex, even though many disorders that affect the hippocampus differentially impact males and females. Here, we therefore tested whether two known pro-neurogenic treatments, running and the NMDA receptor antagonist, memantine, could lead to long-term increases in neurogenesis in male and female rats. We found that continuous access to a running wheel (cRUN) initially increased neurogenesis in both sexes, but effects were minimal after 1 month (both sexes) and completely absent after 5 months (males). Similarly, a single injection of memantine (sMEM) only transiently increased adult neurogenesis in both males and females. To determine whether extended increases in neurogenesis were possible with 2 months of RUN and MEM treatments, we subjected rats to interval running (iRUN), weekly memantine injections (mMEM), or combined treatments (iRUN-mMEM, mMEM-iRUN). We found that 2 months of iRUN increased DCX+ cell density in females but iRUN-mMEM treatment increased DCX+ cell density in males. However, analyses with thymidine analogs revealed that neurogenesis was minimally increased during the initial phases of the 2 month treatments. Collectively, our findings identify sex differences in the efficacy of neurogenic manipulations, which may be relevant for designing plasticity-promoting treatments that target the hippocampus.